Bradykinin receptors: pharmacological properties and biological roles.

Pharmac.Ther.Vol. 56, pp. 131-190,1992 Printed in Great Britain.All fightsreserved

0163-7258/92 $15.00 © 1993PergamonPress Lid

Associate Editor: S. P. WATSON

B R A D Y K I N I N RECEPTORS: PHARMACOLOGICAL PROPERTIES A N D BIOLOGICAL ROLES JUDITH M. HALL

Pharmacology Group, Biomedical Sciences Division, King's College London, London SW3 6LX, U.K. Abstract--Kinins contribute to the acute inflammatory response and are implicated in the pathophysiology of inflammatory disease. The development of therapeutically viable agents that counteract the effects of kinins is, therefore, potentially very rewarding. Since kinin actions are generally mediated via an interaction with cell-surface receptors, one approach is the development of site-specific receptor antagonists. The emphasis in this review is to outline our current understanding of the properties of bradykinin receptors and the potential therapeutic applications for drugs acting at these sites. As a result of the recent introduction of potent bradykinin receptor antagonists and the cloning of bradykinin receptor genes, considerable advances in kinin research can now be confidently anticipated.

CONTENTS 1. Introduction 1.1. Definitions and nomenclature conventions 2. Pharmacology of Bradykinin Receptors 2.1. Historical perspective 2.2. The B~/B2 receptor classification scheme 3. B~ Receptors 3.1. Functional studies---agonists 3.2. Functional studies--antagonists 3.2.1. [Des-Argg]-BK analogues 3.2.2. [Des-Argg]-BK analogues with L-carhoranyl-alanine substitutions 3.2.3. [Des-Arg9]-BK analogues with substitutions at position seven 3.2.4. D-Arg-[Hyp3,Thi 5,D-Tic7 ,Oic8 ,des-Arg9 ]-BK ("des-Argl°[HOE140] '') 3.2.5. Bissuccinimidoalkane peptide dimers 3.2.6. Non-peptide B~ receptor antagonists 3.3. Radioligand binding studies 3.4. B~ receptor heterogeneity 3.5. Induction of Bl receptor responses 3.5.1. Characteristics 3.5.2. Mechanism of B~ receptor response induction--immunological stimuli 3.5.3. Mechanism of B~ receptor response induction--growth regulating ligands 3.6. Receptor-effector coupling mechanisms of B t receptors 3.7. Expression studies the of B~ receptors 3.8. Distribution of B~ receptors 3.9. Summary of B~ receptor characteristics 4. B2 Receptors 4.1. Functional studies--agonists

132 133 135 135 136 137 137 138 138 139 139 139 140 140 140 141 141 141 142 143 143 144 144 144 145 145

Abbreviations--ACE, angiotensin converting enzyme; Bt, bradykinint receptor; Bz, bradykinin 2 receptor; BK, bradykinin; CNS, central nervous system; C-terminal, carboxy terminal; EDRF, endothelium derived relaxing factor; EGF, epidermal growth factor; i.c.v., intracerebroventricular; IL, interleukin; IP 3, inositol 1,4,5 trisphosphate; LPS, lipopolysaccharide; mRNA, messenger ribonucleic acid; MDP, muramyl dipeptide; NO, nitric oxide; N-terminal, amino terminal; PGE2, prostaglandin E2; PGI2, prostacyclin. 131

132

J.M. HALL 4.2. Functional studies--antagonists 4.2.1. [D-Phe7]-BK analogues 4.2.2. [D-TicT]-BK analogues 4.2.3 Cyclic peptide analogues of bradykinin 4.2.4. Bissuccinimidoalkane peptide dimers 4.2.5. Non-peptide analogues 4.3. Radioligand binding studies 4.3.1. Development of radioligands for B2 receptors 4.3.2. Characteristics of B2 receptor binding sites 4.3.3. Addressing the binding paradox 4.4. B2 receptor heterogeneity 4.4.1. B3 receptors, or species-related differences in B2 receptor recognition properties? 4.4.2. Other evidence for Bz receptor heterogeneity 4.5. Receptor-effector coupling mechanisms of B2 receptors 4.6. Regulation of B2 receptor density 4.7. Molecular characterization of B2 receptors 4.7.1. Cloning and expression studies 4.7.2. Receptor isolation studies 4.8. Distribution of B2 receptors 4.9. Summary of B2 receptor characteristics 5. Non-BI/B2 Receptors 6. Bradykinin Receptors--Physiology, Pathophysiology and Therapeutics 6.1. Gastrointestinal smooth muscle 6.1.1. Guinea-pig ileum 6.1.2. Guinea-pig taenia caeci 6.1.3. Rat duodenum 6.1.4. Other intestinal smooth muscle preparations 6.2. Epithelial ion transport 6.2.1. Intestinal preparations 6.2.2. Gall-bladder 6.2.3. Respiratory tract 6.3. Urogenital tract 6.3.1. Urinary bladder 6.3.2. Vas deferens 6.3.3. Uterus and ovary 6.4. Respiratory tract 6.4.1. Lower airways and asthma 6.4.2. Upper airways and rhinitis 6.5. Pain and peripheral inflammatory hyperalgesia 6.6. Inflammation 6.6.1. Bl receptors and inflammation 6.6.2. B2 receptors and inflammation 6.7. Circulation homeostasis 6.7.1. Isolated blood vessels 6.7.2. Blood pressure regulation 6.7.3. Endotoxic shock 6.8. Central nervous system 6.9. Cell growth, repair and mitogenesis 6.10. Ocular tissues 7. Non-Receptor Mediated Actions of Kinins 8. Summary and Future Directions Acknowledgements References

145 145 147 148 148 148 149 149 149 152 153 153 153 156 158 158 158 159 159 159 160 160 160 160 161 161 163 164 164 164 164 165 165 165 165 165 166 168 168 170 170 172 173 173 173 174 174 174 174 175 176 176 176

1. I N T R O D U C T I O N The term kinin (derived from the Greek kineo meaning to move) is, in practice, loosely applied to a number of chemically distinct families of polypeptide mediators that have potent actions on vascular and extravascular smooth muscle and a number of other tissues (see Rocha e Silva, 1962). In this review, the term is restricted to those peptides related in amino acid sequence and pharmacology to bradykinin and kallidin (see Schachter, 1964). The nonapeptide bradykinin ( A r g - P r o - P r o - G l y - P h e - S e r - P r o - P h e - A r g ) is perhaps the best known member of this family; the

Bradykinin receptors

133

name was coined by Rocha e Silva and colleagues in Brazil, in recognition of the slow (bradys) contraction seen in the guinea-pig isolated ileum on application of a peptidic principle released from plasma proteins by trypsin or certain snake venoms (Rocha e Silva et al., 1949). After initial uncertainties, the correct nonapeptide sequence was determined in 1960 (Boissonnas et al., 1960; see Shorley and Collier, 1960; Bhoola et al., 1992). It was then readily established that kallidin was an N-terminal extension of bradykinin, lysyl-bradykinin. Kallidin had been described much earlier, as a bioactive principle released in serum by kallikrein, in the extensive studies of Frey, Werle and colleagues (see Schachter, 1983; Bhoola et al., 1992). A considerable number of kinins have been identified in tissues taken from numerous species of animal covering several phyla (Bertaccini, 1976; Pisano, 1979). The structures of some of these are shown in Table 1 and in terms of phylogenetic evolution they illustrate the unusual feature compared to some other mediator peptides that active members show either or both amino terminal (N-terminal) and carboxy terminal (C-terminal) extensions of the nonapeptide bradykinin sequence. The mammalian kinins are not stored in their active form, but instead constitute a small component of large precursor kininogen molecules from which they are released following limited proteolytic cleavage by diverse serine proteases collectively known as kininogenases, which include the kallikreins. Newly formed kinins participate in a multitude of physiological processes, notably those associated with the acute inflammatory response. The action of released kinins is rapidly terminated on their degradation by tissue peptidases. The biochemical pathways representing the synthesis and metabolism of kinins are well established and are documented in detail elsewhere (Schachter, 1980; Regoli and Barabr, 1980; DeLa Cadena and Colman, 1991; Bhoola et al., 1992). Over-activation of kinin formation, or under-activation of kinin degradation, may be important contributory factors in certain pathophysiological conditions, especially those where inappropriate or prolonged inflammatory responses are an underlying characteristic, such as inflammatory bowel disease, endotoxic shock, viral rhinitis and asthma. Under these circumstances, selective modification of kinin actions (i.e. by inhibitors of kinin generation or antagonists of bradykinin receptors) may result in novel therapies for inflammatory disease or for alleviating inflammatory pain. In this respect, the primary role of kinins as pathophysiological mediators allows a unique opportunity for selective pharmacological intervention. A thorough appreciation of the properties of bradykinin receptors, their subtypes, regulation and distribution, is necessary for the rational design of therapeutically-active agents.

1.1. DEFINITIONS AND NOMENCLATURE CONVENTIONS

Throughout this review, the term bradykinin receptor will be used to describe receptors at which the endogenous kinins and synthetic analogues based on their structures are active. The term kinin will be used to refer to endogenous peptides showing sequence homology with bradykinin and the term kinin analogue will be used to describe synthetic ligands whose structure is modified from that of the endogenous kinin and has pharmacological activity (either agonist or antagonist) at bradykinin receptors. Sequences of all kinin analogues are given as substitutions in relation to the sequence of bradykinin [BK] numbered from the N-terminus, as below (see also Table 1). N-terminal-[Argt-Pro2-Pro3-Glya--PheS-Ser6-ProT-Phe8-Arg 9]-C-terminal. N-terminal extensions are shown to the left of [BK]; substitutions within the BK nonapeptide sequence are shown within square brackets in numerical order and where an analogue has an amino acid deleted from its sequence; this will be donated by the abbreviation des. Thus Lys-[des-Arg9, LeuS]-BK refers to the bradykinin molecule lacking the carboxy-terminal arginine residue with leucine substituted for phenylalanine at position eight and with lysine as an N-terminal extension. Amino acids residues are referred to throughout by the three letter codes defined in Table 2. Certain kinin analogues have been ascribed numerical identities. These are provided in Table 3.

-3

-2

-1

[ 1_

2

Arg- ProLys-Arg- ProArg- ProIie-Ser-Arg- Pro-

0

4

5

_6

_7

Pro- Gly-Phe- Ser- ProPro- Gly-Phe- Ser- ProHyp--Gly-Phe- Ser- ProPro- Gly-Phe- Ser- Pro-

3 PhePhePhePhe-

8 Arg Arg Arg Arg

9_]

10

11

12

C-terminal

Conserved bradykinin residues are shown underlined. aEnjyoji and Kato, 1988. bOkamoto and Greenbaum, 1988. cPisano, 1979. dConlon et al., 1990.

Non-mammalian Glu-Thr-Asn-Lys-Lys-Lys-Leu-Arg-Gly-Arg- Pro- Pro- Gly- Phe- Ser- Pro- Phe- Arg Polisteskinin c Thr-Ala-Thr-Thr-Arg-Arg-Arg-Gly-Arg- Pro- Pro- Gly- Phe- Ser- Pro- Phe- Arg Vespulakinin I c Thr-Thr-Arg-Arg-Arg-Gly-Arg- Pro- Pro- Gly-Phe- Ser- Pro- Phe- Arg Vespulakinin 2¢ Ala-Arg-Arg- Pro- Pro- Gly-Phe- Thr-Pro- Phe- Arg Polisteskinin R c Gly-Arg- Pro- Hyp-Gly-Phe- Ser- Pro- Phe- Arg Vespakinin M c Ala-Arg- Pro- Pro- Giy- Phe- Ser- Pro- Phe- Arg- lie- Val Vespakinin X ~ Arg- Pro- Pro- Gly- Phe- Thr-Pro- Phe- Arg Thr6-bradykinin d Val- Pro- Pro- Giy- Phe- Thr-Pro- Phe- Arg Val~,ThrS-bradykinin c Arg- Pro- Pro- Gly- Phe- Ser- Pro- Phe- Arg- lie- Tyr (SO3H) Phyllokinin c Arg- Pro- Pro- Gly- Phe- Ser- Pro- Phe- Arg- G l y - L y s - Phe- His Bombinakinin O ¢ Arg- Pro- Pro- Gly- Phe- Ser- Pro- Phe- Arg- Val- Ala- Pro- Ala-Ser Ranakinin N c Arg- Pro- Pro- Gly- Phe- Thr-Pro- Phe- Arg- lie- Ala- Pro- Glu-Ile-Val Ranakinin R c

Mammalian Bradykinin Lys-bradykinin Hyp3-bradykinina,c T-kinin b

N-terminal

TABLE 1. Sequence Homology in Some Naturally Occurring Kinins

> tr"

U~


135

TABLE2. Generally-used Abbreviations for Common Natural Amino Acids and Unofficial Codes for Unnatural or Unusual Amino Acids Amino acid

Abbreviation

Alanine ct-Aminoisobutyric acid Arginine Asparagine Aspartic acid L-Carboranyl-alanine p-Chloro o-phenylalanine Cysteine p-Fluoro D-phenylalanine Glutamine Glutamic acid Glycine Histidine Trans-4-hydroxy-proline Isoleucine Leucine Lysine Methionine fl-2-Naphthyl-alanine [(3as,7as)-Octahydroindol-2-yl-carbonyl] Phenylalanine Proline Serine (l,2,3,4-Tetrahydroisoquinolin-2-yl-carbonyl) fl-2-Thienyl-alanine Threonine Tryptophan Tyrosine Valine

Ala Aib Arg Asn Asp Car CDF Cys FDF Gin Glu Gly His Hyp lie Leu Lys Met Nal Oic Phe Pro Ser Tic Thi Thr Trp Tyr Val

TABLE3. Numerical Identities of Kinin Analogues Structure

B

[D-Phe7]-BK [ThiS,a,D-Phe7]-BK [Hyp3,D-PheT]-BK [Hyp3,ThiS'S,D-Phe7]-BK D-Arg-[Hyp3,D-Phe7]-BK Lys,Lys-[Hyp3,D-Phe7]-BK D-Arg-[Hyp2"3,o-Phe 7]-BK o-Arg-[ThiS.S,CDF7 ]-BK D-Arg-[Hyp3,ThiS'S,D-Phe7]-BK D-Arg-[Hyp2.3,ThiS.8,D-Phe7]-BK Lys,Lys-[Hyp3,ThiS.S,D-Phe 7]-BK Lys,Lys-[Hyp2,ThiS'S,D-Phe 7]-BK Lys,Lys-[HypE'3,ThiS.S,D-Phe7]-BK D-Nal-[ThiS.S,D-Phe7]-BK D-Arg-[Hyp3,ThiS,D-Tic7,OicS ]-BK D-Arg-[Hyp3,ThiS,D-Tic7,Tic s]-BK

NPC

-

3592, 4416 3820, 4801 4208, -4280 3824, 3832 4301, 4148 4308 4152

3 6 1

3880, 3926 4146 4801 4162, 4881, 6572 4311, 3814

- -

--

431 392 394 567 412 568 806349 348 415 413 414 573 - -

16,731

HOE - -

-------------140 --

B, Vavrek and Stewart synthesis code (see Stewart and Vavrek, 1991); NPC, NOVA Pharmaceutical Corporation (see Burch et al., 1990); HOE, Hoechst Pharmaceutical Company (see Hock et al., 1991).

2. P H A R M A C O L O G Y

OF BRADYKININ RECEPTORS

2.1. HISTORICAL PERSPECTIVE Comprehensive analysis o f the receptors recognizing the kinins only began to make real headway in the late 1970s, despite the successful chemical synthesis o f bradykinin a decade earlier. This

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J.M. HALL

delay can be attributed to three main factors. First, there were problems in the choice of reliable in vitro bioassay preparations for assessing kinin activities, since many of the actions of kinins were found to be indirect (e.g. through release of endothelial-derived factors, prostaglandins, catecholamines or acetylcholine) (Barab6 et al., 1977, 1979; Regoli et al., 1977). Second was the limited availability of naturally-occurring kinins, especially ones showing appreciable discrimination between bradykinin receptor types. Third, and most significantly, was the lack, until the late 1970s, of synthetic ligands selective for bradykinin receptor types for use in either functional or radioligand binding studies. In the main this stemmed from the fact that, whereas for many peptide families the active residues were delineated by simple (generally N-terminal) deletions from the parent molecule, with the kinin family this approach is not viable as the entire nonapeptide sequence seems necessary for activity. This rule seems also to apply to synthetic analogues which has important consequences for medicinal chemistry. One exception is the metabolically truncated octapeptide sequence, [des-Argg]-BK, which is active at B~ receptors (see Section 3.1). Therefore, early classificational schemes for bradykinin receptors, of necessity, were based on essentially phenomenological observations. This resulted in such proposals as the P receptors supposedly mediating pain stimuli (previously known as A receptors (Antipyretic); Collier and Shorley, 1960; Collier, 1962) and the S receptors mediating swelling, hypotension and contraction of smooth muscle (guinea-pig ileum; veins from various species) (see Regoli and Barab6, 1980). However, such schemes proved of little lasting value both because of the lack of any sound theoretical pharmacological basis and since new findings led to the viewing of much of this early work in a quite different perspective. The most significant of the latter factors was the finding that some actions originally attributed to a direct action of bradykinin (such as bronchoconstriction) were actually due to the release by bradykinin of various prostaglandins; a fact that became more obvious with the demonstration that the major action of aspirin-like compounds was to inhibit cyclooxygenase (Vane, 1971). Further tools for use in the analysis of kinin action were expected following the observation of differential effects of the so-called bradykinin potentiating peptides on some responses to bradykinin, since this might be taken to suggest differences between the bradykinin receptors involved. Unfortunately, in the majority of cases these effects were found to be indirect, such as through inhibition of peptidases (see Stewart, 1979; Schaffel et al., 1991).

2.2. THE B~/B2 RECEPTORCLASSIFICATIONSCHEME The classificational scheme which has proved to be the most successful to date divides bradykinin receptors into two types, termed B t and B2, and is based on sound pharmacological criteria of drug-receptor interaction. These are: (a) relative potencies of agonists, (b) affinities of competitive antagonists in functional studies and (c) affinities or rank-orders of potency for displacement by agonists and antagonists in radioligand binding studies. The first convincing evidence for these bradykinin receptor types was reported in two papers published in the Canadian Journal of Physiology and Pharmacology by Regoli and co-workers in 1977, who provided pharmacological data which they suggested supported the existence of "at least two different types of receptors .for bradykinin", with receptors in the rabbit aorta differing from those in the cat ileum and rat uterus (Barab6 et al., 1977; Regoli et al., 1977). These data, along with other evidence, were presented in a detailed seminal review in 1980 (Regoli and Barab6, 1980). The characteristics of these so-called B~ and B2 receptors seemed to be clearly defined when expressed in terms of rank orders of agonist potencies: Bj receptors (rabbit aorta): [des-Arg9]-BK > [Tyr(Me)8]-BK > BK B2 receptors (rabbit jugular vein, dog carotid artery, cat ileum, rat uterus): [Tyr(Me)8]-BK > BK > [des-Argg]-BK. The pharmacological development and current status of the B~ and B2 receptor classification scheme and their distribution, structure and receptor-effector coupling mechanisms are the main subject of this review. The involvement of B~ and B2 receptors in physiological and pathophysiological processes will be discussed together (Section 6), since in the majority of cases either both


137

of the receptor types seem to be involved in mediating responses, or the predominant receptor type involved is not established.

3. B 1 RECEPTORS 3.1. FUNCTIONALSTUDIES--AGONISTS

The first comprehensive pharmacological investigation of B~ receptors was carried out in the late 1970s (Regoli et al., 1977) using a now classical Bl preparation, the rabbit isolated aortic strip. This preparation was chosen since it had previously been described as the only vascular preparation where bradykinin had a direct action on the smooth muscle and was used despite the fact that it showed low and variable sensitivity to bradykinin for reasons that were not understood at that time (Garrett and Brown, 1972; see Section 3.5). Studies were aimed at determining the chemical groups involved in binding to and stimulation at the bradykinin receptors (Regoli et al., 1977; Drouin et al., 1979a). Truncating the bradykinin molecule by deletion of the C-terminal arginine residue, to form the [des-Argg]-BK octapeptide, resulted in a 6-fold increase in agonist potency. Importantly, this fragment was relatively inactive in preparations containing the B2 receptor. For example, in the cat ileum and rat uterus it was found to be, respectively, 1000-fold and 100-fold less potent than bradykinin (Barab6 et al., 1977); and it had no discernible activity in some other B2 tissues, such as the guinea-pig ileum (Suzuki et al., 1969), rabbit jugular vein, hamster urinary bladder and guinea-pig trachea (Rhaleb et al., 1990a). Further modifications of the bradykinin molecule via additional C-terminal residues resulted in inactive compounds (Regoli et al., 1977). Reduction of the chain length by even a single N-terminal deletion caused a marked reduction in potency; so the octapeptide ([des-Arg~]-BK) has a pD 2 (-log~0 ECs0) of 4.7; reduced from 6.4 for bradykinin (Regoli et al., 1977). A second approach to the identification of Bl-selective agonists was through the use of the N-terminal extended endogenous kinin Lys-BK (kallidin) and Met,Lys-BK (originally, though no longer, thought to be an endogenous mammalian kinin ligand, see Margolius, 1989). These N-terminal sequence extensions increase agonist potency by approximately 10-fold and 100-fold, respectively, at the B~ receptor. In contrast, agonist potency is unchanged (Lys-BK) or reduced (Met,Lys-BK) in preparations containing B2 receptors (Drouin et al., 1979b; Gaudreau et al., 1981b). Other mammalian kinins such as T-kinin (Ile,Ser-BK) and (Hyp3)-BK (see Table 1) were found to be less active than bradykinin at B~ receptors, though Lys-[Hyp3]-BK was 10-fold more potent than bradykinin (Rhaleb et al., 1990a). Also the C-terminally-deleted (des-Arg 9) analogue formed from the N-terminally-extended Lys-BK (i.e. Lys-[des-Argg]-BK) had a 250-fold increase in potency at the Bl receptor. However, this was accompanied by some loss of selectivity, since this analogue was found to be also relatively potent at some B2 receptor sites (cat terminal ileum; Gaudreau et al., 1981b), though low in activity at others (rabbit jugular vein, guinea-pig anterior mesenteric vein; Gaudreau et al., 1981b; Regoli et al., 1990a), or completely inactive at yet others (guinea-pig ileum, hamster urinary bladder, rat vas deferens, guinea-pig trachea) (Regoli et al., 1990a). These results limit the usefulness of this agonist in receptor classification studies, though they may be worth examining in terms of heterogeneity of B2 receptors (Section 4.4), or differential breakdown by peptidases. Analogues containing amino acid substitutions within the linear bradykinin sequence have also been tested for Bl-selectivity. Substitution of phenylalanine at position five of the bradykinin molecule, with the boron-containing unnatural amino acid L-carboranyl-alanine (Car) (Leukart et al., 1976), an amino acid of increased size and hydrophobicity compared to the naturally-present phenylalanine, resulted in an agonist which, although showing decreased potency, had a longer duration of action (Couture et al., 1979). Replacement of proline at position seven with various residues resulted in inactive compounds (Rhaleb et al., 1990a). Very recently, Sar-[D-PheS,des Argg]-BK was described as being a potent and selective B~ receptor stimulant (Regoli et al., 1990b; Rhaleb et al., 1990a). It is now fifteen years since the introduction of the prototype [des-Argg]-BK as a pharmacological tool and this ligand continues to be the most commonly used agonist for the study of B~ receptors. Indeed, the presence of a Bt receptor population is often concluded solely in terms of the

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J.M. HALL

relative activity of [des-Arg9]-BK to bradykinin, though this may well be misleading (see Sections 5 and 7). It is therefore of particular interest to recognize that as early as 1962 it was known that [des-Argg]-BK was formed as a natural product in the vascular circulation via enzymatic cleavage of the bradykinin molecule by a carboxypeptidase, kininase I (also known as carboxypeptidase N) (Erd6s and Sloane, 1962). At this time, the [des-Argg]-BK product was considered to be an inactivation product and its biological activity was not investigated. However, the possibility should be borne in mind, that formation of C-terminal arginine-deleted kinin fragments may serve physiological or pathophysiological purposes, namely acting as endogenous ligands at the B~ receptor. Such a proposal is supported by a number of experimental findings. For example, in the rabbit isolated aorta, the potency of bradykinin is considerably reduced when determined in the presence of the carboxypeptidase inhibitor DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (mergetpa), as compared to that estimated in untreated tissues, whereas the potency of [des-Argg]-BK is unchanged. This suggests that the action of bradykinin on B~ receptors in this preparation is due almost entirely to its conversion to [des-Argg]-BK by carboxypeptidase action with the tissue during incubation (Babiuk et al., 1982; Regoli et al., 1986b). Similar conclusions have been drawn from in vivo studies. Indeed, in view of the higher potency of Lys-[des-Argg]-BK in an in vivo Bl receptor assay, it has been suggested that this agonist may be the endogenous ligand for the Bl receptor (Drapeau et al., 1991). This concept is re-addressed in relation to the role of B~ receptors in inflammation (Section 6.6.1). 3.2. FUNCTIONALSTUDIES--ANTAGONISTS For many peptide-mediator receptors, there has been a considerable time-lag between the proposal of multiple receptor types and the discovery and development of useful antagonists. Whilst this was most certainly true for the B2 receptors (Section 4.2), in the case of the B~ receptor the development of selective Bj receptor agonists (as discussed above) was paralleled by the development of some selective and relatively high affinity peptide Bl receptor antagonists. Stages in the development of B~-selective antagonists have recently been reviewed (Marceau and Regoli, 1991). As with the agonist studies described above, the majority of antagonist studies were carried out using the rabbit isolated aorta preparation. 3.2.1. [ D e s - A r g g ] - B K Analogues Regoli and colleagues (Regoli et al., 1977) showed that substitution at position eight within the Bt-selective [des-Argg]-BK octapeptide altered agonist potency. Replacement of the phenylalanine ring-structure with aliphatic amino acids resulted in receptor antagonists, with increasing affinity with lengthening of the aliphatic chain. For example, substitution with alanine of bradykinin ([des-Arg 9, AlaS]-BK) resulted in an antagonist with a pA2 value of 3.95; whereas substitution with leucine ([LeuS,des-Argg]-BK) yielded increased affinity, a pA2 value of 6.75 in the rabbit isolated aorta (or 7.27; Drouin et al., 1979b). Antagonism by this latter analogue was compatible with competitive kinetics, by Schild analysis (Regoli et al., 1977). Further, this latter antagonist was TABLE4. Affinity (pA2) Estimates for BI Receptor Antagonists in Pharmacological Assays Antagonist [LeuS,des-Argg]-BK

[LeuS,OMeSdes-Argg]-BK

Lys-[Leu8,des-Arg9]-BK

Tissue

pA2

Reference

Rabbit aorta Rabbit aorta Rabbit mesenteric artery Rabbit mesenteric vein Rabbit aorta Rabbit aorta Rabbit pulmonary artery Rabbit renal artery Rabbit aorta Human colon Rat urinary bladder

6.8 7.3 6.5 7.0 6.8 6.7 7.0 6.6 8.4 8.2 8.1

Regoli et al., 1977 Drouin et al., 1979b Churchilland Ward, 1986 Barab~ et al., 1979 Barab6 et al., 1979 Regoli et al., 1977 Barab~ et al., 1977 Barab~ et al., 1977 D r o u i net al., 1979b Couture et al., 1981 Marceauet al., 1980


139

shown to be selective at B~ receptors: it was relatively inactive at B2 receptors (see Regoli et aL, 1990a) as well as at receptors for other unrelated bioactive agents (Regoli et al., 1977). [Leus, des-Argg]-BK remains the most extensively used Bj receptor antagonist, despite the fact that the kallidin equivalent, Lys-[LeuS,des-Argg]-BK and also Met,Lys-[LeuS,des-Argg]-BK were reported as having a 10-fold higher affinity and longer duration of action than [LeuS,des-Argg]-BK (Drouin et al., 1979a,b) with maintained selectivity for the Bl receptor (see Regoli et al., 1990a). Affinities, obtained in functional studies, for the most commonly used of this series of antagonists are given in Table 4. 3.2.2. [Des-Argg]-BK Analogues with L-Carboranyl-alanine Substitutions Attempts to develop further antagonists for the B~ receptor have not been pursued to any great extent. Substitution at position five of the [LeuS,des-Argg]-BK molecule with the L-carboranyl-alanine (see above) to yield [Ca:,LeuS,des-Argg]-BK, although resulting in a competitive antagonist having a longer duration of action, only showed only a slight increase in affinity (pA2 = 7.84) (Couture et al., 1979) as compared to the parent [LeuS,des-Argg]-BK analogue (pA 2 = 7.72; Drouin et al., 1979b). Further, this antagonist was less active than Lys-[LeuS,des-Argg]-BK (pA2 = 8.37; Drouin et al., 1979a). 3.2.3. [Des-Argg]-BK Analogues with Substitutions at Position Seven Substitution of proline at position seven of the [des-Argg]-BK octapeptide with alanine to form [AlaT,des-Argg]-BK resulted in the production of a weak Bl receptor antagonist (Drouin et al., 1979b). In view of this a series of analogues with further residues substituted at position seven was developed. These analogues did prove to be Bl receptor antagonists, with affinity estimates ranging from pA 2 values of 5.56 ([GlyT,des-Argg]-BK) to 7.29 (Lys-[D-AlaT,des-Argg-BK]), though often with residual agonist activity (Barab6 et al., 1984). The pharmacology of these compounds, however, seems not to have been extensively studied. Of interest in relation to these latter structure-activity relationship studies is the proposed interaction with Bl receptors of recently introduced (D-Phe7) substituted B2 receptor antagonists (Section 4.2.1). Thus, two first generation B2 receptor antagonists, [ThiS'8,D-PheT]-BK and Lys-[ThiS,S,D-PheT]-BK, were reported to significantly attenuate B:mediated contractile responses of the rabbit isolated aorta. The possibility that this B t receptor antagonism was due to the decarboxylation of the B2 antagonists, thus converting them to the corresponding B:selective [ThiS's,o-PheT,des-Argg]-BK and Lys-[ThiS'a,D-PheT,des-Argg]-BK antagonist products, was apparently confirmed, indirectly (Regoli et al., 1986b). It was shown that the presence of the carboxypeptidase inhibitor mergetpa, which prevents the removal of the C-terminal arginine from kinins (Skidgel et al., 1984), considerably reduced the ability of the B2 antagonists to inhibit B:responses, as compared to untreated controls (pA2 for [ThiS'S,D-Phe7]-BK in mergetpa treated = 4.92; in control = 6.23). In contrast, the affinity of the B~ antagonist Lys-[LeuS,des-Argg]-BK was unchanged (Regoli et al., 1986b). 3.2.4. D-Arg-[Hyp3,ThiS,D-TicT,0ica,des-Argg]-BK

('des-Arg~°-[HOE140] ')

Considering the antagonism of B~ receptor responses by [D-PheT]-BK substituted B2-selective antagonists described above, along with the development of the potent and stable B2-selective antagonist D-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK (see Section 4.2.2), it was only a matter of time before the corresponding [des-Argg]-BK modification of this latter antagonist was synthesized. The pharmacology of o-Arg-[Hyp3,ThiS,D-TicT,Oica,des-Argg]-BK ('des-Arg~°-[HOEl40]') was published in 1991 (Wirth et al., 1991a) and although an extensive pharmacological analysis was not provided (importantly no tests for competition were carried out), the antagonist was claimed to have high affinity for the B~ receptor. Thus, the IC50 of D-Arg-[Hyp3,ThiS,D-Tic7,OicS,desArgg]-BK in the rabbit aorta was 12 nM, one order of magnitude higher than the IC50 for [LeuS,des-Arg9] BK (IC50 = 110 nM); and this antagonist was three orders of magnitude less potent than the B~ receptor antagonist o-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK in the guinea-pig ileum and pulmonary artery, two B~ receptor preparations. Furthermore, the high metabolic stability of

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D-Arg-[Hyp3,ThiS,D-TiC,OicS]-BK (see Hock et al., 1991) was maintained in D-Arg-[Hyp3,ThiS,DTicT,OicS,des-Argg]-BK. It should be noted that the previously described Brselective antagonist Lys-[LeuS,des-Arg9]-BK is as active as o-Arg-[Hyp3,ThiS,D-Tic7,OicS,des-Arg9]-BK (see above and Table 4) and its selectivity margin for B~ over B2 receptors is not great (Wirth et al., 1992). The higher affinity and metabolic stability of the two antagonists has been attributed to the presence of additional basic N-terminal amino acids in both compounds, whereas these are absent in the less potent antagonist [LeuS,des-Argg]-BK (see Wirth et al., 1991a). 3.2.5. Bissuccinimidoalkane Peptide Dimers A series of bradykinin-receptor antagonists has been developed whose structures result from the replacement of cysteine residues for certain amino acids in the sequence of established bradykinin receptor antagonists, followed by dimerization using bismaleimidoalkane linkers (Whalley et al., 1992; Cheronis et al., 1992a,b; see Section 4.2.4). Antagonists with affinity for B~ receptors have been described (Whalley et al., 1992), including a heterodimer composed of the B~-selective antagonist [Leu8,des-Arg9]-BK linked to the B2-selective antagonist D-Arg-[Hyp3,DPheT,Leu8]-BK (cys-cys 1,6-bis(succinimido)hexane; CP-0364). The compound has affinity at both B~ and B2 receptors in vitro and in vivo, having an IC50 value of 7.5 in the rabbit isolated aorta in vitro (Whalley et al., 1992; see also Section 6.7.3). 3.2.6. Non-peptide BI Receptor Antagonists Crude (non-peptide) extracts of the Brazilian plant Mandevilla velutina have been shown to inhibit responses to [des-Arg9]-BK in the rabbit isolated aorta and mesenteric artery, two B~ receptor preparations (Calixto and Yunes, 1986). However, it should be pointed out that in the same concentration range, these extracts were shown to inhibit contractile responses to bradykinin in the rabbit isolated jugular vein, a B2 receptor preparation (Calixto and Yunes, 1986; see Section 4.2.5) and the nature of the antagonism requires further investigation. 3.3. RADIOLIGAND BINDING STUDIES Original papers describing radioligand binding to B~ receptors are limited and unconvincing. In one study (Barab6 et al., 1982), specific binding of [3H]-[des-Arg9]-BK (obtained by tritiation of [p-Br-Phe8,des-Arg9]-BK) was found in the rabbit anterior mesenteric vein and this binding was displaced by kinin analogues in the order Lys-BK>[Leu8,des-Argg]-BK>[des-Arg9]BK > BK [Tyr(Me)8]-BK, with the Bl-selective agonist being one order of magnitude more potent in displacing [3H]-[des-Arg9]-BK than the B2-selective agonist [Tyr(Me)8]-BK (Section 4.1), a displacement profile compatible with potency data at Bj receptors in functional pharmacological assays. This study has, however, been criticized (Bathon and Proud, 199l) in view of the very low binding-affinity (104 nM) reported, together with lack of presentation of full saturation curves. Furthermore, dense fragments of tissue were used, so presenting potential diffusional problems, and peptide degradation was likely since the studies were performed at 37 °C in the absence of protease inhibitors. More recently, it has been suggested that the saturable binding may, in fact, have represented cellular uptake (Marceau and Regoli, 1991). In a second study, Sung et al. (1988) reported the presence of two sites labelled with [3H]-BK on bovine pulmonary endothelial cells; one having characteristics of a typical high-affinity saturable B2-site (Kd = 1.28 nM; see Section 4.3) and a second low-affinity binding-site which they consider as being of the Brtype since binding was displaced by the Brselective analogues [des-Arg9]-BK and [LeuS,des-Argg]-BK. However, this interpretation has been challenged (Bathon and Proud, 1991) in view of the very high concentrations of [des-Argg]-BK needed to saturate the low affinity site and to induce biological responses in functional studies. Furthermore, the binding was not inhibited by Lys-BK as might be expected (see Section 3.1), but was, in fact, inhibited by dopamine (10 nM) and ATP (1 raM). Perhaps of greatest significance is the inability of Barab6 et al. (1982), to demonstrate specific binding for [3H]-[des-Arg9]-BK in the classical tissue for B~ receptors, the rabbit aorta. Overall, further work is required to confirm these preliminary B~ receptor binding studies. In this


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context, in a recent review (Burch and Kyle, 1992), the successful development of a radiolabel for the B~ receptor was discussed. The ligand, Lys-[(3H)Pro~,des-Argg]-BK was used in B~-receptor characterization studies in rat renal mesangial cells (which also contain B2 receptors; Section 4.3.2) where the Kd for the radioligand was 2.4 nM and specific binding was displaced by the B~-selective analogues [LeuS,des-Argg]-BK, Lys-[LeuS,des-Argg]-BK and [des-Argg]-BK but not by the B2-selective analogue o-Arg-[Hyp3,D-PheT]-BK. The ligand has also been used to identify Bt receptors in RAW264.7 macrophages, where again specific binding was displaced by B~- but not B2-selective ligands (see Burch and Kyle, 1992). 3.4. B~ RECEPTORHETEROGENEITY Although B~ receptor subtypes have been proposed (Paiva et al., 1989; Wiemer and Wirth, 1992), at present there is not sufficient evidence available from functional or radioligand binding studies to seriously address this issue (see Section 5). 3.5. INDUCTIONOF B~ RECEPTORRESPONSES 3.5.1. Characteristics Increased sensitivity to bradykinin with time, for isolated tissues expressing B~ receptors, was first reported by Goldberg et al. (1976) in canine saphenous veins; and the phenomenon was confirmed in the rabbit aorta and mesenteric vein by Regoli and co-workers (Regoli et al., 1977, 1978). This apparently spontaneous induction of the B~ receptor response has been clearly demonstrated in vascular tissues in vitro (Regoli et al., 1977, 1978; Whalley et al., 1983) and in non-vascular tissues in vitro (Marceau et al., 1980; Couture et al., 1982; Boschcov et al., 1984), in vivo (Regoli et al., 1981) and in a rabbit dermis fibroblast cell line in culture (Marceau and Tremblay, 1986). The phenomenon has been shown in almost all B~ receptor systems so far studied, with the notable exceptions of certain cell lines (Goldstein and Wall, 1984; Sung et al., 1988) and the vasculature of the isolated perfused rat kidney (Guimar~.es et al., 1986) and so may be considered a prerequisite for deducing the presence of a B~-receptor population in a particular tissue. Earlier studies relating to the induction of the Bj-receptor response have been reviewed (Marceau et al., 1983). Induction of the Brreceptor response has been characterized in detail in rabbit vascular tissues in vitro. The rabbit isolated mesenteric artery shows a progressive increase in sensitivity to B~-receptor agonists up to 6 hr, but is maximal only after 18-24 hr, whilst responses to other agonists such as noradrenaline and substance P remain unchanged (Regoli et al., 1978). The increase in sensitivity still occurs in tissues pretreated with indomethacin and adrenoceptor antagonists (Regoli et al., 1978) and in endothelium-denuded tissues (Boutillier et al., 1987) and appears to be temperature-dependent (Couture et al., 1982). One very important characteristic of induction of the B~-receptor response is that the rate of sensitization in vitro is also increased by isolated tissue incubation or application of certain noxious agents. This has been demonstrated in the rabbit isolated aorta with agents including bacterial lipopolysaccharide (LPS), adjuvant peptidoglycan muramyl-dipeptide and phorbol myristate acetate (PMA). Several growth factors such as epidermal growth factor (EGF) and endothelial cell growth factor also induce a B~ response, but with distinct characteristics and an apparently distinct mechanism (Boutillier et al., 1987; see Section 3.5.3). Induction of in vivo B~ receptor responses in the rabbit can be identified by a transient hypotensive response to [des-Argg]-BK 5 hr after a sublethal injection of LPS, a response that is not seen in control animals. This model has become a standard for investigations of in vivo B~ receptor response induction (Marceau et al., 1980; Regoli et al., 1981). The induced response is acquired some time prior to sacrifice of the animal, since tissues from LPS-treated rabbits exhibit contractile responses to B~ receptor selective agonists earlier than in control tissues in vitro (Boutillier et aL, 1987; Regoli et al., 1981; Wirth et al., 1992). Further stimuli that cause the induction of the B~ receptor response in the rabbit blood pressure model in vivo include MDP and PMA (Boutillier et al., 1987; Marceau et al., 1984). Further in vivo models of B~ receptor response

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induction include intravascular installation of the detergent Triton X-100 into the rat urinary bladder to cause chemical cystitis (Marceau et al., 1980) and in rat colon, acetic acid installation (Kachur et al., 1986). Investigating the extent of B~ receptor response induction, installation of Triton X-100 into the rat urinary bladder resulted in a localized sensitization to the area of tissue damage (Marceau et al., 1980). However, Farmer et al. (1991c) described findings which they interpret as demonstrating the involvement of circulating mediator(s) (presumed to be cytokines, see below) in induction of the B~ receptor response in remote organs during the inflammatory process. Thus, in rabbits sensitized four weeks previously with intradermal fibrin (in Freund's Complete Adjuvant), arthritis was then induced by intra-articular fibrin. Responses of the isolated aortas removed 24 hr after fibrin challenge to bradykinin and [des-Argg]-BK were significantly greater than those recorded in naive or sensitized control animals; though it should be noted that a higher concentration of bradykinin was used to elicit responses than that required for a maximal contractile response in the earlier work of Regoli and Barab6 (1980). 3.5.2. Mechanism o f B~ Receptor Response Induction: Immunological Stimuli De novo protein synthesis is involved at some stage in the B~ receptor response induction process. Thus, sensitization was reduced in the rabbit anterior mesenteric vein and aorta in vitro by continuous exposure to actinomycin D or cycloheximide (Regoli et al., 1978; Boutillier et al., 1987), in the rat urinary bladder by cycloheximide (Boutillier et al., 1987) and in the rabbit aorta by cycloheximide and anisomycin (Boutillier et al., 1987; DeBlois et al., 1991). The agents were used at concentrations which inhibit protein or RNA synthesis and which had no effect on responses to substance P or to noradrenaline, nor on responses to bradykinin in the rabbit jugular vein, a B2-receptor preparation (Regoli et al., 1978). One suggestion for the increase in sensitivity of Bt receptor tissues in vitro is that de novo synthesis of B~ receptors is induced as a result of products of tissue damage or by noxious agents (Regoli et al., 1978). Significantly, in radioligand binding studies, incubation of chopped mesenteric artery for 24 hr caused a highly significant increase (13-fold after 24 hr; from 0.064).75 pmol mg-t wet weight) in specific binding for [3H]-[des-Argg]BK, an effect that was sensitive to cycloheximide. A high correlation between the time-dependent increase in binding sites and development of the contractile response to [des-Arg 9]-BK was reported (r = 0.98). Further, the number of [3H]-[des-Argg]-BK binding-sites in the anterior mesenteric vein is greater in LPS-treated than in control rabbits (Barab6 et al., 1982). A role has been suggested for endogenously-produced cytokines, released from immunocompetent cells, in the phenomenon of increased tissue responsiveness to Bl-selective agonists (Boutillier et al., 1987; DeBlois et al., 1988). This intriguing possibility is supported by indirect evidence from in vitro and in vivo studies. Both interleukin-1 (IL-1) and interleukin-2 (IL-2) have been shown to increase the rate of development of [des-Argg]-BK responses in vitro in the rabbit isolated aorta (DeBlois et al., 1988) and the modulation by IL-lfl of tissue sensitivity to [des-Argg]-BK was blocked by protein synthesis inhibitors (DeBlois et al., 1991). Continuous exposure to low concentrations of glucocorticoids which, amongst numerous other actions, inhibit IL-1 synthesis (Smith, 1980) prevent the spontaneous development of responses to [des-Argg]-BK in the rabbit isolated aorta (DeBlois et al., 1988). Furthermore, both LPS and MDP, two agents that stimulate in vivo sensitization to [des-Argg]-BK, induce IL-1 secretion by macrophage-like cells in vitro (Tiffany and Burch, 1989; see DeBlois et al., 1988); rabbits injected with LPS also produce IL-lfl in vivo (Cannon et al., 1989) and cultured vascular endothelial and smooth muscle cells produce IL-1 in response to LPS (Libby et al., 1986a,b; see DeBlois et al., 1988). Recent results (DeBlois et al., 1991) provide further evidence for a link between cytokines and the B t receptor response induction process. Thus, inhibition of protein synthesis has been shown to induce the production of IL-1 messenger RNA (mRNA) in vascular smooth muscle (Warner et al., 1987) and in endothelial cells (Libby et al., 1986a); and removal of the protein synthesis inhibitor leads to increased production of proteins corresponding to the accumulated mRNA(s) (Warner and Libby, 1989). These results lead to speculation that a transient inhibition of protein synthesis might increase vascular responsiveness to [des-Argg]-BK (DeBlois et al., 1991). Thus, it was suggested that exposure of the vascular wall to cycloheximide resulted in an increased synthesis


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of IL-1. Protein synthesis inhibitors "pulsed" (i.e. not administered continuously) resulted in an increased response to [des-Argg]-BK and "pulsing" with IL-lfl had a similar effect. Because high concentrations of IL-lfl did not reverse the inhibition of spontaneous sensitization by protein synthesis inhibitors, it was suggested that another protein distinct from IL-lfl was synthesized de novo. This protein could be the Bl receptor which was proposed by Regoli et aL (1978) to account for the increased vascular responsiveness to [des-Argg]-BK. The cellular source of the ILs has been investigated. It was found in one study that neutropaenia did not prevent the in vivo effect of LPS, which suggests that sensitization to Brreceptor agonists was not associated with neutrophil leukocytes (Boutillier et al., 1987). It has been suggested that IL secretion by tissue macrophages (Boutillier et al., 1987) or T-lymphocytes (DeBlois et al., 1988) (presumably in isolated tissue studies, sequestered on to the vascular tissue during isolation) is responsible for Bl receptor response induction. The link between the cytokine release and the change in Bt receptor affinity, second messenger coupling efficiency, or number is unclear. 3.5.3. Mechanism o f Bt Receptor Response Induction--Growth-Regulating Ligands EGF was found to cause potent, selective and rapid potentiation of Bl-receptor mediated responses, increasing both the maximal response and potency of kinins in the rabbit isolated aorta (Boutillier et al., 1987). The potentiation did not involve cyclooxygenase products or endotheliumderived factors (DeBlois et al., 1992). The potentiation differs from the slow up-regulation of the B~ receptor response caused by LPS and other immunological stimuli such as IL-1 (Section 3.5.2). Notably, EGF did not induce the Bj receptor response in vivo (Boutillier et al., 1987), so it was suggested that growth factors may act in synergy with kinins at the level of the smooth muscle cell. The interaction between EGF and [des-Argg]-BK was recently investigated in more detail in the rabbit isolated aorta (DeBlois et al., 1992). EGF and [des-Argg]-BK were shown to synergize to cause contraction of the rabbit aorta and tyrosine kinase inhibitors, such as erbstatin, inhibited the EGF/[des-Argg]-BK synergism, so an interaction at the second messenger level was suggested (DeBlois et al., 1992). EGF has been demonstrated to synergize with bradykinin in stimulating phosphodiesteric cleavage of phosphatidylinositol bisphosphate (Olsen et al., 1988). This effect was proposed as being mediated by the tyrosine kinase activity of the activated EGF-receptor via an action on phosphatidylinositol kinase, resulting in an elevated level of phosphatidylinositol bisphosphate (see Roberts, 1989). 3.6. RECEPTOR--EFFECTORCOUPLING MECHANISMSOF B 1 RECEPTORS Little is known regarding receptor-effector coupling of B~ receptors, with the limited studies available being carried out on isolated vascular preparations or cell lines maintained in culture. In the rabbit isolated aorta, inhibitors of cyclooxygenase do not influence Brmediated contractile responses (Regoli and Barab6, 1980). In this tissue, contractile responses were found to be largely dependent on external Ca 2+, independent of protein kinase C activation and were blocked by NiCI2 (Calixto and Madeiros, 1992b). The involvement of cyclooxygenase products and endothelialderived factors in B j-receptor mediated relaxant responses is tissue-dependent. Thus, B~-receptor mediated relaxation of the rabbit isolated mesenteric artery is not dependent on the presence of an intact endothelium (Cherry et al., 1982) but is prevented by cyclooxygenase inhibitors (Churchill and Ward, 1986; DeBlois and Marceau, 1987). The relaxation of the rabbit isolated coeliac artery is inhibited by both cyclooxygenase inhibitors and an inhibitor of the Na +/H ÷ exchange (Ritter et al., 1989). In contrast, the Bl-receptor mediated relaxation of the canine mesenteric vein is via an endothelium-dependent release of prostacyclin (PGI2) (Toda et al., 1987). Since cleavage of bradykinin by carboxypeptidase releases [des-Argg]-BK and arginine, the latter may be subsequently converted to the vasodilator nitric oxide (NO) by the NO-synthase pathway. Bt receptor coupling has been investigated in several cultured cell lines. In bovine aortic endothelial cells, the B~-selective agonist [des-Argg]-BK releases endothelium-dependent relaxing factor (EDRF; now presumed to be NO) and PGI2 (D'Orl6ans-Juste et al., 1989). In bovine pulmonary artery endothelial cells, [des-Argg]-BK has also been shown to stimulate EDRF release (Sung et al., 1988) and in calf pulmonary tissues, [des-Argg]-BK induced the synthesis of PGI 2 JPTS6/2--B

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and platelet activating factor in endothelial cells and PGI 2 in fibroblasts and smooth muscle cells (Cahill et al., 1988). In human lung foetal fibroblasts, [des-Argg]-BK stimulates protein formation and cell division without activating prostaglandin synthesis (Goldstein and Wall, 1984). In murine macrophages [des-Argg]-BK does not stimulate eicosanoid synthesis (Tiffany and Burch, 1989). In a rabbit dermis cell line (R51) following long-term culture [des-Argg]-BK and bradykinin release prostaglandin E2 (PGE2) and the effect of both peptides is blocked by [Leu8,des-Argg]-BK (Marceau and Tremblay, 1986). In isolated osteoblast-like cells from neonatal mouse calvarial bones, [des-Arg9]-BK also increases prostaglandin E 2 (PGEz) formation and 45Ca release and stimulates PGE2 formation in neonatal mouse calvarial bones and these effects were blocked by [LeuS,des-Argg]-BK (Ljunggren and Lerner, 1990). In rat mesangial cells in culture, [des-Argg]-BK appears to modulate DNA synthesis through activation of protein kinase C (lssandou and Darbon, 1991). The presence of atypical receptors in these latter cell lines is discussed in Section 5. [des-Argg]-BK, bradykinin and Lys-bradykinin potentiate IL-I induced PGE z release in human gingival fibroblast and an interaction at the level of cyclooxygenase was suggested (Lerner and Mod6er, 1991; see Section 6.6.1). 3.7. EXPRESSION STUDIESOF THE B~ RECEPTORS One report claims to have co-expressed Bl receptors with B2 receptors in Xenopus oocytes using mRNA isolated from WI38 human fibroblasts. Responses to the B~-selective agonist [des-Argg]-BK were inhibited by the Brselective antagonist [LeuS,des-Argg]-BK (Phillips et al., 1992). In these experiments, however, only single high concentrations of [des-Argg]-BK and [LeuS,des-Argg]-BK were tested and responses to the agonist were very small. Confirmation of the expression of BI receptors in this system is required. 3.8. DISTRIBUTIONOF B1 RECEPTORS In contrast to B2 receptors (Section 4.8), B l receptors seem restricted in their localization, being demonstrated predominantly in vascular beds, in most cases in tissues from the rabbit, where they often co-exist with B2 receptors. B~ receptors are expressed in a number of cultured cell lines, including bovine pulmonary artery (Cahill et al., 1988), embryonic mice calvarium bones (Ljunggren and Lerner, 1990) and fibroblasts of human (Goldstein and Wall, 1984) and rabbit (Marceau and Tremblay, 1986) origin. There are no reports of B~ receptors in guinea-pig tissues. 3.9. SUMMARYOF B 1 RECEPTOR CHARACTERISTICS B1 receptors appear to have a very limited and somewhat elusive distribution in mammalian tissues. They can be identified by the activity of B~-selective agonists (e.g. [des-Argg]-BK) and inhibition by antagonist ligands (e.g. [LeuS,des-Argg]-BK and D-Arg-[Hyp3,ThiS,D-TicT,OicS,desArgg]-BK), or by the inactivity of B2-selective agonists (e.g. [Tyr(Me)8]-BK and [Hyp3,Tyr(Me)S] BK) and antagonists (e.g. D-Arg-[Hyp3,ThiS"8,D-PheT]-BK and D-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK). Radioligand binding and receptor-effector coupling studies of B~ receptors are sparse and inconclusive. Although subtypes of the Bl receptor may exist, evidence to date is inconclusive. The most striking feature of tissues containing B~ receptors is that sensitivity to B~-receptor agonists shows a gradual increase with time, an effect that is accelerated by treatment with certain toxic agents and is paralleled in vivo in a rabbit hypotensive model. This induction of the Bi-receptor mediated response by immunological stimuli may be associated with the action of cytokines and may involve up-regulation of the BI receptor. Potentiation of B~ receptor responses by growth regulating ligands may involve an interaction at the second messenger level. The induction of the B~ response may represent a fundamental regulatory mechanism whereby normally inactive [des-Argg]-BK kinin metabolites unmask local reactions during inflammation. Known functional roles for B~ receptors are at present limited, but may involve inflammation and long lasting effects of kinins such as collagen synthesis and cell multiplication. The proposed roles for B~ receptors are discussed in Section 6. Importantly, B1 receptors have been identified in an isolated human tissue preparation and in a human cell line in culture.


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4. B2 RECEPTORS 4.1. FUNCTIONALSTUDIES---AGONISTS The naming of receptors distinct from those present in the rabbit isolated aorta (B~ receptors) was reported in the late 1970s (Barabe et al., 1977). These receptors, termed B2 receptors (Regoli and Barab6, 1980), were defined in terms of an agonist rank order of potency [Tyr(Me)S]BK > BK > [des-Argg]-BK. Early structure-activity studies of bradykinin and its agonist homologues and fragments, on B2 receptors, were carried out in preparations of the rat uterus, cat ileum and guinea-pig ileum. In contrast to Bl receptors where removal of the C-terminal arginine residue resulted in a potent agonist (Section 3.1), removal of amino acid residues from either the carboxy or amino termini of bradykinin resulted in a profound reduction in agonist activity (data summarized in Barab6 et al., 1977). N-terminal extended naturally-occurring kinins (such as Lys-BK) showed no change or a 10-fold decrease in potency (Drouin et al., 1979b), while amidation or methylation of the C-terminal carboxyl (Rhaleb et al., 1990a) or N-terminal amidation or acetylation all reduced affinity to varying degrees (Rhaleb et al., 1990a). Cyclic analogues of kinins were found to be low in agonist activity (Chipens, 1983; Whalley, 1987), though a cyclic oxytocin receptor antagonist cyclo[L-Pro, D-Trp, L-Ile, D-pipecolic acid, L-piperazine-2-carboxylic acid, N-Me-D-Phe] was reported to stimulate hydrolysis of phosphatidylinositol in the rat uterus. This, along with contractile responses elicited by this agent, were antagonized by the B2-selective antagonist D-Arg-[Hyp3,ThiS.8,D-Phe7]-BK (Pettibone et al., 1991). In order to develop selective agonists for the B2 receptor, the effect of kinin analogues containing substitutions within the amino acid linear sequence of bradykinin were investigated. The majority of these agents were, however, less potent than bradykinin (see Barabe et al., 1977; Gaudreau et al., 1981b; Rhaleb et al., 1990b). The effect of substitutions at position eight was investigated in view of the known importance of Phe s in the bradykinin molecule in activating Bj receptors (see Section 3.2.1). One compound of particular interest, [Tyr(Me)S]-BK, was found to be a full agonist in several B2-receptor preparations, where it was generally more active than bradykinin itself (Barab6 et al., 1977; Gaudreau et al., 1981a,b) and displaced B2 receptor binding (e.g. Emond et al., 1990) but was inactive at BI receptors (Gaudreau et al., 1981a). More recently, the structure of [Tyr(Me)S]-BK was modified by introduction of hydroxyproline at position three (Rhaleb et al., 1990a,b). This compound [Hyp3,Tyr(Me)S]-BK was found to be inactive at B~ receptors in the rabbit aorta (Rhaleb et al., 1990a; Regoli et al., 1991), but more potent than bradykinin in several B2 receptor preparations. Despite the fact that [Tyr(Me)S]-BK and [Hyp3,Tyr(Me)8]-BK are the most potent and selective B2 receptor agonists yet described, their use by other workers has not been pursued to any great extent, presumably because previously these agents were not commercially available. Several reduced bond "pseudopeptides" agonist analogues have also been developed (Rhaleb et al., 1990a; Vavrek et al., 1992). 4.2. FUNCTIONALSTUDIES--ANTAGONISTS

The need for high affinity discriminative B2 receptor antagonists has long been appreciated, especially in view of the therapeutic potential of such drugs as anti-inflammatory and anti-nociceptive agents. The development of selective B2 receptor antagonists has allowed the question of possible B2 receptor heterogeneity to be addressed; and further, has permitted the exploration of the multiple biological roles of B2 receptors in physiology and pathophysiology (Section 6). 4.2.1. [D-Phe7]-BK Analogues Successful modification of the linear kinin sequence resulting in the formation of weak B2 receptor antagonists, based on a [D-PheT]-BK prototype, was first described by Vavrek and Stewart in the early 1980s, after the design and synthesis of several hundred potential analogues during the previous ten years. Because our knowledge of bradykinin B2 receptors and their function has come as a result of the introduction of these bradykinin B2 receptor antagonists, a section of this review

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will be devoted to a brief overview of the relevant structure-activity relationships. Detailed accounts may be found in several earlier publications (Schr6der, 1970; Stewart, 1979; Vavrek and Stewart, 1985) and more recent extensive (Burch et al., 1990; Bathon and Proud, 1991; Stewart and Vavrek, 1991; Farmer and Burch, 1991) or concise (Steranka et al., 1989) reviews. Structural conformational properties of B2 receptor antagonists are discussed by Kyle et al. (1991a). Early studies involving the replacement of each of the three prolines within the bradykinin sequence with ~-aminoisobutyric acid (Aib) resulted in the identification of a highly selective potent kinin agonist [Aib7]-BK in the guinea-pig ileum, which also exhibited good potency in other B2 receptor systems (Vavrek and Stewart, 1980). This observation prompted the synthesis of numerous analogues with various D-aliphatic and D-aromatic amino acid residues substituted at position seven; aromatic amino acids were favoured in order to confer some stability to degradation by kininase II (angiotensin converting enzyme, ACE) (Yang et al., 1970; see Ward, 1991). The first proposal of sequence-related competitive antagonists of classical B 2 receptor systems in vitro appeared in 1985 based on extensions of this work. The key modification was found to be the replacement of proline at position seven (Pro 7) with D-phenylalanine (D-Phe7). [D-PheT]-BK, although a weak partial agonist on the rat blood pressure assay and a weak antagonist on the rat uterus, was found to be a moderately potent antagonist on the guinea-pig ileum (pA 2 ca. 5). Importantly, antagonism was selective (Vavrek and Stewart, 1985). The delineation of this analogue represented a major breakthrough in the development of selective B2 receptor antagonists. Earlier studies had identified an analogue substituted with the unnatural amino acid fl-(2thienyl)-alanine (Thi), [ThiS'8]-BK, as being equipotent with bradykinin on the guinea-pig ileum, but having five times the activity in the rat uterus (Dunn and Stewart, 1971; Claeson et al., 1979). This observation prompted Stewart's group to combine these substitutions additionally to the structure represented in the newly synthesized antagonist [D-Phe7]-BK. The resulting analogue [ThiS'8,D-Phe7]-BK was tested against bradykinin, Lys-BK and Met,Lys-BK, in the guinea-pig ileum and was found to have pA2 values of 6.3, 6.4 and 5.2, respectively (Vavrek and Stewart, 1985; see Section 4.4.2). The analogue was also an antagonist on the rat uterus (pA 2 = 6.4; Vavrek and Stewart, 1985). The results from the study in the guinea-pig ileum were confirmed in further work by Stewart, Schachter and co-workers, who additionally found this analogue to inhibit bradykinininduced vascular permeability in the rabbit skin (Longridge et al., 1986). Substitution of the original bradykinin sequence with hydroxyproline at positions two and three (Hyp z'3) was employed as this manipulation had previously resulted in potent agonists in the rat uterus (see Stewart and Vavrek, 1991). The formation of N-terminally extended peptides by addition of basic residues such as two lysine residues or D-Arg was also employed to afford protection from metabolic degradation (see Ward, 1991). To date, numerous analogues (first generation antagonists) developed by Stewart's group, based on modification of the bradykinin structure, have been screened using contraction of rat uterus and guinea-pig ileum and hypotensive action in the rat. Specificity of action is clearly important and although most [D-PheV]-BK substituted kinin antagonists seem specific for inhibiting bradykinin responses, certain [D-Arg~,DPhe7]-BK analogues (e.g. [D-Nal I, Thi 5,s, D-Phe7]-BK) have been shown to inhibit vasopressininduced contractions of the rat isolated uterus, acting by an unknown mechanism since they did not displace bradykinin or vasopressin antagonist binding (Farmer et al., 1989a; see Section 4.4.2). More recently, Regoli and co-workers have described the effects of several modified [o-Phe7]-BK antagonist analogues with leucine substituted at position eight, including D-Arg-[Hyp3,D-Phe 7, LeuS]-BK and Ac-D-Arg-[Hyp3,D-PheT,LeuS]-BK (Regoli et al., 1990a,b, 1991). These agents appear, from preliminary studies, to have higher affinities than earlier analogues; and further, the latter ligand has a reduced tendency to cause histamine release (see Section 7), which has been attributed to the acetylation of the C-terminal extended arginine residue. Recently, some reduced bond 'pseudopeptide' antagonist analogues have been described (Vavrek et al., 1992). The affinities of the most commonly used B2 receptor antagonists based on the [D-PheT]-BK structure are shown in Table 5. The application of Bz-selective antagonists to specific in vitro and in vivo systems is discussed in Section 6.


147

TABLE5. Affinity (pKs) Estimates for D-Arg-[Hyp3,ThiS,9-TicT,0icS]-BK in Pharmacological Assays

Assay

pKB

Reference

Guinea-pig Ileum (longitudinal smooth muscle) Ileum (longitudinal smooth muscle) Ileum Ileum Ileum Taenia caeci Trachea Trachea Pulmonary artery Urinary bladder

8.9 9.4 8.8 8.4 8.6 8.4 8.9 7.4 8.3 8.8

Rhalebet aL, 1992 Hall et al., 1992 Perkinset al., 1991 Hock et al., 1991 Griesbacherand Lembeck, 1992a Field et al., 1992a Field et al., 1992a Rhalebet al., 1992 Regoli et al., 1992 Regoli et al., 1992

Rat Uterus Uterus Duodenum

9.7 9.7 10.1

Perkinset al., 1991 Hall et al., unpublished Hall et al., 1992

Rabbit Jugular vein Jugular vein Iris sphincter Vena cava Urinary bladder

9.9 9.2 10.5 9.2 9.2

Hall et al., 1992 Rhalebet al., 1992 Everettet al., 1992 Regoli et al., 1992 Regoli et al., 1992

Pig Iris sphincter

8.4

Everettet al., 1992

Hamster Urinary bladder

8.8

Rhalebet al., 1992

Human Ileum 8.4 Rhalebet aL, 1992 Urinary bladder 8.8 Rhalebet al., 1992 Estimates are shown as apparent pKs values assuming competition at equilibrium. 4.2.2. [D-TicT]-BK Analogues The successful synthesis of antagonist analogues of bradykinin based on the [D-PheV]-BK prototype described above was followed by the development of several further antagonists including D-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK(HOE 140) by the Hoechst Pharmaceutical Company (Hock et al., 1991; Wirth et al., 1991b). The residue substituted at position seven was o-(1,2,3,4tetrahydroisoquinolin-2-yl-carbonyl) (p-Tic), a phenylalanine-like amino acid derivative with L-[(3as,7as)-octahydroindol-2-yl-carbonyl] (Oic) at position eight. Together with the announcement of HOE140, was the apparent simultaneous development of several similar compounds by other groups, including o-Arg-[Hyp3,ThiS,D-TicT,TicS]-BK (see Kyle et al., 1991b). D-Arg-[Hyp3,ThiS,D-Tic7,OicS]-BK was found to be a potent antagonist in several in vitro (Hock et al., 1991; Lembeck et al., 1991; Perkins et al., 1991; Field et al., 1992a; Rhaleb et al., 1992; Wiener and Wirth, 1992) and in vivo assays (Bao et al., 1991; Lembeck et al., 1991; Wirth et al., 1991a; Damas and Remacle-Volon, 1992; Linz and Schrlkens, 1992; Madeddu et al., 1992; Sakamoto et al., 1992). This antagonist is 100-fold more potent than the corresponding [o-PheV]-BK antagonists. The results from various in vitro studies are summarized in Table 5. Concern has been raised regarding the mechanism of inhibition at bradykinin receptors by D-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK, since some of its features suggest noncompetitive antagonism, notably flattening of the log-concentration-response curve at high antagonist concentrations (Field et al., 1992a; Griesbacher and Lembeck, 1992a; Rhaleb et al., 1992). However, in view of the very high affinity of this analogue at bradykinin receptors, combined with its lipophylic nature, it seems possible that the anomalous kinetics could be explained in terms of failure of agonist and antagonist to reach a proper competitive equilibrium state in the assay systems used. The degree of parallel lateral shift of concentration-response curves to bradykinin in the presence of the antagonist before

148

J . M . HALL

flattening is observed will depend on receptor reserve and diffusional-barriers impeding achievement of an equilibrium state. In this respect, work with radiolabelled D-Arg-[Hyp3,ThiS,DTic7,OicS]-BK should help in determining its kinetics of association and dissociation with the B2 receptor. One related feature of the antagonism by D-Arg-[Hyp3,ThiS,D-Tic7,OicS]-BK, both in vitro and in vivo, is the prolonged duration of action. This has been attributed to the presence of Tic 7 stabilizing the 7-8 link and thereby conferring resistance of the analogue to degradation by peptidases; though, since the effects of this analogue are slow to reverse in vitro, this stability must be coupled with a tendency for prolonged binding, as discussed above. 4.2.3. Cyclic Peptide Analogues o f Bradykinin In several peptide families, cyclization of a linear structure has been used to confer metabolic stability of agonists and to develop antagonists. This approach was attempted at an early stage with bradykinin: however, the antagonists were weak and have not proved to be of great value (Spraggs et al., 1983). 4.2.4. Bissuccinimidoalkane Peptide Dimers Very recently a series of B2 receptor antagonists has been developed whose structures result from the systematic replacement of cysteine residues for each amino acid in the sequence of established B2 receptor antagonists, followed by dimerization using bismaleimidoalkane linkers. Parent antagonists include D-Arg-[Hyp3,o-PheT]-BK and D-Arg-[Hyp3,D-Phe 7, LeuS]-BK (Section 4.2.1). The bissuccinimidoalkane dimer of D-Arg-[Hyp3,D-Phe 7, Leu 8]-BK containing cysteine at position 6 ([BSH (L-Cys 6)]- 1 dimer; CP-0127) was a reversible antagonist with 50-100-fold higher affinity than the parent analogue in the guinea-pig ileum (pA2 = 7.7), the rat uterus (pA2 = 8.5) and the rabbit jugular vein (pA2 = 10.5) (Cheronis et al., 1992a,b; Whalley et al., 1992). CP-0127 was also found to be a high affinity and long-acting antagonist of bradykinin-evoked hypotensive response in LPS pretreated rabbits (Whalley et al., 1992; Section 6.7.3). 4.2.5. Non-Peptide Analogues Non-peptide compounds are, in general, more likely to be active following oral administration than are peptide compounds. Consequently, the therapeutic potential of non-peptide bradykinin receptor antagonists is high. The recent discovery of non-peptide antagonists acting at receptors for other peptide mediators (see Freidinger, 1989), such as the tachykinins (CP-96,345; Snider et al., 1991) and angiotensin II (S-8308; Chiu et al., 1988), allows speculation as to similar advances in the bradykinin receptor area. The current status and history of non-peptide bradykinin receptor antagonists has recently been reviewed (Burch et al., 1990; Calixto et al., 1991) and since antagonists are not, as yet, at a stage of pharmacological usefulness, they will be discussed here only briefly. Early non-peptide compounds exhibiting antagonism of bradykinin responses include chemicals as diverse in structure as aspirin (Collier et al., 1959), flavanoids (Leme and Walaszeck, 1967) and the diterpene, jatrophone (Calixto and Sant'Ana, 1987). However, these agents, in general, have proved to be nonselective and/or noncompetitive (see Burch et al., 1990; Calixto et al., 1991). Further, their antagonist effects are probably not generally mediated at the receptor level and depend rather on inhibition within the cell at the second-messenger level (Calixto et al., 1991). The most promising reports of apparently competitive, non-peptide, bradykinin receptor antagonists come from studies of the anti-bradykinin activity in extracts of the Brazilian plant Mandevilla velutina (Apocinaceae). Crude extracts and some pure non-peptide principles have been isolated and tested for inhibitory activity against bradykinin, both in vitro and in vivo. Preparations of unpurified extract were found to antagonize bradykinin responses in various B2-receptor tissues (Calixto and Yunes, 1986; Calixto et al., 1985a,b). Purification revealed the presence of five distinct non-peptide compounds: four steroidal glycosides and one aglycone steroid. All compounds antagonized responses to bradykinin in the rat isolated uterus, four in an apparently competitive manner (Calixto et al., 1988a). In contrast to peptide B2 receptor antagonists (Section 6.1.3), these


149

non-peptides antagonized both bradykinin-evoked contraction and relaxation of the rat duodenum (Calixto et al., 1988b). In vivo, a crude extract of Mandevilla velutina inhibited oedema evoked by local injection of bradykinin, carrageenin, cellulose sulphate and zymosan into the rat hind paw (see Calixto et al., 1991). These findings with zymosan are of interest, since peptidic antagonists are inactive against zymosan-evoked oedema formation (see Section 6.6.2). However, the receptor type involved and the site of action of the anti-bradykinin activity was not determined in the latter study with the non-peptide extracts. Whether the antagonism of bradykinin effects by these steroidal plant extracts proves to be at the receptor or some other level (such as inhibition of arachidonic acid metabolism) awaits confirmation. 4.3. RADIOLIGANDBINDINGSTUDIES 4.3.1. Development of Radioligands for B2 Receptors The first published attempts at radiolabelling the bradykinin molecule were carried out, for radioimmunoassay of bradykinin, in the mid 1960s using [3H]-BK and [ 14C]-labelled bradykinin (Spragg et al., 1966; Rinderknecht et al., 1967). For radioligand binding studies, however, specific activities were generally too low for the detection methods available, and, in an attempt to develop ligands with a higher specific-activity, [~25I]-labelled kinin analogues were synthesized. Sequences of naturally-occurring kinins do not contain residues suitable for iodination and kinin analogues containing an additional iodinated tyrosine residue substituted into the sequence or the amino terminus were therefore developed. Specific activities ranged between 1.2-2.2 Ci/~mol -~. Binding work was initially carried out on bovine uterine particulate myometrium (Odya et al., 1980) and studies were carried out in parallel with determinations of biological potency to assess possible changes in activity due to the introduction of the bulky tyrosine residue into the kinin molecule. It should be pointed out that different tissues from different species (see Section 4.4.1) were used in the bioassay and the binding studies. [~25I-Tyr]-Lys-BK (mono-'25I-Tyr~-kallidin) appeared to be the most useful ligand, since iodination did not effect biological potency to any significant extent and binding was saturable. Further, unlike other tyrosine iodinated analogues (such as ['25I-TyrS]BK) (Odya and Goodfriend, 1973), binding was not inhibited by kininase II inhibitors, indeed it was potentiated. Binding to a Bz-site was confirmed, since the Brsite ligand [des-Argg]-BK did not displace bound ligand (Odya et al., 1980). In 1981, Innis et al. introduced [3H]-BK as a simple radiolabel for bradykinin Bz receptors. Radiolabelling was achieved by tritium exchange of [p-chlorophenyl-alanineS'8]-BK which resulted in a specific activity of 12.2Cimmol-'; and despite being of lower specific activity than the iodinated ligands described above, it was found to be a suitable ligand for detectable labelling of saturable, high affinity binding to crude membrane preparations of guinea-pig and rat tissues. 4.3.2. Characteristics of BE Receptor Binding Sites The majority of subsequent B2-site radioligand binding studies have been carried out using [3H]-BK as the preferred radiolabel, although some very recent studies have reverted to using the higher specific activity [1/5I-Tyr]-BK conjugated ligands (see Table 6). Bradykinin receptor binding is normally defined as being to the Bz receptor site in cases where the B~ receptor ligands [des-Argg]-BK and/or [LeuS,des-Argg]-BK do not displace bound radioligand. Saturable, highaffinity, B2-receptor binding has been demonstrated in solubilized membrane preparations (epithelial, cardiac muscle, intestinal, tracheal and uterine smooth muscle; various brain regions) and cell lines maintained in culture (endothelial, epithelial, neuronal, smooth muscle and fibroblast) and whole tissues (airways). Although direct comparison of data obtained in various studies is compromised by methodological differences, in particular the radiolabel used, some generalities may be discussed. The majority of studies, using radiolabelled bradykinin, identify a single, saturable binding-site, though several studies have reported the presence of a second site and the affinity of bradykinin between tissues and species is variable (Table 6). Two binding-sites were first described by Reissmann et al. (1977) and later by Odya et al. (1980) and have since been identified in the guinea-pig ileum, kidney and

[3H]-BK [3H]-BK

Ileum longitudinal smooth muscleg Ileum circular smooth muscle g

[3H]-BK

[3H]-BK [3H]-BK [ lz5i_Tyr8]-BK [ 125i_Tyr8]-BK [ 3H]-BK [3H]-BK [3H]-BK [3H]-BK [3H]-BK [125I_Tyr]_[X]_BKc

(whole) (whole) smooth muscle epithelium (whole) longitudinal smooth muscle circular smooth muscle mucosa (whole) (whole)

Ileum epithelium

Ileum Ileum Ileum Ileum Ileum Ileum Ileum Ileum Ileum Ileum

[ 3H]-BK

[3H]-BK [3H]-BK

Duodenum (whole) Uterine myometrium

Guinea-pig Ileum (whole)

[125i_Tyr0]_BK [ 3H]-BK [ 125 Tyr]-BK

Ligand

Renal mesangial: cells/cultured/cloned cell line Cortical astrocytes: cultured Brain (embryonic): cultured

Rat

Tissue

16a 289 b 92 20 1800 1600 18 21 20 18 5000 13 910 16,800 18,500 172 191

244a 266b 38 6 58 156 220 182 209 241 25 8 14 2080 2290 341 391

43 58 248

1000

16,000 1000 16 1000

88 352 100

Receptor density (pmol/g)

2000 16,600 1000

Affinity (pM)

Ransom et al., 1992b Ransom et al., 1992b

Tousignant et al., 1992

Farmer et al., 1989b Sharif and Whiting, 1991 Tousignant et al., 1991 Tousignant et al., 1991 Ransom et al., 1992b Ransom et al., 1992b Ransom et al., 1992b Ransom et al., 1992b Innis et al., 1991 Manning et al., 1986

Ransom et al., 1992a

Liebmann et al., 1987 Liebmann et al., 1990

Emond et al., 1990 Cholewinski et al., 1991 Lewis et al., 1985

Reference

TABLE6. Identification and Characteristics o f Bradykinin B : R e c e p t o r Binding Sites

t"

U.

[3H]-BK [3H]-BK

Brain (whole) Nasal turbinates

[3H]-BK [3H]-BK [3H]-BK [3H]-BK

Human Fibroblasts: cultured Fibroblasts: cultured Synovial cells: cultured

Others Canine tracheal epithelium: cultured

a TES buffer (pH = 6.8). bphysiologicai buffer (pH = 7.4). c[X]-BK = [ 12si.Tyr.D_Arg_Hyp3,D_Phe7,Leu 8]_BK. dBasolateral. eApicai. fWhole tissue quantitative autoradiography. gSolubilized receptor. All other studies used membrane preparations.

[3H]-BK

[3H]-BK [3H]-BK [3H]-BK

Bovine Aortic endothelial cells: cultured Uterine myometrium Pulmonary artery endothelia (BPAE): cultured

NGI08-15 (neuroblastoma X glioma)" cultured

[3H]-BK [3H]-BK

Ovine Lung Trachea

[3HI-BK [3H]-BK [3H]-BK [3H]-BK

[3H]-BK [3H]-BK

Ileum mucosa 8 Lung Trachea smooth muscle: cultured Trachea Lung f Lung

257 d 39~ 309 19,400

2200 2300

152 8 1280 >0.5~M

128 342

196 302 496 284 500 15 570 100 60

19d 0.5e 242 491

250 80

5 378 111 > 5000

1

5.2

35 12 45 8 13

1

318 8 221

Wolsing and Rosenbaum, 1991

Denning and Welsh, 1991

Roscher et al., 1990 Etscheid et al., 1991 Bathon et al., 1992

Keravis et al., 1991 Leeb-Lundberg and Mathis, 1990 Sung et al., 1988

Farmer et al., 1989b Farmer et al., 1989b

Fujiwara et al., 1988 Fujiwara et al., 1989

Ransom et al., 1992b Farmer et al., 1989b Farmer et al., 1991b Farmer et al., 1989b Mak and Barnes, 1991 Trifilieff et al., 1991

O

152

J.M. HALL

heart (Manning et al., 1986), guinea-pig lung (Trifilieff et al., 1991) and rat myometrium (Liebmann et al., 1991). A single report is available describing three binding sites in a cloned neuroblastoma cell line (N1E-115, Snider and Richelson, 1984) (see Table 6). Attempts were made by Manning et al. (1986) and Trifilieff et al. (1991) to further characterize the two binding sites in guinea-pig ileum and lung, respectively. However, these studies were unsuccessful, probably because the high concentrations of [3H]-BK used to study the low-affinity site tended to saturate the high-affinity site, compromising discrimination between the two sites. Whether these multiple binding affinities represent different receptors, different affinity states of the same receptor, or binding to non-bradykinin receptor sites (Section 7) is not clear. The presence of multiple B2-receptor binding sites is of particular interest in view of proposals of multiple B2 receptor subtypes from functional experiments (Section 4.4). Binding to peptidases is unlikely since numerous studies have shown peptidase inhibitors to be without effect on binding (e.g. Innis et al., 1981; Cholewinski et al., 1991). In relation to the possibility that apparent multiple sites represent different affinity states of the same receptor, several reports describe effects of guanine nucleotide binding proteins on binding (e.g. Leeb-Lundberg and Mathis, 1990). In particular, in NG108-15 cells guanyl-5'-yl-imidodiphosphate converted the high-affinity site into a low-affinity site with no change in total receptor number (Osugi et al., 1987); a phenomenon demonstrated in numerous other G-protein-coupled receptor systems. Displacement of B2-receptor binding by [D-PheT]-BK analogues has been demonstrated in preparations of the guinea-pig including the lung (Trifilieffet al., 1991), trachea (Field et al., 1992b), nasal turbinate (Fujiwara et al., 1989), ileum (Steranka et al., 1988; Tousignant et al., 1991) and various brain regions (Sharif and Whiting, 1991); the rat including the uterine myometrium (Liebmann et al., 1991), mesangial cells (Emond et al., 1990; Bascands et al., 1991), cerebral cortical astrocytes in culture (Cholewinski et al., 1991); bovine tissues, including aortic endothelial cells (Keravis et al., 1991). In all cases, displacement ICs0 or K~values were found to be in the nanomolar range. A recent report describes displacement studies of radiolabelled Bz-receptor antagonist binding by kinins and analogues (Tousignant et al., 1992). The tyrosine iodinated B2-selective antagonist D-Arg-[Hyp3,D-Phe7,LeuS]-BK (i.e [125I]-Tyr-D-Arg-Hyp3,D-Phe 7, LeuS]-BK) was found to specifically label two sites in guinea-pig ileum epithelial membranes, one having similar characteristics to a site previously reported by this group (Tousignant et al., 1991) using [125I-Tyr8]-BK and a second site not recognized by [~25I-TyrS]-BK. On the second site, Bz-selective agonists and B~-selective agonists and antagonists were inactive, whereas several B2-selective antagonists inhibited binding with Ki values ranging from 16 n~l (D-Arg-[Hyp3,D-PheV,LeuS]-BK) to 6607 nM (D-Arg-[Hyp3,ThiS'8,D-PheV]-BK). In view of the saturability, specificity, high affinity and reversibility, Tousignant et al. (1992) proposed the presence of a novel receptor site recognized by B2-receptor antagonist ligands. Burch and Kyle (1992) have described binding of a radiolabelled B2-antagonist (D-Arg-[3H-Pro2,Hyp3,ThiS,D-TiC,TicS]-BK) to a single site in the guinea-pig ileum (Kd = 0.15 nM).

4.3.3 Addressing the Binding P a r a d o x As discussed above, specific bradykinin receptor binding has been shown to be displaced by Bz-receptor antagonist ligands in a number of B2-receptor preparations. The rank order of affinities of the antagonist ligands in these binding studies correlate well with relative affinity estimates obtained in functional pharmacological studies. However, in absolute terms, there seems a general discrepancy, in that the antagonist affinities as determined from binding studies are higher than those determined from functional studies by a factor of 10-100-fold. The reason for this discrepancy may be attributable to the differing ionic composition of the buffers used in the functional and binding studies: for instance, monovalent and divalent cations have been shown to significantly reduce binding (e.g. Innis et al., 1981; Manning et al., 1986; Emond et al., 1990). Moreover, Ransom et al. (1992a) report that in binding studies in the guinea-pig ileum longitudinal smooth muscle, changing the buffer from one of low ionic-strength (TES) to physiological buffer, the estimated Kd for bradykinin changed from 16 to 289 pM, although the receptor number (Bmax) remained the same. Furthermore, competition experiments with a number of other bradykinin


153

agonists and antagonists revealed a ca. 20-fold reduction in apparent displacement potency when tested in the physiological buffer.

4.4. B 2 RECEPTOR HETEROGENEITY

4.4.1. B3 Receptors, or Species-Related Differences in B2 Receptor Recognition Properties? The B m receptor antagonist [LeuS,des-Argg]-BK and certain B2-receptor antagonists of the [D-PheT]-BK series were found to be relatively inactive against bradykinin-evoked contraction in the epithelium-denuded guinea-pig trachea and did not displace [3H]-BK binding in tracheal smooth muscle membrane preparations (Farmer et al., 1989b). These results were interpreted as indicating the presence of a novel receptor subtype, termed the B 3 receptor, in the guinea-pig trachea. Our own results show that some [D-PheT]-BK antagonists and also D-Arg-[Hyp3,ThiS,DTicT,OicS]-BK have low affinity in the guinea-pig trachea as compared to several B2 receptor preparations (Hall et al., 1991a; Field et al., 1992a,b). These results therefore support the proposal by Farmer et al. (1989b) of the existence of bradykinin receptors with properties different from typical B2 receptors. However, very similar antagonist affinity estimates were obtained for several B2 receptor antagonists both in the guinea-pig trachea and in an intestinal smooth muscle preparation, the guinea-pig taenia caeci (Field et al., 1992a,b), which suggests that the low affinities may be species-related. Affinity data are shown in Table 7 for [D-PheT]-BK analogues and o-Arg-[Hyp3,ThiS,D-TicT,OicS]BK in tissues taken from several species including the guinea-pig. Both series of antagonists show low affinity for bradykinin receptors in the guinea-pig as compared to the other species, highlighting the possibility that the results may reflect species differences. Species-related differences are examined in more detail in Fig. 1, where affinities for two antagonists in individual preparations are plotted against one another. The data are consistent with a fairly constant ratio of affinities of these antagonists (difference in pKB values) represented by a solid line. Of more interest is the marked common association between affinities and species (rabbit > rat > guinea-pig), suggesting the existence of species homologues of Bz receptors. In support of the original proposal of a novel B3 receptor in the guinea-pig trachea, Farmer et al. (1989b) cited lack of displacement of [3H]-BK binding by [D-PheT]-BK antagonists although binding was later shown to be displaced by D-Arg-[Hypa,ThiS,D-TicT,TicS]-BK (Farmer et al., 1991a). However, our own work has not verified the former result; using a very similar protocol, full displacement of [3H]-BK by all antagonists (including D-Arg-[Hyp3,ThiS'S,D-PheV,]-BK, D-Arg[Hyp3,D-PheT]-BK and D-Arg-[Hyp3,ThiS,D-TicT,Oica]-BK) tested was observed both in the guineapig trachea and (with very similar displacing affinities) in the guinea-pig taenia caeci (Field et al., 1992b). The reason for this discrepancy is not known. Overall, whether the properties of these B2-1ike bradykinin receptors in the guinea-pig justify the creation of a distinct receptor class needs confirmation, in particular from structural data from molecular biology studies, the successful development of selective "B3-receptor" agonist or antagonist ligands and the demonstration of both B2 and B 3 receptor types within one species.

4.4.2. Other Evidence for B: Receptor Heterogeneity Early evidence for B2 receptor heterogeneity has been discussed (Braas et al., 1988; Plevin and Owen, 1988). The existence of multiple binding sites which may indicate the presence of distinct B2 receptors was discussed in Section 4.3.2. Differences in agonist and antagonist displacement profiles do not, as yet, allow conclusions to be drawn regarding possible B2 receptor subtypes. There are a limited number of reports of binding studies with labelled antagonists and here complications appear to exist, since a binding site that recognizes only antagonists has been reported (Section 4.3.2). The B 2 receptor antagonist [ThiS'S,o-PheT]-BK may discriminate between B2 receptor subtypes. This analogue has been shown to preferentially displace [3H]-BK binding from a high-affinity site in one tissue (Trifilieff et al., 1991), but to displace preferentially from a low-affinity site in another (Liebmann et al., 1991). In guinea-pig epithelial membrane

TABLE 7. Species-Related Differences in Affinities o f Be-Receptor Antagonists

8.5 c 7.9 g

7.3 c 6.9 d

---

6.5 g

5.8 a 5.9 4 5.8 d, 6.3 h 5.6 e

-8.9 r

-10.5 b 9.9 b, 9.2 f

--

10.1 b

-7.2 r

7.2 f

-6.8 f 6.8 k 6.8 k

9.7 c, 9.7 j

8.4 f 8.8 f

8.8 f

8.4 a 8.9 a, 7.4 f, 8.4 ~ 9.4 b 8.9 f 8.8 k

aField et al., 1992a; bHall et al., 1992; CHall et al., u n p u b l i s h e d ; dBirch et al., 1991; e M a g g i et al., 1989; f R h a l e b et al., 1992; g R h a l e b et al., 1990; h B r a a s et al., 1988; ~Hock et al., 1991; J P e r k i n s et al., 1991; kRegoli et al., 1992.

8. I b 8.0 g, 7.2 b

Rabbit Iris s p h i n c t e r J u g u l a r vein

---

Human Ileum Urinary bladder 7.3 c 7.2 ¢, 6.8 d

7.1 g

Hamster Urinary bladder

Rat Duodenum Uterus

5.9 a 5.9 b 6.5 c, 5.50 6.6 ¢

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FIG. 1. Correlation of antagonist affinities. Affinities of two B2-receptor antagonists, expressed as pK B, plotted against each other for eight preparations taken from three species. The solid line is the fitted slope (b = 1.04; as compared to fl = 1.00) for the model of a constant ratio of affinities (difference in pKa) between the two antagonists. The closeness of fit in this model is given by the coefficient of linear correlation (r) of 0.96 which is highly significant (P < 0.001). The point to note is the marked association of affinity with species (rabbit _>rat > guinea-pig). The data points plotted are from the (0) guinea-pig (1, taenia caeci; 2, trachea; 3, ileum longitudinal smooth muscle), (11) rat (4, duodenum; 5, uterus), (A) rabbit (6, jugular vein; 7, iris sphincter).

preparations, [ThiS'a,D-Phe7]-BK did not inhibit binding of [12SI-Tyr]-D-Arg-[Hyp3,D-PheT,Leua]BK, although it did inhibit [125I-Tyra]-BK binding (Tousignant et al., 1992). Proposals for the existence of subtypes of the B2 receptor come predominantly from isolated tissue studies in vitro. For example, on the rat isolated vas deferens preparation, kinin agonist potency orders differ according to the response under investigation. In addition, the analogue [ThiS's,D-PheT]-BK was a full agonist in respect of the "neurogenic" (nerve-mediated) response, but a partial agonist for the "musculotropic" (direct) response, where it showed antagonist activity. The analogue [Hyp3,ThiS'S,D-PheT]-BK was more potent as an antagonist on the post-junctional response, whereas D-Arg-[Hyp3,ThiS'a,D-PheT]-BK was more potent as an antagonist at the pre-junctional site. These results have been interpreted as suggesting differences between the B2 receptors located pre- and post-junctionally in this preparation (Llona et al., 1987; Rifo et al., 1987; see Section 6.3.2), but responses were not established as being receptor mediated (Section 7). Of interest in relation to [ThiS'S,o-PheT]-BK showing apparent selectivity in the rat vas deferens and in the binding studies described above, is the finding that this analogue has differt pA2 values against bradykinin, Lys-BK and Met,Lys-BK in the guinea-pig ileum (6.3, 6.4 but 5.2 respectively; Vavrek and Stewart, 1985). Several [D-PheT]-BK antagonists were originally reported to discriminate between B2 receptors in peripheral preparations. One series of [ArgJ,D-PheT]-BK substituted antagonists including [D-NaP,ThiS'S,D-PheT]-BK appeared from functional studies to discriminate between uterine and ileum B 2 receptors and to discriminate between bradykinin receptors mediating vascular pain compared with those mediating cutaneous hyperalgesia (Steranka et al., 1988). However, antagonism by this analogue was found to be nonselective and incompatible with competitive B2 receptor interaction (Farmer et al., 1989a). Very recently, Saha et al. (1990, 1991) presented pharmacological data which they interpret as indicating the existence of multiple bradykinin receptors in opossum smooth muscle. Thus, several B2 receptor antagonists including [D-Phe7]-BK, [ThiS.8,D-PheT]-BK, Lys,Lys-[Hyp3,ThiS'S,D-Phe7]-BK and D-Arg-[Hyp3,ThP'S,D-PheT]-BK all caused contraction of the opossum longitudinal smooth muscle (Saha et al., 1990) with the most potent analogue being equiactive with bradykinin. It was suggested that these results reflect the existence of a B4 receptor type. Contraction of the opossum lower oesophageal sphincter was also considered to be a result of B4-receptor stimulation. However, in both tissues, bradykinin is only weakly active and [des-Argg]-BK, the Bcselective agonist, was slightly less active than bradykinin (Saha et al., 1991), though the B~ receptor antagonist [LeuS,des-Argg]-BK, was inactive. Further, relaxation of the

156

J . M . HALL

lower oesophageal sphincter in response to bradykinin was suggested to be mediated via B5 receptors, since Bl-selective agonists and antagonists were inactive, as were the majority of [D-PheT]-BK antagonists. However, Lys,Lys-[Hyp2,3,ThiS,8,D-PheT]-BK and Lys,Lys-[Hyp3,ThiS,S,DPhe7]-BK were quite potent antagonists (pA2 =6.9; Saha et al., 1991). Criticisms of these interpretations include: the concentration of bradykinin required to elicit any of these effects was high (> 100 nM), no cross-tachyphylaxis with bradykinin was demonstrated and no radioligand binding studies were reported. The effects observed may indicate non-receptor mediated actions of kinin analogues, or indeed to interactions with a non-bradykinin receptor (Section 7). The authors' interpretation that their observations suggest multiple receptors is premature. Activation of independent second messenger coupling pathways may give support to the proposal of discrete receptor subtypes within the same tissue. In Madin Darby Canine kidney cells, bradykinin-stimulated phosphatidylinositol hydrolysis and prostaglandin synthesis could be functionally dissociated, suggesting that bradykinin receptors are coupled to phospholipase C and phospholipase A2 via independent mechanisms (Slivka and Insel, 1988). In canine tracheal epithelial cells, independent activation of arachidonic acid release and phosphatidylinositol stimulation by bradykinin was reported. Furthermore, submucosal application of bradykinin stimulates both second messenger systems whereas mucosal application only increased arachidonic acid release. In radioligand binding studies, high-affinity binding sites are seen in apical membrane and low-affinity sites on basolateral membrane preparations. These various results could reflect the existence of two distinct receptors in canine trachealis, although B 2 receptor antagonists block both responses (Denning and Welsh, 1991). Because of likely species differences in B2 receptor recognition properties (Section 4.4.2), this proposal for multiple B2 receptors within the same species is of great interest. 4.5. RECEPTOR--EFFECTOR COUPLING MECHANISMS OF B 2 RECEPTORS B2 receptor stimulation has been linked to the activation of most identified second-messenger systems, with the notable exception of cAMP. Perhaps the most consistent finding is the stimulation of the hydrolysis of inositol phospholipids by phosphatidylinositol specific phospholipase C, with the resultant formation of inositol phosphates (notably inositol 1,4,5-trisphosphate, IP3) and diacylglycerol (see also Farmer and Burch, 1992) and consequent Ca 2+ release and protein phosphorylation. In numerous tissue types, B2 receptor stimulation is also seen to be closely associated with the release of arachidonic acid and metabolites, the eicosanoids (Mod6er et al., 1990; Farmer et al., 1991b). In the majority of cases, this effect of bradykinin appears to result as a consequence of B2 receptor activation of phospholipase A 2 (e.g. Burch and Axelrod, 1987; Slivka and Insel, 1988) though alternative sources of arachidonic acid have been suggested (Clark et al., 1986). Guanine nucleotide-binding proteins appear to couple bradykinin B2 receptors to mediate lipid hydrolysis and to eicosanoid release (Higashida et al., 1986; Burch and Axelrod, 1987; VoynoYasenetskaya et al., 1989). Furthermore, in several B2-binding studies the affinity of B2-selective agonists is decreased by guanine nucleotide analogues (see Section 4.3.2) and at picomolar concentrations bradykinin stimulates GTPase activity in myometrial membrane preparations (Liebmann et al., 1990). Confirmation of G-protein coupling to the B2 receptor comes from the recent cloning of rat and human B2 receptors which have all the characteristics of G-protein coupled receptors (see Section 4.7). G-protein sensitivity to pertussis toxin is tissue-dependent, with sensitivity to the toxin being described in some cell types (Higashida et al., 1986), though not in others (Clark et al., 1986; Fasolato et al., 1988; Voyno-Yasenetskaya et al., 1989). Direct evidence for the pertussis-toxin sensitive G-proteins in the coupling of B2 receptors to cell response has been described (Ewald et al., 1989). Here, following endogenous G-protein inactivation with pertussis toxin in rat dorsal root ganglia cells, re-addition of G~0 and G~i2 together reconstituted the ability of bradykinin to initiate Ca 2÷ currents. In contrast, in NG108 cells, pertussis-toxin insensitive G-proteins are implicated in coupling B2 receptors to phospholipase C and here Gq proteins have been shown to play a prominent role in receptor coupling (Gutowski et al., 1991). Interactions between the two main B2-receptor transduction mechanisms have been described. Thus, phospholipase C can release diacylglycerol from which arachidonic acid may be released by


157

the action of diacylglycerol lipase or monoacylglycerol lipase (see Farmer and Burch, 1992) and calcium released by products of the phosphatidylinositol pathway may be used for phospholipase A 2 activation. Recently, phosphatidylcholine-specific phospholipase C and phospholipase D/phosphatidic acid hydrolase pathways have been shown to be activated by bradykinin (Horwitz, 1991; Purkiss et al., 1991). One interesting question is, whether individual B2 receptors couple to separate and specific signal transduction pathways, or whether the same receptor is capable of activating more than one G-protein and multiple second-messenger pathways. Several studies have shown independent activation of both phospholipase C and phospholipase A2 by bradykinin within the same cell type (Burch and Axelrod, 1987; Kaya et al., 1989). It does, however, appear that more than one G-protein type may be involved in coupling B2 receptors to the same second-messenger pathway. For example, pertussis toxin caused a 30% decrease in phospholipase C activation and intracellular Ca 2÷ in Swiss 3T3 fibroblasts and NCB-20 neuronal cells (Chuang and Dillon-Carter, 1988; Fu et al., 1988). Whether different B2 receptor subtypes couple to different G-proteins and second messenger systems can only be resolved by the use of suitable receptor antagonists. There is little evidence for a direct activation of adenylyl cyclase by B2 receptor stimulation. Bradykinin increases cAMP in several tissues (Stoner et al., 1973; Brunton et al., 1976), though in the majority of cases this appears to be a secondary effect of prostaglandins (Stoner et al., 1973: Brunton et al., 1976; Burch, 1990). One notable apparent exception is the accumulation of cAMP in response to bradykinin in the rat isolated duodenum (Liebmann et al., 1987). Bradykinin has been shown to increase cGMP in several tissues (Stoner et al., 1973; Snider and Richelson, 1984). In porcine aortic endothelial cells, bradykinin is thought to increase NO which in turn stimulates soluble guanylate cyclase to increase cGMP (Boulanger et al., 1990). Here, bradykinin has been proposed to stimulate Ca2÷-influx through a direct activation of a G-protein which leads to the subsequent formation of NO (Graier et al., 1992). In many neuronal cells, electrophysiological responses have been described following B2-receptor activation, often resulting from the release of products of phosphatidylinositol hydrolysis (Miller, 1987). In numerous cells, B2-receptor activation causes membrane hyperpolarization resulting from the opening of Ca2+-activated K÷-channels, the Ca 2+ being released by IP 3 in most cell types such as in NG108-15 neuroblastoma-glioma hybrid cells (Higashida and Brown, 1986) and visceral sensory neurons of the rabbit nodose ganglion (Weinreich, 1986), though in some cell lines, extracellular Ca 2+ may also be involved (Reiser e t al., 1990). In NG108-15 neuroblastoma-glioma hybrid cell line (Higashida and Brown, 1986) and human fibroblasts (Estacion, 1991), the Ca2÷-activated K÷-channels are blocked by apamin whereas in polyploid rat glioma cells the Ca2+-activated K÷-channels are insensitive to apamin but are blocked by charybdotoxin (Reiser et al., 1990). The initial hyperpolarization is often followed by membrane depolarization (Weinreich, 1986; Higashida and Brown, 1986; Tertoolen et al., 1987). In NGI08-15 cells, this results from the inhibition of the M-current, though a further depolarization may be due to the opening of non-specific channels (Higashida and Brown, 1986). In cultured sensory neurons, a rapid inward (depolarizing) current resulting from Na ÷ entry has been reported (Burgess et al., 1989). In neuroblastoma X dorsal root ganglion neuron hybrid cells (ND7/23), B2 receptor activation is associated with increased phosphatidylinositol hydrolysis and results in an inward depolarizing current due to the opening of Ca2÷-activated C1- channels (Dunn et al., 1991). Protein kinase C activated as a result of diacylglycerol released by phosphatidylinositol metabolism has been implicated in mediating B: receptor effects in several tissues. In NGI08-15 cells, phosphorylation by protein kinase C has been suggested to cause inhibition of the M-current and the corresponding membrane depolarization following B2 receptor stimulation (Higashida and Brown, 1986). In the hamster cheek pouch microcirculation, protein kinase C inhibitors attenuated B2-mediated formation of leaky sites (Murray et al., 1991). In the rabbit jugular vein (Calixto and Medeiros, 1991) and circular muscle of the guinea-pig ileum (Calixto and Medeiros, 1992b) protein kinase C has also been implicated in contributing to smooth muscle responses. In murine 3T3 cells, Issandou and Rozengurt (1990) have shown bradykinin to stimulate the transient phosphorylation of a cellular protein known to be a specific substrate for protein kinase C and here phorbol ester down-regulation of protein kinase C abolished the bradykinin stimulation of phosphorylation.

158

J.M. HALL 4.6. REGULATION OF B 2 RECEPTOR DENSITY

Several reports describe altered expression of bradykinin receptors by oncogenes. For example, in several cultured cell lines, transfection with the ras oncogene increases the number of receptors present on the cell surface (Parries et al., 1987; Downward et al., 1988). The oncogene dbl has also been shown to increase expression of bradykinin receptors (Ruggiero et al., 1989). The mechanism for the oncogene-induced increase in bradykinin binding is unknown, though transformation per se does not appear to be the reason (Downward et al., 1988; Ruggeriero et al., 1989). In human synovial tissue in culture, B2 receptors are present at a higher density in IL-1 treated cells than in control cells. Further, a higher density of B: receptors are found in intact rheumatoid than in osteoarthritic synovia (Bathon et al., 1992). Decreases in apparent bradykinin receptor number have been reported. For example, in waterdeprived rats, or those fed on a low salt diet, bradykinin receptor number in glomeruli cells was significantly reduced (Emond et al., 1989). Because renal kallikrein (and presumably kinin level) was increased, it was suggested that the change in receptor density represented a ligand-induced down regulation in response to bradykinin. Such a mechanism of receptor regulation is supported by functional and radioligand binding studies (Roberts and Guillick, 1989; Wolsing and Rosenbaum, 1991) and may be associated with internalization of the bradykinin-receptor complex (Roscher et al., 1990). In one study, steroid hormones were found to decrease receptor density (Roscher et al., 1990), though in another study, sex hormones altered affinity rather than receptor density (Weinberg et al., 1976). 4.7. MOLECULAR CHARACTERIZATION OF B 2 RECEPTORS 4.7.1. Cloning and Expression Studies The successful expression of mammalian Bz receptors was first described by Mahan and Burch (1990) (see also Farmer and Burch, 1992). Here, mRNA from murine Balb/c3T3 fibroblast clone SV-T2 was injected into Xenopus oocytes preloaded with 45Ca. Bradykinin increased 45Ca-efflux (ECs0 = 15 riM) and IP3 accumulation. These effects were not inhibited by the Bt receptor antagonist [LeuS,des-Argg]-BK, but were inhibited by the B2-receptor antagonist o-Arg-[Hyp3,D-PheT]-BK. The approximate size of the mRNA was 4.5 Kb. In 1992, Phillips et al. described expression of functional bradykinin receptors in Xenopus oocytes, with mRNA prepared from cultured cells and various tissues. Biological responses were measured in terms of membrane current under voltage-clamp. The mRNA obtained from rat uterus, human fibroblast cell line WI38 and NG108-15 cells yielded similar responses to bradykinin, as did total mRNA from dorsal root ganglion neurons; however, no responses were obtained in oocytes injected with rat brain mRNA. Of particular relevance, the B2-receptor antagonist D-Arg-[Hyp3,ThiS,D-Tic7,Oicg]-BK blocked responses to bradykinin with all tissue mRNA, whereas the B~-selective antagonist [LeuS,des-Argg] BK was inactive, except with W138 cell mRNA which was, therefore, proposed to encode both B t and B2 receptors (Section 3.7). An increase in the size of the response from NG108 and uterine mRNA was obtained following enrichment of the receptor-encoding mRNA following sucrose density-gradient centrifugation and a size of 4.5 Kb for the rat uterus and NG108 receptor mRNA was estimated, in agreement with the studies on the murine fibroblast clone discussed above. Cloning of the genes and expression of the B2 receptor from rat uterus was described in 1991 (McEachern et al., 1991). The B2 receptor belongs to the seven transmembrane-domained G-protein-coupled super family and has a predicted sequence of 366 amino acids and a MW of 41,696 Da. This predicted sequence contains putative sites for protein kinase C and protein kinase A phosphorylation. The expressed receptor is not stimulated by the B~ receptor agonist [des-Argg] BK, though it is activated by both bradykinin and Lys-BK (ECs0 = 3 nM). Generally lower levels of mRNA encoding the B2 receptor was found in other rat tissues, including the heart, brain, ileum, lung, kidney, testis and vas deferens. The potential for expression of multiple receptor forms was suggested by the occurrence of multiple message species. Very recently, Hess et al. (1992) reported the successful cloning and pharmacological characterization of a human bradykinin B2 receptor gene. The receptor gene was cloned from lung fibroblast


159

cell line (CCD-16Lu). The cDNA was found to encode a 364 amino acid protein, having characteristics of a G-protein coupled seven transmembrane domained receptor. The predicted amino acid sequence has 81% identity to the rat uterus B2 receptor described by McEachern et al. (1991). The most striking difference between the rat and human receptor is a two amino acid deletion that occurs in the N-terminal region of the human receptor. Transfection of the human clone into cos-7 cells resulted in specific [3H]-BK binding sites (Kd = 0.13 riM). Importantly, both D-Arg-[Hyp3,ThiS'8,D-PheT]-BK and o-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK, two B2 receptor antagonists, had high affinity (ICs0s were 27 nM and 65 pM, respectively) while the Bl-selective ligands [des-Argg]-BK and [LeuS,des-Argg]-BK were inactive. At high bradykinin concentrations, there was evidence for a second low affinity binding site (Kd > 10 riM), which may have represented the low affinity form of the expressed B2 receptor. Three potential sites of N-glycosylation are present in the rat receptor (McEachern et al., 1991) and are conserved in the human form (Hess et al., 1992). The sequence also contains several consensus sites for protein kinase A- and protein kinase C-dependent phosphorylation, which may be involved in desensitization. Expression of the cloned B2 receptor in human tissues showed highest levels in the kidney, uterus and lung, with lower levels of expression in the testis, pancreas, brain and heart; a similar distribution to that seen with the cloned rat receptor. Now that two sequences are known, cloning from a number of other tissues can be confidently expected and this will shed light on species differences and heterogeneity of bradykinin receptors. 4.7.2. Receptor Isolation Studies Solubilization of bradykinin receptors has been attempted in uterus (Fredrick and Odya, 1987) and NG 108-15 neuroblastoma-glioma cells (Snell et al., 1990) with a fairly low yield. An increased yield (70%) was obtained in cultured human foreskin fibroblasts using 3-[(3-cholamidopropyl)dimethylammonio]-l-propane sulfonate (CHAPS; Faussner et al., 1991). Bradykinin bound to the solubilized receptor with an affinity (Kd) of 1.68 nM and the potency order for displacement by bradykinin analogues was similar to that obtained in intact fibroblasts. Gel filtration gave an apparent MW of 250,000 for the solubilized receptor complex (Faussner et al., 1991). CHAPS was also used to solubilize bradykinin receptors in guinea-pig ileum, mucosa and longitudinal and circular smooth muscle with an approximately 80% yield. In all these tissues, [3H]-BK bound to a similar site, but with a 10-fold lower affinity than in membrane preparations (Ransom et al., 1992b). 4.8. DISTRIBUTION OF B 2 RECEPTORS Bradykinin B2 receptors have been identified by pharmacological and/or radioligand binding studies in most tissue types (see Section 6). Of particular interest is the autoradiographic localization of B2 receptors to nociceptive pathways (Steranka et al., 1988), which reinforces the proposed role of bradykinin as a pain mediator signalling cell damage (see Section 6.5). 4.9. SUMMARYOF n 2 RECEPTOR CHARACTERISTICS B2 receptors have a widespread distribution which is consistent with the multitude of biological effects that have been attributed to this receptor type. B2 receptors were originally identified by the lack of agonist or antagonist effect of BI receptor selective ligands (e.g. [des-Argg]-BK and [LeuS,des-Argg]-BK). But this evidence should be taken in conjunction with high potency for the B2-selective agonists ([Hyp3,Tyr(Me)8]-BK) and by antagonism with B2-selective antagonists (e.g. D-Arg-[Hyp3,D-PheT]-BK, D-Arg-[Hyp3,ThiS'S,D-PheT]-BK, D-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK). B2 receptors can be successfully radiolabelled using [3H]-BK or [t25I]-conjugated ligands and, in general, relative binding activities correlate well with data obtained in functional experiments using isolated tissue. Subtypes of the B2 receptor probably exist, since there are significant differences in the affinities of B2 receptor antagonists in functional experiments in different tissues; further, multiple bradykinin binding sites have been reported. However, the evidence at present suggests that these differences are related, at least in part, to between-species variations in B2 receptors. The Jlrf 56/2---C

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ubiquitous distribution of the B 2 receptor and the numerous roles proposed for this receptor type, means that the therapeutic potential for B2 receptor antagonists is high. 5. NON-B1/B2 RECEPTORS A third type of bradykinin receptor has been proposed in the perfused microvasculature of the guinea-pig hind brain. Here, the B~-selective agonist [des-Arg9]-BK was inactive and the B2-selective agonist [Tyr(Me)S]-BK was a partial agonist. Bradykinin-evoked vasoconstriction was attenuated by the B~-selective antagonist [LeuS,des-Arg9]-BK but also by the B2-selective antagonist D-Arg[Hyp3,D-PheT]-BK (Cohen-Laroque et al., 1990). Both bradykinin and [des-Argg]-BK increase cGMP levels in cultured bovine aortic endothelial cells. The response to [des-Arg9]-BK was inhibited by [LeuS,des-Arg9]-BK and D-Arg-[Hyp3,ThiS,D TicT,Oic8,des-Arg9]-BK; whereas the responses of both bradykinin and [des-Arg9]-BK were inhibited by D-Arg-[Hyp2,ThiS'8,D-Phe7]-BK and D-Arg-[Hyp3,ThiS,D-TicT,Oic8]-BK (Wiemer and Wirth, 1992; Wirth et al., 1992). The authors suggest that these responses are mediated via an interaction with unusual bradykinin receptors. In serum starved rat mesangial cells in culture, [des-Argg]-BK stimulates DNA synthesis. Surprisingly, bradykinin and Lys-[des-Arg9]-BK are ineffective. The [des-Arg9]-BK effect was partially inhibited (ca. 40%) by the B~ receptor antagonist [LeuS,des-Arg9]-BK, though also by several B2 antagonists. In these cells, the effects of [des-Arg9]-BK may be due to an interaction with a non-B~ o r B 2 receptor, though a direct activation of G-proteins has been suggested (Section 7) (Issandou and Darbon, 1991).

6. BRADYKININ RECEPTORS--PHYSIOLOGY, PATHOPHYSIOLOGY AND THERAPEUTICS Convincing evidence for the involvement of kinins and their receptors in physiology and pathophysiology is now possible with the advent of bradykinin receptor antagonists, particularly of the B2-type. Of greatest interest is the application of bradykinin receptor antagonists in vivo, where their effects on endogenously released kinins can be investigated. 6.1.

GASTROINTESTINAL SMOOTH MUSCLE

Kinins have diverse actions on gastrointestinal smooth muscle causing relaxation and/or contraction which may involve the release of other mediators such as prostaglandins or autonomic neurotransmitters. These effects result from an interaction with either or both B~ and B2 receptors. Examples of the better characterized actions of the kinins on specific gastrointestinal smooth muscle types will be considered individually. 6.1.1. Guinea-pig Ileum The contractile response of the guinea-pig isolated ileum has been used as a primary assay in the study of kinin actions, mechanisms and receptors and for the screening of putative antagonists. This was one of the original preparations demonstrating kinin bioactivity (Rocha e Silva et al., 1949) (see Section 1). Contractility and radioligand binding (Section 4.3.2) studies suggest that the smooth muscle of the guinea-pig ileum contains principally receptors of the B2-type. No studies to date have reported agonist or antagonist activity of B1 receptor selective agonist or antagonist agents. Typical pA~ estimates for [D-PheT]-BK antagonist analogues are in the range 5.5~.4 and for D-Arg[Hyp3,ThiS,o-Tic7,OicS]-BK, 8.4-9.4 (see Table 5 and Section 4.2). The predominant action of bradykinin on the guinea-pig ileum smooth muscle is contraction of the longitudinal smooth muscle; an initial relaxant response may predominate in precontracted tissues (Hall and Bonta, 1973). Moreover, bradykinin is able to release acetylcholine from the guinea-pig ileum via an indomethacin-sensitive process (Goldstein et al., 1983; Yau et al., 1986) and B 2 receptor activation


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results in a biphasic response (contraction followed by relaxation) of the circular smooth muscle (Calixto and Medeiros, 1991). Coupling of bradykinin receptors to contraction in the longitudinal smooth muscle of the guinea-pig ileum involves the hydrolysis of phosphatidylinositol (Hall, 1990; Ransom et al., 1992a). In an elegant recent study, bradykinin and several agonists were shown to cause a concentrationrelated increase in [3H]-inositol monophosphate accumulation. The effect of bradykinin (ECs0 = 13 nM) was inhibited in a concentration-related manner by various B2 receptor antagonists with an order of potency similar to that reported for displacement of specific [3H]-bradykinin binding. In relation to B l receptors, [des-Argg]-BK (10/~M) was inactive at stimulating phosphatidylinositol hydrolysis and [LeuS,des-Argg]-BK (10~tM) did not inhibit bradykininstimulated phosphatidylinositol hydrolysis; neither B~-selective ligand displaced [3H]-BK binding (Ransom et al., 1992a). 6.1.2. Guinea-pig Taenia Caeci The taenia of the guinea-pig caecum responds to bradykinin with an initial relaxant response followed by a delayed contractile response. Radioligand binding studies identify a single binding site for [3H]-bradykinin in membrane preparations of the smooth muscle (Field et al., 1992b), which suggests that the same receptor type, or receptor types with similar recognition properties, are involved in mediating both phases of the response. The recognition characteristics of the receptor(s) involved in the two phases are of the B2 rather than the B 1 receptor types, since the Bl-selective ligands [des-Argg]-BK and [Leua,des-Argg]-BK are inactive in functional studies (Den Hertog et al., 1988; Field et al., 1988, 1992a) and do not displace [3H]-BK binding from taenia caeci membrane preparations (Field et al., 1992b). On the other hand, B2 receptor antagonists inhibit both phases of the bradykinin response with a similar affinity (Fig. 2; also see Section 4.4.1 in relation to the "B3" receptor). The mechanism underlying the two phases of the response to bradykinin has been investigated. Ion substitution and electrophysiological studies describe an initial Ca2÷-dependent hyperpolarization associated with a membrane conductance increase (Den Hertog et al., 1988). The initial relaxant response involves the opening of apamin-sensitive Ca~+-activated K÷-channels (Gater et al., 1985; Carter et al., 1986). The initial hyperpolarization is followed by depolarization, which appears to involve the opening of ligand-gated Na÷-channels (Aarsen and van Caspel-De Bruyn, 1970; Aarsen, 1977; Den Hertog et al., 1988). This increase in Na+-permeability most probably underlies the depolarization associated with the contractile phase of the response to bradykinin. Calcium release from intracellular stores apparently provides calcium for the initial hyperpolarization and probably contributes to the later contraction (Den Hertog et al., 1988). Bradykinin stimulates hydrolysis of phosphatidylinositol in the taenia caeci (Hall, 1990; Field et al., 1992c). It is therefore likely that production of IP 3 leads to mobilization of Ca 2÷ from intracellular stores and this increase in [Ca2+]i opens Ca2÷-activated K÷-channels resulting in membrane hyperpolarization. With the continued elevation of [Ca2+]i and entry of Ca 2÷ via voltage-operated Ca2÷-channels (following bradykinin-gated depolarization via Na÷-channel opening), there follows a delayed contraction. The hydrolysis of phosphatidylinositol seems to be causally associated with B2 receptor activation, since the log-concentration-response curve for accumulation of inositol phosphates is shifted to the right in a parallel manner by the B2 receptor antagonist D-Arg[Hyp3,ThiS,o-TicT,Oicg]-BK with similar affinity to that obtained in functional studies for either relaxation or contraction (Field et al., 1992c; Fig. 2). 6.1.3. R a t Duodenum The predominant and best characterized, response of the rat isolated duodenum to bradykinin is relaxation. This response, however, is changed into a biphasic response (relaxation followed by contraction) by lowering the Ca2+-concentration (Antonio, 1968); and a contractile response to bradykinin can be elicited under normal conditions with a higher concentration ( > 10 nt,l) (Faber and Van der Meer, 1973), or if tissues from spontaneously hypertensive rats are used (Feres et al., 1992). The two phases seem to be due to a direct action on the smooth muscle (Antonio, 1968;

J. M. HALL

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FIG. 2. Recognition properties of bradykinin receptors mediating functional responses to bradykinin in the guinea-pig taenia caeci: characterization with B2-receptor antagonists. (A) Control (0) contractile and relaxant responses to bradykinin in Krebs' solution are inhibited by the B2-receptor antagonist D-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK32 n~ (A), 100 nM (11) and 320 nM (V). (B) Bound [3H]-bradykinin is displaced by bradykinin (O), D-Arg[HypJ,ThiS,D-TicT,OicS]-BK (11), D-Arg-[Hyp3,D-PheT]-BK, (A) and D-Arg-[Hyp3,ThiS'S,DPheT]-BK, (V). (C) Membrane potential-independent control contractile responses to bradykinin in high-K+-containing medium (0) are inhibited by D-Arg-[Hyp3,ThiS,DTicV,OicS]-BK (32 riM) (m). (D) Bradykinin-stimulated accumulation of total [3H]-inositol phosphates (PI turnover; (0)) is inhibited by D-Arg-[Hyp3,ThP,D-Tic7,OicS]BK(32 nM) (11). (For methods, see Field et al., 1992a,b; Hall and Morton, 1991b.)

Ufkes and Van der Meer, 1975). In contrast to the guinea-pig taenia caeci as discussed above, it has been suggested that the two phases of the response are mediated by distinct receptor types (Boschcov et al., 1984), though binding studies have only identified a single site for bradykinin in this preparation (Liebmann et al., 1987). The relaxant response is a consequence of B2 receptor stimulation since it is inhibited by the B2 receptor antagonists Lys,Lys-[Hyp3,ThiS'S,D-PheT]-BKand D-Arg-[Hyp3,ThP,D-Tic7,OicS]-BK in a competitive manner with pA 2 estimates of 7.3 and 10.1, respectively (Hall and Morton, 1991a; Hall et al., 1992). The relaxation involves the opening of Ca2÷-activated K÷-channels since bradykinin increased efltux of 86Rb from K÷-depolarized duodenal longitudinal smooth muscle in a concentration-related manner. These increases in K+-permeability were inhibited by the B2 receptor antagonist Lys,Lys-[Hyp3,ThP'8,D-Phe7]-BK and also by the Ca2÷-activated K÷-channel blocker apamin. Apamin also inhibited the relaxant response to bradykinin in normal solution (Hall and Morton, 1991a; Fig. 3). The relaxant response to bradykinin is lost in high K÷-containing medium (Antonio, 1968; Hall and Morton, 1991a) which favours a voltage-dependent mechanism of action rather than an increase in cAMP (Paegelow et al., 1977; Liebmann et al., 1987), since fl-adrenoceptor activation elevates cAMP and can still relax gastrointestinal smooth muscle in a high-K + medium (Jenkinson and Morton, 1967). In contrast to relaxant responses, the contractile response is resistant to antagonism by first generation B2 receptor antagonists (Pereira and Paiva, 1989). Early studies suggested that these contractile responses were mediated via an interaction with B mreceptors, since the Bl-selective

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FIG. 3. Bradykinin-evoked efflux of 86Rb from rat duodenum longitudinal smooth muscle strips in a high K+-depolarizing medium. Rate coefficients are shown as means (+ SE; n = 7) and the application of bradykinin (BK 1 #M; 9 min) is shown by the horizontal bar. (A) Control preparations. (B) Preparations in the presence of the Ca2÷-activated K+-channel blocker apamin (100 nM). (C) Preparations in the presence of the B2-receptor antagonist Lys,Lys[Hypa,ThiS's,D-Phe7]-BK (1 gM). Significant increase from control for a given time period is shown as * = P < 0.05. For methods, see Hall and Morton (1991a). Reprinted from Hall and Morton (1991) with permission of the copyright holder Elsevier Science Publishers, Amsterdam. agonist [des-Arg9]-BK elicits only contraction (Boschcov et al., 1984; Paiva et al., 1989). Furthermore, contractile responses to [des-Argg]-BK increase with time by 3.7-fold after 8 hr tissue incubation (Altinkurt and (3ztiJrk, 1990). However, the Bl-receptor antagonist [LeuS,des-Argg]-BK also causes a contractile response in this preparation which has led to the suggestion that B~ receptor mediating contraction is of a subtype distinct from previously described Bl receptors (Paiva et al., 1989). 6.1.4. Other Intestinal Smooth Muscle Preparations

Bradykinin has a weak contractile effect in the longitudinal strip of the rat colon, which is predominantly mediated by B2 receptors; although B~ receptor responses may be induced in vitro (Couture et al., 1982). In the rat ileum, the contractile effect of bradykinin acting on the mucosal surface of the isolated perfused tissue involves prostaglandin synthesis (Walker and Wilson, 1979). Bradykinin causes a biphasic response in the rabbit isolated ileum (t0fkes and Van der Meer, 1975) and the relaxant action is associated with the opening of Ca2+-activated K÷-channels (Gater et al., 1985). The rat isolated stomach fundus also responds in a biphasic manner (contraction followed by relaxation) to bradykinin (Calixto and Madeiros, 1992a). Strips of the human isolated colon contain BI receptors (Couture et al., 1981). Bradykinin, at relatively high concentrations, causes a direct biphasic (relaxation followed by contraction) response of the lower oesophageal sphincter

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J.M. HALL

and contraction of the oesophageal longitudinal muscle. The relaxant response is blocked by apamin and the contraction of both the longitudinal muscle and the lower oesophageal sphincter by the Ca2+-channel blocker nifedipine (Saha et al., 1990, 1991). Overall, although there is abundant evidence showing bradykinin to be potent and varied in its actions on gastrointestinal smooth muscle motility, there is limited direct evidence for a physiological or pathophysiological role for kinins in the control of gastrointestinal motility. However, where there is increased production of kinins in inflammatory conditions, there are likely to be accompanying changes in motor activity. 6.2. EPITHELIAL ION TRANSPORT

6.2.1. Intest&al Preparations Kinins have potent effects on intestinal electrolyte transport processes and may contribute to conditions such as inflammatory bowel disease (Zeitlin and Smith, 1973). Kinins stimulate chloride secretion in the guinea-pig ileum (Gaginella and Kachur, 1989) and the receptors mediating this response have been localized to the mucosa. Radioligand binding studies (Manning et al., 1982) and functional studies indicate that the receptors are of the B2-type, since kinin responses are blocked by the first generation B2-receptor antagonist [D-PheT]-BK but not by the B~-receptor antagonist [Leu8,des-Argg]-BK (Gaginella and Kachur, 1989; Kachur et al., 1987). Furthermore, the Brselective agonist [des-Argg]-BK does not stimulate electrolyte transport across the ileum mucosa (Kachur et al., 1987; Manning et al., 1982); and specific binding of [3H]-BK is displaced by BE- but not Bj-selective ligands (Manning et al., 1982). In both guinea-pig (Musch et al., 1983) and rabbit (Hojvat et al., 1983) ileal mucosa, prostaglandins are involved in responses to bradykinin. In rat colonic epithelium preparations devoid of submucosal layers, a biphasic transport response to kinins is observed (Perkins et al., 1988). The first phase of the current-flow represents a net secretion of CI- ions from the basolateral to apical side (Cuthbert and Margolius, 1982; Manning et al., 1982). The second phase of C1--efflux appears to be an effect of kinins on capsaicin-sensitive nerve terminals within the epithelium (Perkins et al., 1988). Prostaglandins, principally released from cells in the sub-epithelial (lamina propria) layer, contribute to the kinin response (Phillips and Hoult, 1988). Receptors mediating secretion in these in vitro models are of the B2-type, since kinin effects on short-circuit current are antagonized by the B2 receptor antagonist D-Arg-[Hyp3, ThiS'8,D-Phe7]-BK (Baron et al., 1987). In contrast, in vivo instillation of acetic acid into the rat colon to produce inflammation, results in a 100% increase in the B~-mediated ([des-Argg]-BK) response on mucosal Cl--secretion (Kachur et al., 1986). 6.2.2. Gall-bladder In animal models of gallstone-induced cystic duct obstruction, net fluid secretion is characteristic (Svanvik et al., 1981). In the guinea-pig gall-bladder, kinins stimulate bicarbonate secretion (Baird and Margolius, 1989), an effect enhanced by peptidase inhibitors (Woods and Baird, 1992). The principal site of action is likely to be in the epithelial layer since in the voltage-clamped gall-bladder, bradykinin is more potent when applied mucosally than serosally and the kinin effect is dependent on prostaglandin production (Baird and Margolius, 1989). 6.2.3. Respiratory Tract Specific binding sites for bradykinin are present in canine isolated mucosa epithelial cells and bradykinin stimulates Cl--secretion and PGE2 release in this tissue (Leikauf et al., 1985). The effect of kinins on transmembrane ion-conductance is inhibited by the B2 receptor antagonist o-Arg[Hyp3,ThiS's,D-PheT]-BK and Bt-selective ligands are inactive, suggesting the involvement of B 2 receptors (Rangachari et al., 1990). The presence of two distinct types of B2 receptor in canine epithelial cells is discussed in Section 4.4.2.


165

6.3. UROGENITALTRACT 6.3.1. Urinary Bladder Both B1 and B2 receptor stimulation cause contraction of the rat urinary bladder (Marceau et ai., 1980) and bradykinin potentiates electrical sympathetic nerve-mediated contractile responses and ATP-mediated contractions. These latter two effects were inhibited by the B2 receptor antagonist n-Arg-[Hyp3,ThiS'8,o-PheT]-BK (Acevedo et al., 1990). The guinea-pig isolated urinary bladder contracts in response to B2 receptor stimulation via an indomethacin-sensitive mechanism (Maggi et al., 1989; Hall et al., 1992). Bradykinin has been shown to increase the release of calcitonin gene-related peptide-like immunoreactivity, presumed to be from capsaicin-sensitive primary afferents from guinea-pig bladder preparations (Maggi et al., 1989). Bradykinin also relaxes the carbachol-precontracted guinea-pig urinary bladder preparation and this effect is blocked by the BE receptor antagonist and by the Ca2+-activated K+-channel blocker apamin (Maggi et al., 1989). The canine and hamster urinary bladders contain B2 receptors (Regoli et al., 1986a; Rhaleb et al., 1990b). 6.3.2. Vas Deferens The in vitro sympathetic-nerve field-stimulated rat vas deferens preparation responds to bradykinin with an increase in twitch height (neurogenic effect) and a rise in basal tone (musculotropic effect); the epididymal section of the vas deferens has been used to evaluate post-junctional and the prostatic section pre-junctional actions of bradykinin (Huidobro-Toro et al., 1986; Llona et al., 1987; Tousignant et al., 1987). In the rat vas deferens, bradykinin-evoked an increase in [3H]-overflow in [3H]-noradrenaline-loaded prostatic sections and contraction of the epididymal sections following neuronal denervation (Llona et al., 1987, 1991); and in sympatheticallydenervated preparations, bradykinin potentiates ATP-evoked, but not noradrenaline-evoked contractions by acting post-junctionally (Donoso and Huidobro-Toro, 1989). B t receptors do not contribute to these responses (Llona et al., 1987). It has been proposed that different B2 receptors are located pre- and post-junctionally in this preparation (see Section 4.4.1). In the mouse vas deferens, bradykinin increases [3H]-overflow in the [3H]-noradrenaline preloaded preparations (Llona et al., 1991) and in the guinea-pig vas deferens, bradykinin potentiates the twitch response to sympathetic nerve stimulation (Zetler and Kampmann, 1979). 6.3.3. Uterus and Ovary Whalley (1978) showed that the contractile response to bradykinin of the rat uterus in estrous is due to a direct action on the smooth muscle and an indirect effect involving prostaglandin release from the endometrium. The contractile response is mediated by B2 receptors since D-Arg[Hyp3,ThiS,o-Tic7,OicS]-BK and [D-PheT]-BK analogues block the response (Birch et al., 1991; Perkins et al., 1991). The isolated rat uterus preparation was one of the three key screening assays used in the development of peptide B2 receptor antagonists (Section 4.2.2) and non-peptide antagonists (Section 4.2.5). Two binding sites have been reported in bovine and rat myometrium (Odya et al., 1980; Fredrick et al., 1984; Liebmann et al., 1991). Recently, the B2 receptor of the rat uterus has been cloned (Section 4.7.1). It has been suggested that kinins contribute to the contractile effect of glandular kallikrein in the rat isolated uterus, since both bradykinin and kallikrein cause contraction and these effects are inhibited by D-Arg-[Hyp3,D-Phe7]-BK (Orce et al., 1989). In the perfused rabbit ovary in situ, bradykinin or human chorionic gonadotrophin-induced ovulation is inhibited by [ThiS'8,D-Phe7]-BK (but not D-Arg-[Hyp3,o-PheT]-BK). These results suggest a role for kinins in follicle rupture during ovulation (Yoshimura et al., 1988). 6.4. RESPIRATORYTRACT One of the earliest identified biological effects of pure bradykinin was bronchoconstriction (Collier et al., 1960) and kinins have been implicated in the pathogenesis of inflammatory diseases

166

J.M. HALL

of the airways for many years. Inhaled bradykinin (Herxheimer and Stresemann, 1961) and i.v. bradykinin (Newball et al., 1975) cause transient bronchoconstrictor responses in human asthmatic, but not normal, subjects. Also in the upper airways, irrespective of atopic state, bradykinin induces symptoms of sore throat and rhinitis (Proud et al., 1988). Furthermore, increases in systemic or local components of the kinin-generating system correlate with the associated symptoms of rhinitis (Proud et al., 1983; Pongracic et al., 1991a) and asthmatic attacks (Abe et al., 1967). The background knowledge and recent evidence for a role of kinins in control of airways function has been reviewed extensively (Collier, 1970; Farmer, 1991a,b; Pongracic et al., 1991a). This discussion, therefore, is restricted to studies investigating the receptor types involved in the various effects of kinins in the airways. In this area of kinin research, bradykinin antagonists have now reached the stage of clinical evaluation. 6.4.1. L o w e r A i r w a y s and A s t h m a Kinins have potent effects in the lower airways of most species tested, resulting in bronchoconstriction and stimulation of sensory nerves, increased mucus secretion and promotion of airways microvascular leakage with oedema formation (see Barnes et al., 1988). Bradykinin receptor antagonists may therefore have a role in the prophylaxis of bronchial asthma. In the airways of several species, specific bradykinin binding is displaced by B2 receptor but not Bj receptor selective ligands (Field et al., 1992b; Trifilieff et al., 1991; but see Section 4.4.1). Autoradiographic studies have demonstrated bradykinin binding in guinea-pig and human lung with dense labelling over pulmonary and bronchial blood vessels, the lamina propria immediately subjacent to the basal epithelial layer in large airways and also over the smooth muscle, submucosal glands, nerve fibres and alveolar walls (Mak and Barnes, 1991). In vivo bronchoconstriction by bradykinin in most species is mediated via stimulation of peripheral endings of afferent fibres, which elicit reflex bronchoconstriction via acetylcholinerelease from post-ganglionic vagal nerve endings (Fuller et al., 1987; Ichinose et al., 1990). Using an in vitro preparation, Fox et al. (1992) have directly demonstrated that bradykinin stimulates the peripheral endings of single vagal C-fibres, but not A6-fibres in the guinea-pig trachea by a cyclooxygenase independent mechanism (Fig. 4). In vitro, in contrast to most species, bradykinin is a potent direct stimulant of guinea-pig (Collier et al., 1960; Bhoola et al., 1962; Farmer et al., 1989b) and also ferret airways smooth muscle (Kyle and Widdicombe, 1987; Farmer et al., 1992). Most in vitro studies have been carried out on guinea-pig isolated airways tissues, particularly tracheal preparations, where bradykinin causes either contraction (Bhoola et al., 1962) or, in precontracted preparations, relaxation (Mizrahi et al., 1982; Rhaleb et al., 1988). Some workers have reported an epithelium-dependent relaxation of basal tracheal tone by bradykinin (Bramley et al., 1988; Farmer et al., 1989b). Both relaxation (Bramley et al., 1988; Rhaleb et al., 1988) and contraction with low concentrations of bradykinin (Bhoola et al., 1962; Bramley et al., 1988, 1990; Farmer et al., 1989b) may involve the release of prostaglandins. In guinea-pig tracheal smooth muscle cells in culture, bradykinin elicits a concentration-related release of PGE z and the PGIz metabolite 6-keto-PGF 1~ and this is inhibited by the B2-selective antagonist o-Arg-[Hypa,o-PheT]-BK (Farmer et al., 1991b). Receptors involved in the relaxant response to bradykinin in the guinea-pig isolated trachea are not of the B~ receptor type since B~-selective ligands are inactive (Mizrahi et al., 1982). However, despite the high activity of the B2-selective agonist [Tyr(Me)8]-BK, a number of B2 receptor antagonists, including D-Arg-[Hyp3,D-PheV]-BK, D-Arg-[Hyp3,ThiS'8,D-PheV]-BK and [ThiS"8,DPheV]-BK, do not inhibit bradykinin-evoked relaxation of the precontracted tracheal preparation (Rhaleb et al., 1988). The involvement of B2 receptors in the relaxation is therefore controversial. Indeed, it has been suggested that the bradykinin-induced prostaglandin-dependent relaxant component of the response to bradykinin in the guinea-pig isolated trachea is via a non-receptor mediated mechanism (Mizrahi et al., 1982; Rhaleb et al., 1988; Regoli et al., 1990a,b; see Section 7). Bradykinin-induced contractions of the epithelium-denuded guinea-pig tracheal preparation are also insensitive to the B~-receptor selective antagonist [LeuS,des-Argg]-BK and the B~ receptor agonist [des-Arg9]-BK does not elicit contraction (Farmer et al., 1989b; Field et al., 1992a). Certain [D-PheT]-BK B2 receptor antagonists have low affinities in this preparation, but D-Arg-[Hyp3,ThiS,D-


167

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bradyldnin (0.3/~M) FIG. 4. Bradykinin excites single vagal sensory C-fibres in the guinea-pig trachea. The recording was made from a preparation of the trachea and main bronchi with attached right vagus nerve of the guinea-pig maintained in vitro. The upper panel shows C-fibre discharge in response to a 30 sec application of bradykinin (0.3/aM) directly onto the receptive field located on the epithelial surface of the trachea. In the lower panel, this information is transformed into a post-stimulus time histogram illustrating the frequency of discharge of the fibre. For methods, see Fox et al. (1992). TicT,OicS]-BK (Perkins et al., 1991; Field et al., 1992a) and D-Arg-[Hyp3,ThiS,D-TicT,TicS]-BK (Farmer et al., 1991a) do block at this site. The characteristics of the bradykinin receptors mediating contraction of this preparation are somewhat controversial and these reservations are discussed in more detail in Section 4.4.1. The stimulant effect of bradykinin in the epitheliumdenuded airway smooth muscle may have relevance to the aetiology of asthma where disruption and sloughing of airways epithelium occurs, which contributes to airways hyper-reactivity. The type of bradykinin receptors in guinea-pig airways has also been studied in vivo, where B2 receptor antagonists also have lower affinities; although the effect of B2 receptor antagonists on bradykinin-induced bronchoconstriction seems dependent on the route of administration. In the guinea-pig, i.v. bradykinin induces bronchoconstriction unaffected by the B t receptor antagonist [LeuS,des-Arga]-BK; further, the B~ receptor agonist [des-Argg]-BK is not a bronchoconstrictor. In contrast, i.v. administration of the B2 receptor antagonist D-Arg-[Hyp3,ThiS'S,D-PheT]-BK (Jin et al., 1989) at a relatively high dose and more recently D-Arg-[Hyp3,ThiS,D-Tic7,OicS]-BK (i.v. or s.c.) (Lembeck et al., 1991; Wirth et al., 1991b; Sakamoto et al., 1992), inhibit the bronchoconstrictor response to bradykinin. A partial inhibition of the effects of i.v. bradykinin on pulmonary inflation pressure by D-Arg-[Hyp3,D-Phe7]-BK has been reported. This group (Farmer et al., 1989b), however, were unable to show substantial inhibition of the effects of aerosolized bradykinin by aerosolized D-Arg-[Hyp3,ThiS'S,D-Phe 7]-BK, although weak inhibition of the effect of i.v. bradykinin with aerosolized D-Arg-[Hyp3,ThiS'S,D-PheT]-BK and D-Arg-[Hyp3,D-PheT]-BK was reported (Farmer et al., 1989b).

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In addition to the B2 receptor mediated smooth muscle effects in the airways, kinins also activate airways epithelial C1--secretion, an effect likely to involve B2 receptors (Section 6.2.3), which have been localized to epithelial cells (Leikauf et al., 1985; Mak and Barnes, 1991). Further, B2 receptors may be involved in the control of ciliary beat-frequency induced by bradykinin (Tamaoki et al., 1989). Bradykinin infused i.v. induced an increase in plasma extravasation in the rat trachea which was abolished by the B2 receptor antagonist D-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK (Lembeck et al., 199l). Bradykinin (i.v. or inhaled) causes microvascular leakage in airways of guinea-pigs, an effect inhibited by the B2 receptor antagonist D-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK (Sakamoto et al., 1992). Bradykinin has been shown to increase the release of substance P-like immunoreactivity in the perfused guinea-pig lung (Saria et aL, 1988). The allergic sheep provides a useful model for study of airways function, since it responds in a similar manner to allergic asthmatics following inhalation of Ascar suum antigen (see Abraham, 1991). In this model, it has been shown that B2 receptor antagonists inhaled, significantly inhibited bradykinin-induced neutrophil influx and bronchial hyper-reactivity and the late response to allergen challenge (Abraham, 1991; Abraham et al., 1991). 6.4.2. Upper A i r w a y s and Rhinitis There is now abundant evidence supporting a contribution by kinins in the symptoms of several types of rhinitis in man. Specific binding to B2-sites has been demonstrated in the nasal turbinate of guinea-pigs (Fugiwara et al., 1989) and man (Baraniuk et al., 1990). Kinins appear to contribute to both the initial and late phases of allergic rhinitis and in rhinitis associated with Rhinovirus (Proud et al., 1983; Nacleiro et al., 1985, 1987). Since Rhinovirus is strongly implicated in the symptomonity of the common cold, the potential use of bradykinin receptor antagonists in the treatment of the common cold is of the greatest interest. Advances in this area of kinin research has largely been a consequence of the pioneering work of Proud and colleagues, who used a sensitive lavage method which allows the estimation of concentrations of mediators present in the nasal cavity of man (Naclerio et al., 1985, 1987). The methodology and studies carried out by this group have recently been reviewed (Proud and Kaplan, 1988; Pongracic et al., 1991a) and the findings concerned with identifying the bradykinin receptors involved are summarized below. Intranasal administration of bradykinin in normal human subjects induces symptoms characteristic of rhinovirus infection, along with the associated increase in vascular permeability (Proud et aL, 1988). The receptors involved in causing these effects appear to be of the B2 receptor type since the B,-selective agonist [des-Argg]-BK does not produce any symptoms (Rajakulasingam et al., 1991). The NOVA Pharmaceutical Corporation has therefore carried out clinical trials to investigate the potential of the Bz-antagonist D-Arg-[Hyp3,D-PheT]-BK (NPC567) for the treatment of the common cold. These studies represented the first placebo controlled, double blind study of a bradykinin receptor antagonist in humans. Unfortunately, the antagonist failed to inhibit the symptoms, or the increase in vascular permeability, in response to bradykinin (Pongracic et al., 1991b) and these trials were therefore discontinued. Various explanations have been offered for the ineffectiveness of the antagonist in this system, including the inability of the antagonist to gain access to the receptors, the presence of non-B 2 receptors mediating the responses or the low affinity of the antagonist. In a further trial, the effect of D-Arg-[Hyp3,D-PheT]-BK was tested on human volunteers having Rhinovirus-induced colds. However, yet again, the antagonist was ineffective at alleviating symptoms (Higgins et al., 1990). In view of possible species differences in affinities of B2 receptor antagonists (Section 4.4.1) coupled with the paucity of studies on the human B2 receptor, the introduction of the high-affinity B2 receptor antagonist o-Arg-[Hyp3,ThiS,D-TicT,OicS]BK should help to clarify the reason for the ineffectiveness of first generation B2 receptor antagonists in the treatment of rhinitis. 6.5. PAIN AND PERIPHERAL INFLAMMATORYHYPERALGESIA

Bradykinin itself is both algesic (Armstrong et al., 1952, 1953) and hyperalgesic (Steranka et al., 1988); it is present in damaged tissues at concentrations sufficient to cause pain (Kellermeyer and Graham, 1968), and stimulates and sensitizes C- and Ar-sensory fibres that encode noxious stimuli


169

(Szolsc~inyi, 1987). Furthermore, bradykinin binding sites have been localized to neuronal pathways associated with nociception (Steranka et al., 1988). Such observations have led to suggestions of a role for locally-produced kinins at the actual site of tissue trauma in eliciting pain and associated inflammatory hyperalgesia (see Armstrong, 1970). With the availability of bradykinin receptor antagonists, their application to animal models of pain and hyperalgesia has allowed a direct test of these proposals and the investigation of the characteristics of the bradykinin receptors involved. In all cases except one (see below), the receptors involved are not of the B~-type, since Bl-selective agonists do not elicit pain or hyperalgesia and B,-receptor antagonists are ineffective at counteracting kinin-induced pain or hyperalgesia. The one exception is thermal and mechanical hyperalgesia produced during persistent inflammation in rats where the B,-selective agonist [des-Argg]-BK decreases pain threshold (Perkins et al., 1992). Bradykinin-evoked pain and hyperalgesia via B2 receptor stimulation has been demonstrated using a number of models: bradykinin-evoked pain in the human blister base (Whalley et al., 1987b); in the reflex nociceptive hypotension response to bradykinin perfused through the rabbit ear (Griesbacher and Lembeck, 1987; Lembeck et al., 1991; see Fig. 5) and in the bradykinin-elicited vascular pain and cutaneous hyperalgesia in the rat (Steranka et al., 1988). Electrophysiological studies also support a role for B2 receptors in pain and hyperalgesia. Thus,

A

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FIG. 5. Nociceptor stimulation in the rabbit. Hypotensive reflex in the anaesthetized rabbit resulting from sensory nerve activation following injection of agents into the functionallyseparated perfused ear artery with auricular nerve intact. (A) Original tracing showing the effects of acetylcholine, bradykinin in the absence and presence of the B2-receptor antagonist o-Arg-[Hyp3,ThiS.g,D-PheT]-BK and the B~-selective agonist [des-Argg]-BK. (B) Reversible antagonism of the hypotensive response to bradykinin by the B2-receptor antagonist D-Arg[Hyp3,ThiS'a,D-Phe7]-BK (32 riM). Control responses (Q), responses in the presence of D-Arg[Hyp3,ThiS.g,D-PheT]-BK(11) and responses obtained 30 min after antagonist washout (O). The figure illustrates a single representative experiment. For methods, see Juan and Lembeck (1974).

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J.M. HALL

bradykinin excites neurons in the dorsal horn of the spinal cord in the anaesthetized rat and the B2-receptor antagonist D-Arg-[Hyp3,ThiS.8,l)-Phe7]-BK (but not the B~-receptor antagonist [LeuS,des-Arg9]-BK) inhibits this response (Haley et al., 1989); bradykinin evoked responses of polymodal nociceptors in the dog testis spermatic nerve are inhibited by the first generation B2-receptor antagonist [ThiS.8,o-PheT]-BK, but not by the B~-receptor antagonist [LeuS,des-Arg9]BK (Mizumura et al., 1990) and bradykinin excites unmyelinated nociceptive afferents supplying the rat hairy skin in a saphenous nerve-skin assay (Koltzenburg et al., 1992). Bradykinin acting via B2 receptors can depolarize the central, as well as the peripheral (Dray et al., 1992) terminals of primary afferents in the rat neonatal spinal cord which suggests a possible role for locally produced kinins in central nociceptive transmission (Dunn and Rang, 1990). Of greatest interest is the use of B2-receptor antagonists against pain and hyperalgesia caused by endogenously-released kinins by pathophysiological stimuli associated with the inflammatory response. Evidence has accumulated from both electrophysiological and in vivo studies. For example, D-Arg-[Hypa,ThiS'8,D-PheV]-BK inhibited responses of dorsal horn neurons to s.c. formalin (Haley et al., 1989) and D-Arg-[Hyp3,D-PheT]-BK inhibited urate-induced hyperalgesia in the rat (Steranka et al., 1988). A recent report demonstrated inhibition of thermal and mechanical hyperalgesia by the Bj-selective antagonist [LeuS,des-Arg9]-BK though not by the B2-selective antagonist D-Arg-[Hyp3,ThiS,D-TicV,OicS]-BK (Perkins et al., 1992). The evidence for the role of B2 receptors in pain and hyperalgesia is now quite extensive and is summarized in Table 8. 6.6. INFLAMMATION

The kallikrein-kinin system participates in various facets of the acute and chronic inflammatory response. The pro-inflammatory effect of the kinin system has been extensively reviewed (Lewis, 1970; Marceau et al., 1983; Roch-Arveiller et al., 1985; Hargreaves et al., 1988; Proud and Kaplan, 1988; Bhoola et al., 1992). Also, for the role of kinins in asthma see Section 6.4.1 and rhinitis see Section 6.4.2. The application of bradykinin receptor antagonists to inflammatory conditions has recently been reviewed (Steranka and Burch, 1991). 6.6.1. B1 Receptors and Inflammation The suggestion that B~ receptors play a role in inflammation is an attractive proposition since Bl receptors are induced in response to tissue damage or noxious stimuli and by other components of the inflammatory response such as cytokines (Section 3.5.2). Since kininase I is a plasma protein, it could be present in inflammatory exudates where it might promote the production of B~ receptor stimulants locally. The intriguing possibility exists that during the inflammatory response, metabolites of kinins such as [des-Argg]-BK, which are normally inactive, can now activate B~ receptors, which may be formed as a result of tissue damage, in order to initiate local reactions involved in the inflammatory response. Interestingly, under the activation of carboxypeptidase N, both kinins and complement factor C5a are transformed into metabolites with different spectra of biological activities: an interesting hypothesis is that carboxypeptidase N generates mediators of the late phases of inflammatory responses (see Marceau et al., 1983). Furthermore, the arginine residue released from kinins by carboxypeptidase action could theoretically be used to produce NO by the NO-synthase pathway, thereby promoting inflammation by the production of this potent vasodilator. There are limited reports describing a role for B~ receptors in other models of inflammatory state. A role for B1 receptors (and B2 receptors, though with different time courses) in inflammatory induced bone resorption in areas of chronic inflammatory processes such as periodontitis, rheumatoid arthritis and osteomyelitis (Ljunggren and Lerner, 1990) and for Bt receptors in a rat bladder model of chronic cystitis (Marceau et al., 1980) have been described. A recent interesting report showed that tachykinin-mediated capsaicin-evoked oedema in the mouse ear was inhibited more potently by [LeuS,des-Arg9]-BK than D-Arg-[Hyp3,D-PheT]-BK suggests the presence of B~ (and B2) receptors on capsaicin-sensitive fibres modulating neurogenic inflammation in this species (Mantione and Rodriguez, 1990). An interesting role for B t receptors has been proposed in

Model

Rat paw s.c. carrageenin: thermal latency Mouse i.p. acetic acid: writhing response

Steranka et al., 1988

Costello and Hargreaves, 1989 Steranka et al., 1987

D-Arg-[Hyp3,D-Phe7]-BK D-Arg-[Hyp3,ThiS'8,D-Phe 7]-BK D-Arg-[Hyp3,D-Phe7]-BK

Whalley et al., 1987b

D-Arg-[Hyp3,ThiS.S,D-Phe7]-BK

Human blister base, topical bradykinin: pain score

Lys,Lys-[HypZ.3ThiS,S,D-Phe7 ]-BK D-Arg-[Hyp3,D-Phe7]-BK D-Arg-[Hyp3,ThiS.a,D-Phe7 ]-BK

Steranka et al., 1988

D-Arg-[Hyp3,D-Phe7 ]-BK D-Arg-[Hyp3,ThiS,S,D-Phe7 ]-BK

Rat paw i.d. bradykinin: pressure threshold

Experimental pain/hyperalgesia Rat paw s.c. urate: pressure threshold

Griesbacher and Lembeck, 1987 Lembeck et al., 1991

Lys,Lys-[Hyp3,ThiS.S,D-Phe7 ]-BK D-Arg-[Hyp3,ThiS,D-Tic,Oics]-BK

Rabbit ear artery, bradykinin perfusion: nociceptive reflex

Reference Steranka et al., 1988

Antagonist Lys,Lys-[Hyp2'3,ThiS'S,D-Phe 7]-BK D-Arg-[Hyp3,D-Phe7]-BK D-Arg-[Hyp3,ThiS,S,D-Phe7 ]-BK

Exogenous kinin Rat intra-coronary artery bradykinin: behavioural response

TABLE 8. Animal and Human Models where Be-Receptor Antagonists are Effective

Q

?,

ca.

172

J . M . HALL

modulation of enkephalin production following noxious stimuli to the dental pulp where B, receptor triggers [Met-enkephalin]-like peptide content following cavity formation (see Inoki and Kudo, 1986).

6.6.2. B 2 Receptors and Inflammation 6.6.2.1. Interactions with other inflammatory mediators. Kinins cause both direct inflammatory responses and, in addition, interact with other mediators to amplify inflammatory effects, often at the second-messenger level. Such interactions have been reported with the cytokines (Burch et al., 1988; Bathon et al., 1989; Burch and Tiffany, 1989) by a proposed mechanism of induction of phospholipase A2, cyclooxygenase and GTP-binding regulatory proteins (Burch et al., 1988) and with the eicosanoids (Juan and Lembeck, 1974; Burch et al., 1988; O'Neill and Lewis, 1989). Under certain circumstances, complex interactions occur. For example, in 3T3 fibroblasts, prior priming the cells with cytokines greatly amplifies B2 receptor bradykinin-stimulated PGE2 synthesis (Burch et al., 1988; Burch and Tiffany, 1989). In human gingival fibroblasts treated with IL-I~ and IL-lfl, potentiation of responses to bradykinin (and also the B~ agonist [des-Argg]-BK) was observed. It was suggested that the interaction between IL-1 and bradykinin was at the level distal to PLA2 activity since no interaction between bradykinin and IL-lfl was seen on arachidonic acid release (Whiteley and Needleman, 1984; Lerner and Mod6er, 1991). These complex amplification processes may be considered to be mechanisms involved in the maintenance of chronic inflammation. 6.6.2.2. Vascular permeability. An increase in the permeability of vascular endothelium to fluid and plasma proteins results in oedema, one of the cardinal signs of inflammation. Kinins increase vascular permeability and B2 receptors seem involved in this response (Schachter et al., 1987; Whalley et al., 1987c; Cirino et al., 1991). [D-PheT]-BK antagonists block bradykinin-induced vascular permeability increase in rabbit skin (Schachter et al., 1987; Griesbacher and Lembeck, 1987; Whalley et al., 1987c) and in rat skin (Steranka et aL, 1989). In various organs of the rat, D-Arg-[Hyp3,Thi%D-TicT,OicS]-BK inhibits bradykinin-evoked plasma extravasation (Lembeck et al., 1991; Sakamoto et al., 1992). The receptors involved in the bradykinin-induced increase in permeability have been investigated in the microvascular of the hamster cheek pouch visualized using intravital microscopy and fluorescein isocyanate dextran. The B2-receptor antagonist D-Arg-[Hyp3,ThiS'8,o-Phe7]-BK inhibited the formation of leaky sites in response to bradykinin, suggesting an involvement of B2 receptors in the increased vascular permeability (Murray et al., 1991). Release of bradykinin and its subsequent stimulation of B2 receptors has also been implicated in the oedema induced by several other agents in models of inflammation in the rat where kinin levels are elevated. For example, peptidergic B2 antagonists block plasma extravasation induced by carrageenin (Costello and Hargreaves, 1989; Burch and deHaas, 1990; Wirth et al., 1991a; Damas and Remacle-Volon, 1992) by urate crystals (Damas and Remacle-Volon, 1992), phospholipase A2 (Cirino et al., 1991), though not by zymosan (Damas and Remacle-Volon, 1992). Very recently, the novel potent B2-receptor antagonist D-Arg-[Hyp3,Thi%D-TicT,OicS]-BK was shown to block caerulein-induced oedema in the pancreas, presumably by antagonizing the effect of endogenously released kinins. This may have relevance to the treatment of acute pancreatitis (Griesbacher and Lembeck, 1992b). In the mouse paw (Shibata et al., 1986) and ear (Mantione and Rodriguez, 1990), the bradykinin-induced vascular permeability was partially antagonized by the tachykinin receptor antagonists [D-Argl,D-Pro2,D-TrpT.9,Leull]-SP(1-11) and [D-Pro2,D-Trp7'9]-SP(1-11), suggesting a release of tachykinins from peripheral endings of primary afferents by bradykinin. 6.6.2.3. Other effects. Kinins are well-known stimulators of primary afferents which results in the release of other pro-inflammatory mediators including tachykinins and calcitonin gene-related peptide; certain kinin analogues also release histamine (Section 7). These various effects further amplify inflammatory processes. Bradykinin, acting via B2 receptors, has been shown to inhibit rat polymorphoneutrophil chemotaxis (Roch-Arveiller et al., 1981).


173

6.7. CIRCULATIONHOMEOSTASIS A role for kinins in the control of blood pressure and circulatory homeostasis has been suggested in view of the potent hypotensive effects of peripherally-administered kinins in vivo and the potent contractile or relaxant effects of kinins on isolated vascular smooth muscle; along with the elaborate machinery for the synthesis of bradykinin and Lys-BK from blood elements. Several excellent reviews describe the possible roles of bradykinin in circulation homeostasis in normal and pathophysiology (Margolius, 1989; Sharma, 1988; Gavras and Gavras, 1991). This discussion will be limited to describing studies where the receptor types involved in different aspects of cardiovascular control have been investigated. 6.7.1. Isolated Blood Vessels Kinins both contract and relax vascular smooth muscle, which may involve either or both B, or B2 receptors and the release of intermediary mediators such as prostaglandins or endothelial derived factors (such as NO). In canine isolated blood vessels, bradykinin acting via Bz receptors relaxes the PGF2~ precontracted coronary artery via an endothelium-dependent mechanism; and in the renal artery relaxation via a mechanism involving B2 receptor evoked release of PGI2 and EDRF. In contrast, in the canine mesenteric vein, PGI 2 liberated from endothelial and sub-endothelial tissues results in relaxation, but this response is attenuated by the B 1 antagonist [LeuS,des-Argg]-BK (Toda et al., 1987). Canine carotid artery relaxes in response to kinins via B2 receptor stimulation (Couture et al., 1980; D'Orl6ans-Juste et al., 1985). Kallikrein also causes relaxation, an effect inhibited by the B2-selective antagonist D-Arg-[Hyp3,ThiS,D-Tic7,OicS]-BK, suggesting that kallikrein generates kinins from endogenous kininogens present in the vessel wall (Mombouli and Vanhoutte, 1992). Guinea-pig mesenteric vein is contracted by kinins via B2 receptor activation (Gaudreau et al., 1981b). The rat renal vasculature contains both B t and B2 receptors (Guimar~es et al., 1986); and the bradykinin-evoked vasodilation of the cat submandibular gland is inhibited by o-Arg-[Hyp3,ThiS'S,D-Phe 7]-BK, suggesting the involvement of B2 receptors (Barton et al., 1988). In rabbit coeliac artery, endothelium-independent relaxation in response to kinins is via a Bl-mediated release of cyclooxygenase products, but may also involve cellular Na+/H ÷ exchange (Ritter et al., 1989). The contractile response of the rabbit isolated jugular vein is due to B2 receptor stimulation (Gaudreau et al., 1981a,b). The B~ receptor mediated contraction of the rabbit anterior mesenteric vein and aorta is discussed in Sections 3.1 and 3.2. There are limited studies analysing the receptor types involved in vascular effects of kinins in human tissues. In one report, B2 receptor mediated relaxation of the human basilar artery was described (Whalley et al., 1987a). 6.7.2. Blood Pressure Regulation Systemic administration of bradykinin in the rat results in a fall in blood pressure. Most evidence points to an involvement of the B2 receptor type in mediating this effect (Griesbacher et al., 1989; Lembeck et al., 1991). Indeed, the rat blood pressure in vivo was one of the original assays used in the screening of peptide B2 receptor antagonists (Section 4.2.1). The role of kinins and B2 receptors in the regulation of blood pressure in normal animals has also been investigated and in general first generation Bz-receptor antagonists (D-Arg-[Hyp3,Th?,D-TicT,OicS,]-BK has not yet been tested), at concentrations that block the depressor response to exogenous bradykinin, seem to be without effect in normotensive rats (Benetos et al., 1986; Aubert et al., 1988; Madeddu et al., 1992). One study, however, reported that very high concentrations of D-Arg-[Hyp3,ThiS'S,D-PheT]BK did cause a transient biphasic effect on blood pressure when injected into the ascending aorta of conscious restrained rats through renal prostaglandin release (Carbonell et al., 1988). In view of the possible contribution of altered breakdown of bradykinin to the antihypertensive effect of ACE inhibitors, B2-receptor antagonists have been tested on blood pressure in rats pretreated with such inhibitors. These studies also reported no effect with the antagonists. However, kinins acting at B 2 receptors have been implicated in the antihypertensive effect of ACE inhibitors in renovascular hypertensive rats (see Gavras and Gavras, 1989); and inhibition by D-Arg-

174

J.M. HALL

[Hyp3,ThiS,8,D-PheT]-BK of the ACE inhibitor enalapril stimulated production of PGI2 from aortic tissue has been demonstrated in vitro (Beierwaltes and Carretero, 1989). The pressor effect of centrally administered bradykinin may also involve B2 receptors. Thus, in the rat, intracerebroventricular (i.c.v.) application of [des-Argg]-BK has no effect on blood pressure, whereas the pressor effect to i.c.v, bradykinin is blocked by the B2-receptor antagonist D-Arg[Hyp3,ThiS'8,D-PheT]-BK but not by the Bt-receptor antagonist [Leu8,des-Argg]-BK both in normotensive and spontaneously hypertensive animals (Lindsey et al., 1989; Martins et al., 1991). 6.7.3. Endotoxic Shock Endotoxic shock, which results from an interaction of endotoxin produced from bacterial cell walls with cells of the reticuloendothelial system, is characterized by a profound fall in mean arterial blood pressure within a few minutes of endotoxin administration, which is followed, after a transient recovery, by a further decrease as the animal approaches death. There is a well established literature pointing to a role for kinins in endotoxic shock (see Colman and Wong, 1979). In the rat, i.v. infusion of the B2-receptor antagonist Lys,Lys-[Hyp2.3,ThiS'S,D-Phe7]-BK administered prior to intravenous bolus of endotoxin substantially reduced the fall in blood pressure (Weipert et al., 1988) and in another study, D-Arg-[Hyp3,D-Phe7]-BK infusion inhibited the initial fall in blood pressure and significantly reduced mortality (Wilson et al., 1989). Very recently (Section 4.2.4), Cortech have developed a series of bissuccinimidoalkanes dimer antagonists which have been tested in vivo. The homodimer of D-Arg-[Hyp3,D-Phe 7, LeuS]-BK ([BSH(L-Cys6)]-I dimer; CP-0127) was found to inhibit bradykinin-induced hypotensive response in LPS-pretreated rabbits and the heterodimer CP-0364 to inhibit both bradykinin and [des-Argg]-BK induced hypotensive responses in LPS-pretreated rabbits (Whalley et al., 1992). 6.8. CENTRAL NERVOUS SYSTEM

Bradykinin injected i.c.v, exerts behavioural effects (Capek, 1962) and bradykinin-like immunoreactivity has been localized to the rat brain (Correa et al., 1979) and spinal cord (Perry and Snyder, 1984). Bradykinin binding sites have been identified in the central nervous system (CNS) of the guinea-pig (Fujiwara et al., 1988; Sharif and Whiting, 1991) and rat embryonic brain in culture (Lewis et al., 1985). Therefore, it has been suggested that kinins may act in the CNS as neurotransmitters or neuromodulators (see Clark, 1979). Of interest, Phillips et al. (1992) failed to obtain responses to bradykinin in oocytes injected with mRNA isolated from rat brain, which correlates with the paucity of bradykinin binding sites in adult rat brain (Innis et al., 1981). 6.9. CELL GROWTH, REPAIR AND MITOGENESIS There is an emerging role for bradykinin as a modulator of animal cell proliferation (see Roberts, 1989). Bradykinin is mitogenic in murine 3T3 cells (Issandou and Rozengurt, 1990). In foetal lung human fibroblasts, B~ receptors promote the formation of collagen, cell division and multiplication and in these cells, prostaglandins may act as negative modulators of cell growth during bradykinin action (Goldstein and Wall, 1984). The Bl-selective agonist [des-Arg9]-BK also has a mitogenic effect on a minority of fibroblast lines derived from rabbit dermis (R51 line) following long-term culture (Marceau and Tremblay, 1986). In both cases, the trophic effect of [des-Argg]-BK was inhibited by the Bl-receptor antagonist [Leu8,des-Arg9]-BK. In contrast, in human breast fibroblasts, Bl receptor mediated inhibition of DNA synthesis was reported (Patel and Schrey, 1992), an effect partially reversed by indomethacin. In serum-starved mesangial cells in culture, [des-Arg9]BK induced DNA synthesis, however, bradykinin was inactive. Protein kinase C was implicated in the modulation of DNA synthesis by [des-Arg9]-BK (Issandou and Darbon, 1991). 6.10. OCULARTissuEs In the porcine isolated iris sphincter, bradykinin causes contraction, presumably by a direct action on the smooth muscle, since contractions are not affected by in vitro capsaicin-treatment and bradykinin does not release substance P or calcitonin gene-related peptide-like immunoreactivity

Bradykinin receptors A

B

10

9

8

7

6

5

10 9


~" lOO

175

8

7

6

5

4


C

3

g~

~2 50

x

.

E 0

~,

r,,"

o

oJ 10 9

8

7

6

5

4


11

10

9

8

-Log [HOE1403 (M)

FIG. 6. Bradykinin contracts the rabbit isolated iris sphincter indirectly via release of tachykinins from sensory nerves. (A) Control responses to bradykinin (0). Responses to bradykinin obtained in the presence of to-conotoxin GVIA (0.1 # M; II). (B) Control responses to bradykinin (O), responses obtained in the presence of the tachykinin NK~-receptor antagonist GR82334 (1 #M; II). (C) Control responses to bradykinin (0) and those obtained in the presence of 0.32 nM (A), 1 nM (11) and 3.2 nM (V) D-Arg-[Hyp3,ThiS,D-TicT,OicS]-BK. (D) Data shown in (C) displayed as a Schild plot, where antagonism was compatible with competitive kinetics (so unity slope is imposed) and a pKB estimate of 10.46 (_ 0.15; n = 11) was calculated. GR82334=[D-Prog[Spiro?Lactam]Leut°,Trpll]-physalaemin. For general methods, see Hall et al. (1991b). (Geppetti et al., 1990). The bradykinin receptors involved are both of the B]- and B2-type (Everett et al., 1992). In contrast, in the rabbit iris sphincter, bradykinin contracts the preparation via an indirect action involving release of tachykinin and calcitonin gene-related peptide from capsaicinsensitive primary afferent sensory nerves (Ueda et al., 1984; Wahlestedt et al., 1985). The bradykinin receptors on the sensory nerves are of the B2-type since Brselective ligands are inactive (Everett et al., 1992) and B2-antagonists of the [D-PheT]-BK (Field et al., 1988) and [D-TicT]-BK series have high affinity (Hall et al., 1992) (Fig. 6).

7. NON-RECEPTOR MEDIATED ACTIONS OF KININS Bradykinin and analogues including [des-Argg]-BK, [LeuS,des-Argg]-BK and several [D-Phe7]-BK and [D-Tic7]-BK analogues release histamine from rat peritoneal mast cells (Devillier et al., 1985, 1988; Regoli et al., 1992), though not human basophils, lung mast cells or skin mast cells (Lawrence et al., 1989). It has been suggested that bradykinin and its analogues act in a similar manner to substance P, compound 48/80 and mastoparan to release histamine via a non-receptor-mediated mechanism involving interaction with the sialic acid residues of the cell surface and then with Gi-like proteins. Bradykinin has been shown to activate the GTPase activity of GTP-binding proteins (Bueb et al., 1990). These interactions result in phospholipase C activation and subsequent Ca 2+-mobilization and histamine release (see Bueb et al., 1990; Mousli et al., 1990). Other proposed non-receptor-mediated effects of kinins, possibly involving a direct activation of a G-protein, include relaxation of the guinea-pig isolated trachea (Mizrahi et al., 1982; Rhaleb et al., 1988) JPT 56/2--D

176

J.M. HALL

(Section 6.4.1) and adrenaline release from the adrenal medulla and noradrenaline from sympathetic ganglia (Collier, 1970). Certain [D-PheT]-BK analogues have C-termini that are similar to known kallikrein inhibitors and some kinin analogues including Lys, Lys-[Hyp2'3,ThiS'8,D-PheT]-BK (K~ = 0.3 ~tM) have been shown to competitively inhibit the amidolytic activity of human kallikrein (Spragg et al., 1988). Some [D-PheT]-BK analogues have also been shown to inhibit kininase II, although the inhibition was noncompetitive and weak (Togo et al., 1989)

8. S U M M A R Y A N D F U T U R E D I R E C T I O N S Mediators discovered as active principles from tissue or fluid extracts tend to have perceived physiological roles shaped by their circumstances of discovery. Since bradykinin and Lys-BK (kallidin) can be formed from blood elements in virtually inexhaustible amounts, and are of near unparalleled potency in their actions on the vasculature, it is not surprising that these aspects have dominated earlier research. This emphasis, however, has apparently distracted from a search of other roles, including modulation of fluid transport and the regulation of cell growth, which have consequently been slow to be recognized or appreciated. Furthermore, although the potent pain-producing action of bradykinin in man was delineated relatively early on, it seems only recently that the kinins have come to be regarded as major activators of sensory nerve function following tissue damage. In spite of quite early claims of bradykinin-like immunoreactivity in the CNS, there has also been an apparent disregard of a possible role for kinins as neurotransmitters. Of relevance to this latter point is the emergence of angiotensin as an important CNS transmitter, which demonstrates that peptides known to be formed from blood can also be synthesized in neural tissue. In many of the above cases, the claims for physiological roles for the kinins could most easily be established by the appropriate use of bradykinin-receptor antagonists. High-affinity and selective agents are now becoming available. Studies using these agents, along with those employing molecular biology techniques, will identify the characteristics of bradykinin receptors; and in particular identify subtypes and determine the extent to which the human receptor(s) resembles those of experimental animals. In the author's opinion, the relative roles of Bl as compared to Bz receptor mediated events will be the future topic of greatest interest and potential importance and here investigations into the chronic, as opposed to the acute, actions of kinins may lead to an appreciation of a quite different type of pharmacological spectrum. It is hoped that this review has made the case that selective bradykinin-receptor antagonists and agonists have now come of age and, consequently, considerable advances in our understanding of kinin function can confidently be expected with the eventual development of therapeutic agents. Acknowledgements--I wish to thank Debra Mitchell for her expert technical assistance throughout our

bradykinin studies. I am grateful to Julie Field, Alyson Fox, Debra Mitchell and Alex Chin for use of their original data and Dr Ian K. M. Morton for helpful criticism of this manuscript and for preparing the illustrations. Some of the experiments carried out in the author's laboratory were funded by the Sandoz Institute for Medical Research, London. The author's work on the rabbit ear artery described in the text was performed at the Institute for Experimental and Clinical Pharmacology, Graz, Austria at the invitation of Prof. F. Lembeck. I thank the Wellcome Trust for support.

REFERENCES

AARSEN,P. N. (1977) The effects of bradykinin and the bradykinin potentiating peptide BPPs~ on the electrical and mechanical responses of the guinea-pig taenia coli. Br. J. Pharmac. 61: 523-532. AARSEN,P. N. and VANCASPEL-DEBRUYN,M. (1970) Effect of changes in ionic environment on the action of bradykinin on the guinea-pig taenia caeci. Eur. J. Pharmac. 12: 348-358. ABE, K., WATANABE,N., KUMAGAI,N., MOURI,T., SEKI,Z. and YOSHINAGA,K. (1967) Circulating plasma kinin in patients with bronchial asthma. Experientia 23: 626-627. ABRAHAM,W. M. (1991) Bradykinin antagonists in a sheep model of allergic asthma. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 261-276, BURCH,R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hong Kong. ABRAHAM,W. M., BURCH, R. M., FARMER,S. G., SIELCZAK,M. W., AHMED,A. and CORTES,A. (1991) A


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bradykinin antagonist modifies allergen-induced mediator release and late bronchial responses in sheep. Am. Rev. Resp. Dis. 143: 787-796. ACEWDO, C. G., LEWIN, J., CONTRERAS,E. and HUIDOBRo-ToRo,J. P. (1990) Bradykinin facilitates the purinergic motor component of the rat bladder neurotransmission. Neurosci. Lett. 113: 227-232. ALTINKLrgT,O. and OZTORK,Y. (1990) Bradykinin receptors in isolated rat duodenum. Peptides 11: 39-44. ANTONIO,A. (1968) The relaxing effect of bradykinin on intestinal smooth muscle. Br. J. Pharmac. Chemother. 32: 78-86. ARMSTRONG,D. (1970) Pain. In: Handbook o f Experimental Pharmacology: Bradykinin, Kallidin and Kallikrein, pp. 434-481, ERD6S, E. G. (ed.) Springer-Verlag., Berlin. ARMSTRONG,D., DRY, R. M. L., KEELE,C. A. and MARKHAM,J. W. (1952) Pain-producing substances in blister fluid and in serum. J. Physiol. 117: 4P-5P. ARMSTRONG,D., DRY, R. M. L., KEELE,C. A. and MARKHAM,J. W. (1953) Observation on chemical excitants of cutaneous pain in man. J. Physiol. 120: 326-351. AUaERT,J. F., WAEBER,B., NUSSBERGER,J., VAVREK,R. J., STEWART,J. M. and BRUNNER,H. R. (1988) Influence of endogenous bradykinin on blood pressure response to vasopressors in normotensive rats assessed with a bradykinin antagonist. J. cardiovasc. Pharmac. 11: 51-55. BAaXUK,C., MARCEAU,F., ST-PIERRE,S. and REGOLI,D. (1982) Kininases and vascular responses to kinins. Eur. J. Pharmac. 78: 167-174. BAIRD, A. W. and MARGOLIUS,H. S. (1989) Bradykinin stimulates electrogenic bicarbonate secretion by the guinea pig gall-bladder. J. Pharmac. exp. Ther. 248: 268-272. BAO, G., QADRI, F., STAUSS,B., STAUSS,H., GOHLr,E, P. and UNGER,T. (1991) HOE 140, a new highly potent and long-acting bradykinin antagonist in conscious rats. Eur. J. Pharmac. 200: 179-182. BARABI',J., DROUIN,J.-N., REGOLI,D. and PARK, W. K. (1977) Receptors for bradykinin in intestinal and uterine smooth muscle. Can. J. Physiol. Pharmac. 55: 1270-1285. BARAB~,J., MARCEAU,F., TH~RIAULT,B., DROUIN,J.-N. and REGOLI,D. (1979) Cardiovascular actions of kinins in the rabbit. Can. J. Physiol. Pharmac. 57: 78-91. BARAB~,J., BABIUK,C. and REGOLI,D. (1982) Binding of [3H]des-Argg-BK to rabbit anterior mesenteric vein. Can. J. Physiol. Pharmac. 60: 1551-1555. BARA8~,J., CARANIKAS,S., D'ORI'ANS-JusTE,P. and REGOLI,P. (1984) New agonist and antagonist analogues of bradykinin. Can. J. Physiol. Pharmac. 62: 627-629. BAgANIUK,J. N., LUNDGREN,J. D., MIZOGUCHhH., GAWIN,A., MERIDA,M., S~LTAMER, J. J. and KAU~,,~R, M. A. (1990) Bradykinin and respiratory mucous membranes. A. Rev. Respir. Dis. 141: 706-714. BARNES,P. J., PAGE,C. P. and CHUNG,K. F. (1988) Inflammatory mediators and asthma. Pharmac. Rev. 40: 49-84. BARON, D. A., MAgGOLIUS,H. S., MILLER,D. H., STEWART,J. M. and VAVREK,R. J. (1987) Antagonists of bradykinin-induced chloride secretion and concomitant morphological change. Br. J. Pharmac. 91: 485P. BARTON,S., KARPINSKI,E. and SCHACHTEg,M. (1988) The effect of a bradykinin antagonist on vasodilator responses with particular reference to the submandibular gland of the cat. Experientia 44: 897-898. BASCANDS, J. L., EMOND, C., PECrIER, C., REGOLI, D. and GmOLAMI,J. P. (1991) Bradykinin stimulates production of inositol (1,4,5) trisphosphate in cultured mesangial cells of the rat via a BK2-kinin receptor. Br. J. Pharmac. 102: 962-966. BATnON, J. M. and PROUD,D. (1991) Bradykinin antagonists. A. Rev. Pharmac. Toxic. 31: 129-162. BATnON,J. M., PROUD,D., KRACKOW,K. and WmLEV,F. M. (1989) Preincubation of human synovial cells with IL-I modulates prostaglandin E2 release in response to bradykinin. J. lmmun. 143: 579-586. BATnON, J. M., MANNING,D. C., GOLDMAN,D. W., TOWNS,M. C. and PROUD, D. (1992) Characterization of kinin receptors on human synovial cells and upregulation of receptor number by interleukin-1. J. Pharmac. exp. Ther. 260: 384-392. BEIERWALTES,W. H. and CARRETERO,O. A. (1989) Kinin antagonist reverses converting enzyme inhibitorstimulated vascular prostaglandin 12 synthesis. Hypertension 13: 754-758. BENETOS,A., GAVRAS,H., STEWART,J. M., VAVREK,R. J., HATINOGLOU,S. and GAVRAS,I. (1986) Vasodepressor role of endogenous bradykinin assessed by a bradykinin antagonist. Hypertension 8: 971-974. BERTACCINI,G. (1976) Active peptides of non mammalian origin. Pharmac. Rev. 28: 127-177. BHOOLA,K. D., COLUER, H. O. J., SCHACHTER,M. and SHORLEV,P. G. (1962) Actions of some peptides on bronchial muscle. Br. J. Pharmac. Chemother. 19: 190-197. B,OOLA, K. D., FIGUEROA,C. D. and WORTHY,K. (1992) Bioregulation of kinins: kallikreins, kininogens and kininases. Pharmac. Rev. 44: 1-80. BIRCH,P. J., FERNANDEZ,L., HARRISON,S. M. and WILKINSON,A. (1991) Pharmacological characterization of the receptors mediating the contractile response to bradykinin in the guinea-pig ileum and rat uterus. Br. J. Pharmac. 102: 170P. BOISSONNAS,R. A., GUTTMANN,ST., JAQUENOUD,P.-A., KONZETT,H. and STf3RMER,E. (1960) Synthesis and biological activity of peptides related to bradykinin. Experientia 16: 326. BOSCHCOV,P., PAIVA,A. C. M., PAIVA,T. B. and SHIMUTA,S. I. (1984) Further evidence for the existence of two receptor sites for bradykinin responsible for the diphasic effect in the rat isolated duodenum. Br. J. Pharmac. 83: 591-600. BOULANGER, C., SCHINh V. B., MONCADA, S. and VANHOUTTE,P. M. (1990) Stimulation of cyclic GMP

178

J.M. HALL

production in cultured endothelial cells of the pig by bradykinin, adenosine diphosphate, calcium ionophore A23187 and nitric oxide. Br. J. Pharrnac. 101: 152-156. BOUTILLIER,J., DEBLOIS,D. and MARCEAU,F. (1987) Studies on the induction of pharmacological responses to des-Arg9-bradykinin in vitro and in FIFO. Br. J. Pharrnac. 92:257 264. BRAAS, K. M., MANNING, D. C., PERRY, D. C. and SNYDER,S. H. (1988) Bradykinin analogues: differential agonist and antagonist activities suggesting multiple receptors. Br. J. Pharrnac. 94: 3-5. BRAMLEY,A. M., SAMHOUN,M. N. and PIPER, P. J. (1988) Modulation of bradykinin-induced responses by indomethacin and removal of the epithelium in guinea-pig trachea in vitro. Br. J. Pharrnac. 95: 774. BRAMLEY,A. M., SAMHOUN,M. N. and PIPER, P. J. (1990) The role of the epithelium in modulating the responses of guinea-pig trachea induced by bradykinin in vitro. Br. J. Pharrnac. 99: 762-766. BRUNTON,L. L., WIKLUND,R. A., VAN ARSDALE,P. M. and GILMAN,A. G. (1976) Binding of [aH] prostaglandin E l to putative receptors linked to adenylate cyclase of cultured cell clones. J. biol. Chem. 251: 3037-3044. BUEB, J. L., MOUSLI, M., BRONNER,C., ROUTOT, B. and LANDRY,Y. (1990) Activation of G~-like proteins, a receptor-independent effect of kinins in mast cells. Molec. Pharrnac. 38: 816-822. BURCH, R. M. (1990) Kinin signal transduction: role of phosphoinositides and eicosanoids. J. cardiovasc. Pharrnac. 15: $44-$45. BURCH, R. M. and AXELROD,J. (1987) Dissociation of bradykinin-induced prostaglandin formation from phosphatidylinositoi turnover in Swiss 3T3 fibroblasts: evidence for a G protein regulation of phospholipase A 2. Proc. hath. Acad. Sci. U.S.A. 84: 6374-6378. BURCI-I,R. M. and DEHAAS,C. (1990) A bradykinin antagonist inhibits carrageenin edema in rats. Naunyn Schmiedeberg 's Arch. Pharmac. 342: 189-193. BURCH, R. M. and KYLE, O. J. (1992) Recent developments in the understanding of bradykinin receptors. Life Sci. 50: 829-838. BURCH, R. M. and TIFFANY,C. W. (1989) Tumor necrosis factor causes amplification of arachidonic acid metabolism in response to interleukin 1, bradykinin and other agonists. J. Cell Physiol. 141: 85-89. BURCH, R. M., CONNOR,J. R. and AXELROD,J. (1988) Interleukin 1 amplifies receptor-mediated activation of phospholipase A~:,in 3T3 fibroblasts. Proc. natn. Acad. Sci. U.S.A. 85: 6306-6309. BURCH, R. M., FARMER, S. G. and STERANKA,L. R. (1990) Bradykinin receptor antagonists. Med. Res. Rev. 10: 237-269. BURGESS, G. M., MULLANEY,I., MCNEILL, M., DUNN, P. M. and RANG, H. P. (1989) Second messengers involved in the mechanism of action of bradykinin in sensory neurons in culture. J. Neurosci. 9:3314-3325. CAHILL,M., FISHMAN,J. B. and POLGAR,P. (1988) Effect of des-Arginine9-bradykinin and other bradykinin fragments on the synthesis of prostacyclin and the binding of bradykinin by vascular cells in culture. Agents Actions 24: 224-231. CALIXTO,J. B. and MADEIROS,Y. S. (1991) Characterization of bradykinin mediating pertussis toxin-insensitive biphasic response in circular muscle of the isolated guinea-pig ileum. J. Pharrnac. exp. Ther. 259: 659-665. CALIXTO,J. B. and MADEIROS,Y. S. (1992a) Bradykinin-induced biphasic response in the rat isolated stomach fundus: functional evidence for a novel bradykinin receptor. Life Sci. 50: PL47-PL52. CALIXTO,J. B. and MADEIROS,Y. S. (1992b) Effect of protein kinase C and calcium on bradykinin-mediated contractions of rabbit vessels. Hypertension 19: 87-93. CALIXTO,J. B. and SANT'ANA,A. E. G. (1987) Pharmacological analysis of the inhibitory effect of jatrophone, a diterpene isolated from Jatropha elliptica, on smooth and cardiac muscle. Phytother. Res. 1: 122-126. CALIXTO,J. B. and YUNES,R. A. (1986) Effect of a crude extract of Mandevilla velutina on contractions induced by bradykinin and [des-Argg]-bradykinin in isolated vessels of the rabbit. Br. J. Pharmac. 88: 937-941. CALIXTO,J. B., NICOLAU,M., PIZZOLATTI,M. G. and YUNES,R. A. (1985a) A selective antagonist of bradykinin action from a crude extract of Mandevilla velutina. Part II. Effect on non-uterine smooth muscle. In: Proceedings of the Third Congress of the Brazilian Society of Pharmacology and Experimental Therapeutics. Braz. J. Med. Biol. Res. 18: 729A. CALIXTO,J. B., NICOLAU,M. and YUNES, R. A. (1985b) The selective antagonism of bradykinin action rat isolated uterus by crude Mandevilla velutina extract. Br. J. Pharrnac. 85: 729-731. CALIXTO,J. B., PIZZOLATTI,M. G. and YUNES, R. A. (1988a) The competitive antagonistic effect of compounds from Mandevilla velutina on kinin-induced contractions of rat uterus and guinea-pig ileum in vitro. Br. J. Pharrnac. 94: 1133-1142. CALIXTO,J. B., STROBEL,G. H., CRUZ, A. B. and YUNES, R. A. (1988b) Blockade of the bradykinin-evoked diphasic responses of isolated rat duodenum by the crude extract and of compounds obtained from Mandevilla velutina. Braz. J. Med. Biol. Res. 21: 1015-1018. CALIXTO,J. B., YUNES, R. A., RAE, G. A. and MEDEIROS,Y. S. (1991) Nonpeptide bradykinin antagonists. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 97-129, BURCH, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hong Kong. CANNON, J. G., CLARK, B. O., WINGfiELD,P., SCHMEISSNER,U., LOSBERGER,C., DINARELLO,C. A. and SHAW, A. R. (1989) Rabbit IL-1. Cloning, expression, biologic properties and transcription during endotoxemia. J. Immun. 142: 2299-2306. CAPV.K, R. (1962) Some effects of bradykinin on the central nervous system. Biochern. Pharrnac. 10: 61~5. CARBONNEL,L. F., CARRETERO,O. A., MADEDDU,P. and SClCLI,A. G. (1988) Effects of a kinin antagonist on mean blood pressure. Hypertension 11: 84-88.


179

CARTER, T. D., HALL, J. M., McCABE, D. V., MORTON,I. K. M. and SCnACHTER,M. (1986) Biphasic actions of bradykinin in the guinea-pig taenia caeci preparation. Br. J. Pharmac. 90: 137P. CHERONIS,J. C., WHALLEY,E. T. and BLODGETT,J. K. (1992) Bradykinin antagonists: synthesis and in vitro activity of bissuccinimidolalkane peptide dimers. In: Recent Progress on Kinins, Vol. 38/I, pp. 551-558, BONNER,G., FRITZ, H., UNGER,TH., ROSCHER,A. and LUPPERTZ,K (eds.) Birkhaiiser Verlag, Basel, Boston, Berlin. CHERONIS,J. C., WHALLEY,E. T., NGUYEN, K. T., EUBANKS,S. R., ALLEN,L. G., DUGGAN,M. J., LoY, S. D., BONHAM,K. A. and BLODGETT,J. K. (1992b) A new class of bradykinin antagonists: synthesis and in vitro activity of bissuccinimidoalkane peptide dimers. J. Med. Chem. 35: 1563-1572. CHERRY,P. D., FURCHGOTT,R. F., ZAWADZKI,J. V. and JOTHIANANDAN,D. (1982) Role of endothelial cells in relaxation of isolated arteries by bradykinin. Proc. natn. Acad. Sci. U.S.A. 79:2106-2110. CHIPENS, G. (1983) Cyclic analogues of bradykinins: potential significance. Surv. Immun. Res. 2: 102-108. CHIU, A. T., CARINI,D. J., JOHNSON,A. L., MCCALL,O. E., PRICE,W. A., THOOLEN,M. J. M. C., WONG, P. C., TABER, R. I. and TIMMERMAN,P. B. M. W. M. (1988) Non-peptide angiotensin II receptor antagonists. II. Pharmacology of S-8308. Eur. J. Pharmac. 157: 13-21. CHOLEW1NSKI,A. J., STEVENS,G., MCDERMOTT,A. M. and WILKIN,G. P. (1991) Identification of B2 bradykinin binding sites on cultured cortical astrocytes. J. Neurochem. 57: 1456-1458. CHUANG, D.-M. and DILLON-CARTER,O. (1988) Characterization of bradykinin-induced phosphoinositide turnover in neurohybrid NCB-20 cells. J. Neurochem. 51: 505-513. CHURCHILL,L. and WARD, P. E. (1986) Relaxation of isolated mesenteric arteries by des-Arg9-bradykinin stimulation of B1 receptors. Eur. J. Pharmac. 130: ll-18. C1RINO, G., CICALA,C., SORRENTINO,L. and REGOLI, D. (1991) Effect of bradykinin antagonists, N Gmonomethyl-L-arginine and L-NC-nitroarginine on phospholipase A2 induced oedema in rat paw. Gen. Pharmac. 22: 801-804. CLAESON,G., FARREED,J., EARSSON,C., KINDLE,G., ARIELLY,S., SIMONSSON,R., MESSMORE,H. and BALLS,U. (1979) Inhibition of the contractile action of bradykinin on isolated smooth muscle preparations by derivatives of low molecular weight peptides. Adv. exp. Med. Biol. 120: 691-713. CLARK,M. A., CONWAY,T. M., BENNETT,C. F., CROOKE,S. T. and STADEL,J. M. (1986) Islet-activating protein inhibits leukotriene D4- and leukotriene C4- but not bradykinin- or calcium ionophore-induced prostacyclin synthesis in bovine endothelial cells. Proc. natn. Acad. Sci. U.S.A. 83: 7320-7324. CLARK,W. G. (1979) Kinins and the peripheral and central nervous system. In: Handbook o f Pharmacology. Bradykinin, Kallidin and Kallikrein, pp. 312-356, ERD6S, E. G. (ed.) Springer-Verlag, Berlin, Heidelberg, New York. COHEN-LAROQUE,E.-S., BI~NY,J.-L. and HUGGEL,H. (1990) Microvascular effects of bradykinin in the isolated perfused guinea-pig hindbrain: method and characterization of a possible third type of bradykinin receptor. Microvasc. Res. 40: 55--62. COLLIER,H. O. J. (1962) Antagonists of bradykinin. Biochem. Pharmac. 10: 47-59. COLLIER,H. O. J. (1970) Kinins and ventilation of the lungs. In: Handbook o f Experimental Pharmacology. Bradykinin, Kallidin and Kallikrein, pp. 409-420, ERD6S, E. G. (ed.) Springer-Verlag, Berlin, Heidelberg, New York. COLLIER,H. O. J. and SHORLEY,P. G. (1960) Analgesic antipyretic drugs as antagonists of bradykinin. Br. J. Pharmac. Chemother. 15: 601-610. COLLIER,H. O. J., HOLGATE,J. A., SCHACHTER,M. and SHORLEY,P. G. (1959) An apparent bronchoconstrictor action of bradykinin and its suppression by some anti-inflammatory agents. J. Physiol. 149: 54P. COLLIER,H. O. J., HOLGATE,J. A., SCHACHTER,M. and SHORLEY,P. G. (1960) The bronchoconstrictor action of bradykinin in the guinea-pig. Br. J. Pharmac. Chemother. 15: 290-297. COLMAN,R. W. and WONG, P. Y. (1979) Kallikrein-kinin system in pathologic conditions. In: Handbook o f Experimental Pharmacology. Bradykinin, Kallidin and Kallikrein, pp. 569-607, ERD6S, E. G. (ed.) SpringerVerlag, Berlin, Heidelberg, New York. CONLON, J. M., HICKS, J. W. and SMITH, D. D. (1990) Isolation and biological activity of a novel kinin ([Thr6]-bradykinin) from the turtle, Pseudemys scripta. Endocrinology 126: 985-991. CORREA,F. M. A., INNIS,R. B., UHL,G. R. and SNYDER,S. H. (1979) Bradykinin-like immunoreactive neuronal systems localized histochemically in rat brain. Proc. natn. Acad. Sci. U.S.A. 76: 1489-1493. COSTELLO,A. H. and HARGREAVES,K. M. (1989) Suppression of carrageenan-induced hyperalgesia, hyperthermia and edema by a bradykinin antagonist. Eur. J. Pharmac. 171: 259-263. COUTURE,R., DROUIN,J.-N., LEUKART,O. and REC,OLI, D. (1979) Biological activities of kinins and substance P-octapeptides (4-11) in which phenylalanine residues have been replaced with L-carboranylalanine. Can. J. Physiol. Pharmac. 57: 1437-1442. COUTURE,R., GAUDREAU,P., ST. PIERRE,S. and REGOLI,D. (1980) The dog common carotid artery: a sensitive bioassay for studying vasodilator effects of substance P and of kinins. Can. J. Physiol. Pharmac. 58: 1234-1244. COUTURE, R., MIZRAHI,J., REGOLI,D. and DEVROEDE,G. (1981) Peptides and the human colon: an in vitro pharmacological study. Can. J. Physiol. Pharmac. 59: 957-964. COUTURE, R., MIZRAHI,J., CARANIKAS,S. and REGOLI,D. (1982) Acute effects of peptides on the rat colon. Pharmacology 24: 230-242.

180

J . M . HALL

CUTHBERT,A. W. and MARGOLIUS,H. S. (1982) Kinins stimulate net chloride secretion by the rat colon. Br. J. Pharmac. 75: 587-598.

DAMAS,J. and REMACLE-VOLON,G. (1992) Influence of a long-acting bradykinin antagonist, HOE 140, on some acute inflammatory reactions in the rat. Eur. J. Pharmac. 211: 81-86. DEBLOIS, O. and MARCEAU,F. (1987) The ability of des-Arg9-bradykinin to relax rabbit isolated mesenteric arteries is acquired during in vitro incubation. Eur. J. Pharmac. 142: 141-144. DEBLOIS, O., BOUTILLIER,J. and MARCEAU,F. (1988) Effect of glucocorticoids, monokines and growth factors on the spontaneously developing responses of the rabbit isolated aorta to des-Arg9 bradykinin. Br. J. Pharmac. 93: 967-977. DEBLOIS, O., BOUTILLIER,J. and MARCEAU,F. (1991) Pulse exposure to protein synthesis inhibitors enhances vascular responses to des-Arg9-bradykinin: possible role of interleukin-1. Br. J. Pharmac. 103: 1057-1066. DEBLOlS, D., DRAPEAU,G., PETITCLERC,E. and MARCEAU,F. (1992) Synergism between the contractile effect of epidermal growth factor and that of des-Arg9-bradykinin or of ~t-thrombin in rabbit aortic rings. Br. J. Pharmac. 105: 959-967. DELA CADENA,M. and COLMAN,R. W (1991) Structure and functions of human kininogens. Trends Pharmac. Sci. 12: 272-275. DEN HERTOG, A., NELEMANS,A. and VAN DEN AKKER,J. (1988) The multiple action of bradykinin on smooth muscle of guinea-pig taenia caeci. Eur. J. Pharmac. 151: 357-363. DENNING, G. M. and WELSH, M. J. (1991) Polarized distribution of bradykinin receptors on airway epithelial cells and independent coupling to second messenger pathways. J. biol. Chem. 266: 12932-12938. DEVILLIER, P., RENOUX, M., GIROUD, J. P. and REGOLI, D. (1985) Peptides and histamine release from rat peritoneal mast cells. Eur. J. Pharmac. 117: 89-96. DEVILLIER,P., RENOUX,M., DRAPEAU,G. and REGOLI,D. (1988) Histamine release from rat peritoneal mast cells by kinin antagonists. Fur. J. Pharmac. 149: 137-140. DONOSO, M. V. and HUIDOBRO-TORO,J. P. (1989) Involvement of post-junctional purinergic mechanisms in the facilitatory action of bradykinin in neurotransmission in the rat vas deferens. Fur. J. Pharmac. 160: 263-273. D'ORL~ANS-JUSTE, P., DION, S., MIZRAHI, J. and REGOLI, D. (1985) Effects of peptides and non-peptides on isolated arterial smooth muscles: role of endothelium. Eur. J. Pharmac. 114: 9-21. D'ORLI~ANS-JusTE,P., DENUCCI,G. and VANE,J. R. (1989) Kinins act on B, or BEreceptors to release conjointly endothelium-derived relaxing factor and prostacyclin from bovine aortic endothelial cells. Br. J. Pharmac. 96: 920-926. DOWNWARD,J., DEGUNZBURG, J., RIEHL, R. and WEINBERG,R. A. (1988) p21 raS induced responsiveness of phosphatidylinositol turnover to bradykinin is a receptor number effect. Proc. natn. Acad. Sci. U.S.A. 85: 5774-5778. DRAPEAU,G., DEBLOIS, D. and MARCEAU,F. (1991) Hypotensive effects of Lys-des-Arg9-bradykinin and metabolically protected agonists of Bj receptors for kinins. J. Pharmac. exp. Ther. 259: 997-1003. DRAY, A., PATEL. I. A., PERKINS, M. N. and RUEEF, A. (1992) Bradykinin-induced activation of nociceptors: receptor and mechanistic studies in the neonatal rat spinal cord-tail prepatation in vitro. Br. J. Pharmac. 107:1129-1134. DROUIN, J.-N., GAUDREAU, P., ST. PIERRE, S. and REGOLI, D. (1979a) Structure-activity studies of des-Arg9bradykinin on the B 1 receptor of the rabbit aorta. Can. J. Physiol. Pharmac. 57: 562-566. DROU1N, J.-N., GAUDREAU,P., ST. PIERRE, S. and REGOLI, D. (1979b) Biological activities of kinins modified at the N- or at the C-terminal end. Can. J. Physiol. Pharmac. 57: 1018-1023. DUNN, F. W. and STEWART,J. M. (1971) Analogues of bradykinin containing fl-2-thienyl-L-alanine. J. Med. Chem. 14: 779-781. DUNN, P. M. and RANG, H. P. (1990) Bradykinin-induced depolarization of primary afferent nerve terminals in the neonatal rat spinal cord in vitro. Br. J. Pharmac. 100: 6564560. DUNN, P. M., COOTE, P. R., WOOD, J. N., BURGESS, G. M. and RANG, H. P. (1991) Bradykinin evoked depolarization of a novel neuroblastoma X D R G neuron hybrid cell line (ND7/23). Brain Res. 545: 80-86. EMOND, C., BASCANDS,J.-L., GHISLAINE-BOUTOT,G., PECHER, C. and GIROLAMI,J.-P (1989) Effect of changes in sodium or water intake on glomerular B2-kinin-binding sites. Am. J. Physiol. 257: F353-F358. EMOND, C., BASCANDS,J.-L., PECHER, C., CABOS-BOUTOT,G., PRADELLES,P., REGOLI, D. and GIROLAMI,J.-P. (1990) Characterization of a B2-bradykinin receptor in rat renal mesangial cells. Fur. J. Pharmac. 190: 381-392. ENJYOJI, K. and KATO, H. (1988) Hydroxypropyl3-bradykinin in high molecular mass kininogen." presence in human and monkey kininogens, but not in kininogens from bovine, rat, rabbit, guinea-pig and mouse plasmas. F E B S Lett. 238: 1-4. ERDf2S, E. G. and SLOANE,E. M. (1962) An enzyme in human blood plasma that inactivates bradykinin and kallidins. Biochem. Pharmac. 11: 585-592. ESTACION, M. (1991) Acute electrophysiological responses of bradykinin-stimulated human fibroblasts. J. Physiol. 436: 603~520. ETSCHEID, B. G., Ko, P. H. and VILLEREAL,M. L. (1991) Regulation of bradykinin receptor level by cholera toxin, pertussis toxin and forskolin in cultured human fibroblasts. Br. J. Pharmac. 103: 1347-1350. EVERETT, C. M., HALL, J. M., MITCHELL,O. and MORTON, I. K. M. (1992) Contrasting properties of bradykinin receptor subtypes mediating contractions of the rabbit and pig isolated iris sphincter pupillae preparation.


181

In: Recent Progress on Kinins, Vol. 38/1, pp. 378-381, BONNER, G., FmTZ, H., UNGER,TH., ROSCHER,A. and LUPPERTZ, K. (eds.) Birkhaiiser Verlag, Basel, Boston, Berlin. EWALD, D. A., PANG, I.-H., STERNWEIS,P. C. and MILLER, R. J. (1989) Differential G protein-mediated coupling of neurotransmitter receptors to Ca 2+ channels in dorsal root ganglion neurons in vitro. Neuron 2: 1185-1193. FABER, O. B. and VAN DER MEER, C. (1973) A study of some bradykinin potentiating peptides derived from plasma proteins. Arch. Int. Pharmacodyn. 205: 226-243. FARMER, S. G. (1991a) Airways pharmacology of bradykinin. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 213-236, BURCH, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hong Kong. FARMER, S. G. (1991b) Role of kinins in airway diseases, lmmunopharmacology 22: 1-20. FARMER, S. G. and BURCH, R. M. (1991) The pharmacology of bradykinin receptors. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 1-31, BURCH, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hong Kong. FARMER,S. G. and BURCH,R. M. (1992) Biochemical and molecular pharmacology of kinin receptors. A. Rev. Pharmac. Toxic. 32:511-536. FARMER,S. G., BURCH, R. M., DEHAAS,C., TOGO,J. and STERANKA,L. R. (1989a) [o-Arg L, D-Phe7]-substituted bradykinin analogues inhibit bradykinin and vasopressin-induced contractions of uterine smooth muscle. J. Pharmac. exp. Ther. 248: 677-681. FARMER,S. G., BURCH,R. M., MEEKER,S. N. and WILKINS,D. E. (1989b) Evidence for a pulmonary B3 bradykinin receptor. Molec. Pharmac. 36: 1-8. FARMER, S. G., BURCH, R. M., KYLE, D. J., MARTIN,J. A., MEEKER,S. A. and ToGo, J. (1991a) D-Arg-[Hyp3ThiS-D-TicT-TicS]-bradykinin, a potent antagonist of smooth muscle BK2 receptors and BK3 receptors. Br. J. Pharmac. 102: 785-787. FARMER, S. G., ENSOR,J. E. and BURCH, R. M. (1991b) Evidence that cultured airway smooth muscle cells contain bradykinin BE and B3 receptors. Am. J. Resp. Cell. Mol. Biol. 4: 273-277. FARMER, S. G., McMILLAN, B. A., MEEKER, S. N. and BURCH, R. M. (1991c) Induction of vascular smooth muscle bradykinin B 1 receptors in vivo during antigen arthritis. Agents Actions 34: 191-193. FARMER, S. G., DE SIATO,M. A. and BROOM,T. (1992) Effects of kinin receptor agonists and antagonists in ferret isolated tracheal smooth muscle: evidence that bradykinin-induced contractions are mediated by BE receptors. Br. J. Pharmac. 107: 32. FASOLATO, C., PANDIELLA,A., MELDOLESI,J. and POZZAN, T. (1988) Generation of inositol phosphates, cytosolic Ca 2+ and ionic fluxes in PCI2 cells treated with bradykinin. J. biol. Chem. 263: 17350-17359. FAUSSNER,A., HEINZ-ERIAN,P., KLIER,C. and ROSCHER,A. A. (1991) Solubilization and characterization of B2 bradykinin receptors from cultured human fibroblasts. J. biol. Chem. 266: 9442-9446. FERES,T., VIANNA,L. M., PAIVA,A. C. M. and PAIVA,T. B. (1992) Effect of treatment with vitamin D 3 on the responses of the duodenum of spontaneously hypertensive rats to bradykinin and to potassium. Br. J. Pharmac. 105: 881-884. FIELD, J. L., FOX, A. J., HALL, J. M., MAGBAGBEOLA,A. O. and MORTON,I. K. M. (1988) Multiple bradykinin BE receptor subtypes in smooth muscle preparations. Br. J. Pharmac. 93: 284P. FIELD, J. L., HALL, J. M. and MORTON,I. K. M. (1992a) Bradykinin receptors in the guinea-pig taenia caeci are similar to proposed BK3 receptors in the guinea-pig trachea and are blocked by HOE 140. Br. J. Pharmac. 105: 293-296. FIELD,J. L., HALL,J. M. and MORTON,I. K. M. (1992b) Putative novel bradykinin BK 3 receptors in the smooth muscle of the guinea-pig taenia caeci and trachea. In: Recent Progress on Kinins, Vol. 38/II, pp. 540-545, BrNNER, G., FRITZ, H., UNGER,TH., ROSCHER,A. and LUPPERTZ, K (eds.) Birkhaiiser Verlag, Basel, Boston, Berlin. FIELD, J. L., HALL, J. M. and MORTON,I. K. M. (1992c) The nature of the bradykinin receptors involved in phosphatidylinositol hydrolysis and functional responses in the smooth muscle of the guinea-pig taenia caeci. Br. J. Pharmac. 107: 30. Fox, A. J., BARNES,P. J., URBAN, L. and DRAY, A. (1992) Selective activation of single vagal C fibres by capsaicin and bradykinin in the guinea-pig trachea in vitro. J. Physiol. 452: 203P. FREDRICK, M. J. and ODYA,C. E. (1987) Characterization of soluble bradykinin receptor-like binding sites. Eur. J. Pharmac. 134: 45-52. FREDRICK, M. J., VAVREK, R. J., STEWART,J. M. and ODYA, C. E. (1984) Further studies of myometrial bradykinin receptor-like binding. Biochem. Pharmac. 33: 2887-2892. FP,EIDINGER,R. M. (1989) Non-peptide ligands for peptide receptors. Trends Pharmac. Sci. 10: 270-274. Fu, T., OKANO,Y. and NOZAWA,Y. (1988) Bradykinin-induced generation of inositol 145-trisphosphate in fibroblasts and neuroblastoma cells: effects of pertussis toxin, extracellular calcium and down regulation of protein kinase C. Biochem. biophys. Res. Commun. 157: 1429-1435. FUJIWARA,Y., MANTIONE,C. R. and YAMAMURA,H. I. (1988) Identification of B2 bradykinin binding sites in guinea-pig brain. Eur. J. Pharmac. 147: 487-488. FUJIWARA,Y., BLOOM,J. W., MANTIONE,C. R. and YAMAMURA,H. I. (1989) Identification of B2 bradykinin binding sites in the guinea-pig nasal turbinate. Peptides 10: 701-703. FULLER, R. W., DIXON, C. M. S., Cuss, F. M. C. and BARNES,P. J. (1987) Bradykinin-induced bronchoconstriction in humans: mode of action. Am. Rev. Resp. Dis. 135: 176-180.

182

J.M. HALL

GAGINELLA,T. S. and KACHUR,J. F. (1989) Kinins as mediators of intestinal secretion. Am. J. Physiol. 256: Gl~15. GARRETT, R. L. and BROWN,J. H. (1972) Bradykinin interaction with 5-hydroxytryptamine, norepinephrine and potassium chloride in rabbit aorta. Proc. Soc, exp. Biol. Med. 139: 1344-1348. GATER, P. R., HAYLETT,D. G. and JENKINSON,D. H. (1985) Neuromuscular blocking agents inhibit receptormediated increases in the potassium permeability of intestinal smooth muscle. Br. J. Pharmac. 86: 861-868. GAUDREAU,P., BARABI~,J., ST. PIERRE,S. and REGOLI,D. (1981a) Pharmacological studies of kinins in venous smooth muscles. Can. J. Physiol. Pharmac. 59: 371-379. GAUDREAU,P., BARABI~,J., ST. PIERRE,S, and REGOLI,D. (1981b) Structure-activity study of kinins in vascular smooth muscles. Can. J. Physiol. Pharmac. 59: 380-389. GAVRAS,H. and GAVRAS,I. (1991) Effects of bradykinin antagonists on the cardiovascular system. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 171-189, BURCH, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hong Kong. GEPPETTI, P., PATACCHINI,R., CECCONI,R., TRAMONTANA,M., MEINI, S., ROMANI,A., NARD1,M. and MAGGI, C. A. (1990) Effects of capsaicin, tachykinins, calcitonin gene-related peptide and bradykinin in the pig iris sphincter muscle. Naunyn-Schmiedeberg's Arch. Pharmac. 341: 301-307. GOLDBERG, M. R., CHAPWICK,B. M., JOINER,P. D., HYMAN, A. L. and KADOWITZ,P. J. (1976) Influence of inhibitors of prostaglandin synthesis on venoconstrictor responses to bradykinin. J. Pharmac. exp. Ther. 198: 357-365. GOLDSTEIN,O. J., ROPCHAK,T. G., KEISER,H. R., ATTA,G. J., ARGIOLAS,A. and PISANO,J. J. (1983) Bradykinin reverses the effect of opiates in the gut by enhancing acetylcholine release. J. biol. Chem. 258: 12122-12124. GOLDSTEIN,R. H. and WALL,M. (1984) Activation of protein formation and cell division by bradykinin and des-Argg-bradykinin. J. biol. Chem. 259: 9263-9268. GRAIER,W. F., SCHMIDT,K. and KUKOVETZ,W. R. (1992) Is the bradykinin-induced Ca 2+ influx and the formation of endothelium-derived relaxing factor mediated by a G protein? Eur. J. Pharmac. (Molec. Pharmac.) 225: 43-49. GRIESBACHER,T. and LEMBECK,F. (1987) Effect of bradykinin antagonists on bradykinin-induced plasma extravasation, venoconstriction, prostaglandin E 2 release, nociceptor stimulation and contraction of the iris sphincter muscle of the rabbit. Br. J. Pharmac. 92: 333-340. GRIESBACHER,T. and LEMBECK,F. (1992a) Analysis of the antagonistic actions of HOE 140 and other novel bradykinin analogues on the guinea-pig ileum. Eur. J. Pharmac, 211: 393-398. GRIESBACHER,T. and LEMBECK,F. (1992b). Effects of the bradykinin antagonist HOE 140 in experimental pancreatitis. Br. J. Pharmac. 107: 356-360. GRIESBACHER,T., LEMBECK,F. and SARIA,A. (1989) Effects of the bradykinin antagonist B4310 on smooth muscles and blood pressure in the rat and its enzymatic degradation. Br. J. Pharmac. 96: 531-538. GUIMAR~,ES,J. A., VIERA,M. A. R., CAMARGO,M. J. F. and MAACK,T. (1986) Renal vasoconstrictive effect of kinins mediated by Bt-kinin receptors. Eur. J. Pharmac. 130: 177-185. GUTOWSKI,S., SMRCKA,A., NOWAK, L., WU, D., SIMON,M. and STERNWEm,P. C. (1991) Antibodies to the ~tq subfamily of guanine nucleotide-binding regulatory protein ct subunits attenuate activation of phosphatidylinositol 4,5-bisphosphate hydrolysis by hormones. J. biol. Chem. 266: 20519-20524. HALEY, J. E., DICKENSON,A. n. and SCHACHTER,M. (1989) Electrophysiological evidence for a role of bradykinin in chemical nociception in the rat. Neurosci. Lett. 97: 198-202. HALL, O. W. R. and BONTA,I. L. (1973) The biphasic response of the isolated guinea-pig ileum by bradykinin. Eur. J. Pharmac. 21: 147-154. HALL,J. M. (1990) Neuropeptide receptors and mechanisms in smooth muscle preparations of the guinea-pig and rat. Ph.D. Thesis, University of London. HALL, J. M. and MORTON,I. K. M. (1991a) Bradykinin BE receptor evoked K + permeability increase mediates relaxation in the rat duodenum. Eur. J. Pharmac. 193: 231-238. HALL,J. M. and MORTON,I. K. M. (1991b) Subtypes and excitation-contraction coupling mechanisms for neurokinin receptors in smooth muscle of the guinea-pig taenia caeci. Naunyn-Schmiedeberg's Arch. Pharmac. 344: 225-234. HALL, J. M., FIELD,J. L. and MORTON,I. K. M. (1991a) Putative BK3 receptors in the guinea-pig taenia caeci. Br. J. Pharmac. 104: 140P. HALL, J. M., MITCHELL,O. and MORTON, I. K. M. (1991b) Neurokinin receptors in the rabbit iris sphincter characterised by novel agonist ligands. Eur. J. Pharmac. 199: 9-14. HALL, J. M., MITCHELL,D., CHIN, S. Y., FIELD,J. L., EVERETT,C. M. and MORTON,I. K. M. (1992) Differences in affinities of bradykinin B2-receptor antagonists may be attributable to species. Neuropeptides 22: 28-29. HARGREAVES,K. M., TROULLOS,E. S., DIONNE, R. A., SCHMIDT,E. A., SCHAEER,S. C. and JORIS,J. L. (1988) Bradykinin is increased during acute and chronic inflammation: therapeutic implications. Clin. Pharmac. Ther. 44:613-621. HERXHEIMER,H. and STRESEMANN,E. (1961) The effect of bradykinin aerosol in guinea-pigs and in man. J. Physiol. 158: 38P-39P. HEss, J. F., BORKOWSKI,J. A., YOUNG, G. S., STRADER,C. D. and RANSOM,R. W. (1992) Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor. Biochem. biophys. Res. Commun. 184: 260-268.


183

HIGASmDA,H. and Bgowr~, D. A. (1986) Two polyphosphatidylinositide metabolites control two K + currents in a neuronal cell. Nature 323: 333-335. HIGASrnDA, H., STP,~TY, R. A., KLEE, W. and NII~NBERG,M. (1986) Bradykinin-activated transmembrane signals are coupled via N O or Ni to production of inositol 1,4,5-trisphosphate, a second messenger in NG108-15 neuroblastoma-glioma hybrid cells. Proc. natn. Acad. Sci. U.S.A. 83: 942-946. HIC_,GnqS,P. G., BARROW, G. I. and TYgRELL,D. A. J. (1990) A study of the efficacy of the bradykinin antagonist, NPC 567 in rhinovirus infections in human volunteers. Antiviral Res. 14: 339-344. HOCK, F. J., WIRTH,K., ALBUS,U., LINZ, W., GERHARDS,H. J., WIEMER,G., HENKE,ST., BREIPOHL,G.,KON1G, W., KNOLLE,J. and SCHtLKENS,B. A. (1991) Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies. Br. J. Pharmac. 102: 769-773. HOJVAT,S. A., MU$CH,M. W. and MILLER,R. J. (1983) Stimulation of prostaglandin production in rabbit ileal mucosa by bradykinin. J. Pharmac. exp. Ther. 226: 750-755. HORWITZ,J. (1991) Bradykinin activates a phospholipase D that hydrolyses phosphatidylcholine in PCI2 cells. J. Neurochem. 56: 509-517. HUIIX)BRO-TORo,J. P., HERREROS, R. and PINTO-CORgADO,A. (1986) Pre- and postsynaptic bradykinin responses in the rat vas deferens: asymmetric distribution of the postsynaptic effect. Eur. J. Pharmac. 121: 305-311. ICHINOSE,M., BELVISI,M. G. and BARNES,P. J. (1990) Bradykinin-induced bronchoconstriction in guinea-pig in vivo : role of neural mechanisms. J. Pharmac. exp. Ther. 253: 594-599. INNIS,R. B., MANNING,D. C., STEWART,J. M. and SNYDER,S. H. (1981) [3H]Bradykinin receptor binding in mammalian tissue membranes. Proc. natn. Acad. Sci. U.S.A. 78: 2630-2634. INOKI,R. and KUDO,T. (1986) Enkephalins and bradykinin in dental pulp. Trends Pharmac. Sci. 275: 275-277. ISSANDOU,M. and DARBON,J.-M. (1991) Des-arg9-bradykinin modulates DNA synthesis, phospholipase C and protein kinase C in cultured mesangial ceils. J. biol. Chem. 266: 2103%21043. ISSANOOU,M. and ROZENGURT,E. (1990) Bradykinin transiently activates protein kinase C in Swiss 3T3 cells. J. biol. Chem. 265: 11890-11896. JENKINSON,D. H. and MORTON,I. K. M. (1967) The role of ~t- and/~-adrenergic receptors in some actions of catecholamines on intestinal smooth muscle. J. Physiol. 188: 387-402. JIN, L. S., SEEDS,E., PAGE,C. P. and SCI~C~ITER,M. (1989) Inhibition of bradykinin-induced bronchoconstriction in the guinea-pig by a synthetic B2 receptor antagonist. Br. J. Pharmac. 97: 598-602. JUAN, H. and LEMBECK,F. (1974) Action of peptides and other algesic agents on paravascular pain receptors of the isolated perfused rabbit ear. Naunyn-Schmiedeberg's Arch. Pharmac. 283: 151-164. KACHUR,J. F., ALLBEE,W. and GAGINELLA,T. S. (1986) Effect of bradykinin and des-Arg9-bradykinin on ion transport across normal and inflamed rat colonic mucosa. Gastroenterology 90: 1481. KACHUR, J. F., ALLBEE, W., DANHO, W. and GAGINELLA,T. S. (1987) Bradykinin receptors: functional similarities in guinea pig gut muscle and mucosa. Regul. Pept. 17: 63-70. KAYA, H., PATTON, G. M. and HONG, S. L. (1989) Bradykinin-induced activation of phospholipase A 2 is independent of the activation of polyphosphoinositide-hydrolyzing phospholipase C. J. biol. Chem. 264: 4972-4977. KELLERMEYER,R. W. and GRAHAM,R. C. (1968) Kinins--possible physiologic and pathologic roles in man. New Engl. J. Med. 279: 754-759. KERAVIS,T. M., NEHLIG,H., DELACROIX,M.-F., REGOLI,D., HILEY, C. R. and STOCLET,J.-C. (1991) Highaffinity bradykinin B2 binding sites sensitive to guanine nucleotides in bovine aortic endothelial cells. Eur. J. Pharmac. (Molec. Pharmac.) 207: 149-155. KOLTZENBURG,M., KRESS, M. and REE~q,P. W. (1992) The nociceptor sensitization by bradykinin does not depend on sympathetic neurons. Neuroscience 46: 465-473. KYLE, H. and WtODICOMEE,J. G. (1987) The effects of peptides and mediators on mucus secretion rate and smooth tone in the ferret trachea. Agents Actions 22: 86-90. KYLE,D. J., HICKS,R. P., BLAKE,P. R. and KL1MKOWSKI,V. J. (1991a) Conformational properties of bradykinin and bradykinin antagonists. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 131-146, BugcH, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hong Kong. KYLE, D. J., MARTIN,J. A., FARMER,S. G. and BURGH,R. M. (1991b) Design and conformational analysis of several highly potent bradykinin receptor antagonists. J. Med. Chem. 34: 1230-1233. LAWRENCE, I. D., WARNER, J. A., COHAN, V. L., LICHTENSTEIN,L. M., KAGEY-SOBOTKA,A., VAVREK, R. J., STEWART,J. M. and PROUD, D. (1989) Induction of histamine release from human skin mast cells by bradykinin analogues. Biochem. Pharmac. 38: 227-233. LEEB-LUNDBERG,L. M. F. and MATHIS,S. A. (1990) Guanine nucleotide regulation of B2 kinin receptors. J. biol. Chem. 265: 9621-9627. LEIKAUF,G. D., UEKI, I. F., NADEL,J. A. and WIDDICOMnE,J. H. (1985) Bradykinin stimulates CI- secretion and prostaglandin E2 release by canine tracheal epithelium. Am. J. Physiol. 248: F48-F55. LEMBECK,F., GRIESBACHER,T., ECKHARDT,M., HENKE,S., BREIPOHL,G. and KNOLLE,J. (1991) New, long-acting, potent bradykinin antagonists. Br. J. Pharmac. 102: 297-304. LEME,J. G. and WALASZECK,E. J. (1967) Antagonists of pharmacologically active peptides: effect on guinea-pig ileum and inflammation. Pharmacologist 9: 242. LERNER, U. H. and MODI~ER,T. (1991) Bradykinin BI and B2 receptor agonists synergistically potentiate interleukin-l-induced prostaglandin biosynthesis in human gingival fibroblasts. Inflammation 15: 427-436.

184

J.M. HALL

LEUKART,O., CAVIEZEL,M., EBERLE,A., ESCHER,E., TUNKYI,A. and SCHWYZER,R. (1976) L-O-Carboranylalanine, a boron analogue of phenylalanine. Helv. Chim. Acta 59: 2184-2187. LEWIS, G. P. (1970) Kinins in inflammation and tissue injury. In: Handbook o f Pharmacology. Bradykinin, Kallidin and Kallikrein, pp. 516-530, ERD6S, E. G. (ed.) Springer-Verlag, Berlin, Heidelberg, New York. LEWIS, R. E., CHILDERS,S. R. and PHILLIPS,M. I. 0985) [~25I]-Tyr-bradykinin binding in primary rat brain cultures. Brain Res. 346: 263-272. LIBBY, P., ORDOVAS,J. M., AUGER, K. R., ROBBINS,A. H., BIRINYI,L. K. and DINARELLO,C. A. (1986a) Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am. J. Path. 124: 179-185. LIBBY,P., ORDOVAS,J. M.,BIRINYI,L. K., AUGER,K. R. and DINARELLO,C. (1986b) Inducible interleukin-1 gene expression in human vascular smooth muscle cells. J. clin. Invest. 78: 1432-1438. LIEBMANN,C., REISSMANN,S., ROaBERECHT,P. and AROLD,H. (1987) Bradykinin action in the rat duodenum: Receptor binding and influence on the cyclic AMP system. Biomed. Biochim. Acta 46: 469-478. LIEBMANN,C., OffERMANNS,S., SPICHER,K., HINSCH, K.-D., SCHNITTLER,M., MORGAT,J. L., REISSMANN,S., SCHULTZ,G. and ROSENTHAL,W. (1990) A high-affinity bradykinin receptor in membranes from rat myometrium is coupled to pertussis toxin-sensitive G-protein of the G~-family. Biochem. biophys. Res. Commun. 167: 910-917. LIEBMANN,C., SCHNITTLER,M., STEWART,J. M. and REISSMANN,S. (1991) Antagonist binding reveals two heterogenous B2 bradykinin receptors in rat myometrial membranes. Eur. J. Pharmac. 199: 363-365. LINDSEY,C. J., NAKAIE,C. R. and MARTINS,D. T. O (1989) Central nervous system kinin receptors and the hypertensive response mediated by bradykinin. Br. J. Pharmac. 97: 763-768. LINZ, W. and SCH()LKENS,B. A (1992) A specific BE-bradykinin receptor antagonist HOE 140 abolishes the antihypertrophic effect of ramipril. Br. J. Pharmac. 105: 771-772. LJUNGGREN, O. and LERNER,U. H. (1990) Evidence for BKI bradykinin-receptor-mediated prostaglandin formation in osteoblasts and subsequent enhancement of bone resorption. Br. J. Pharmac. 101: 382-386. LLONA, I., VAVREK,R., STEWART,J. and HUIDOBRO-TORO,J. P. (1987) Identification of pre- and postsynaptic bradykinin receptor sites in the vaN deferens: evidence for different structural prerequisites. J. Pharmac. exp. Ther. 241: 608--614. LLONA,I., GALLEGUILLOS,X., BELMAR,J. and HUIDOBRO-TORO,J. P. (1991) Bradykinin modulates the release of noradrenaline from van deferens nerve terminals. Life Sci. 48: 2585-2592. LONGRIDGE,D. J., SCHACHTER,M., STEWART,J. M., UCHIDA,Y. and VAVREK,R. J. (1986) Synthetic competitive antagonists of bradykinin on vascular permeability in the rabbit. J. Physiol. 372: 73P. MADEDDU,P., ANANIA,V., PARPAGLIA,P. P., DEMONTIS,M. P., VARONI,M. V., PISANU,G., TROFFA,C., TONOLO, G. and GLORIOSO,N. (1992) Effects of Hoe 140, a bradykinin BE-receptor antagonist, on renal function in conscious normotensive rats. Br. J. Pharmac. 106: 380-386. MAGGI, C. A., PATACCHINI,R., SANTICIOLI,P., GEPPETTI, P., CECCONI,R., GIULIANI,S. and MELI, A. (1989) Multiple mechanisms in the motor responses of the guinea-pig isolated urinary bladder to bradykinin. Br. J. Pharmac. 98: 619~29. MAHAN, L. C. and BURCH, R. M. (1990) Functional expression of B2 bradykinin receptors from Balb/C cell mRNA in Xenopus oocytes. Molec. Pharmac. 37: 785-789. MAK, J. C. W. and BARNES,P. J. (1991) Autoradiographic visualization of bradykinin receptors in human and guinea-pig lung. Eur. J. Pharmac. 194: 37-43. MANNING, D. C., SNYDER, S. H., KACHUR, J. F., MILLER, R. J. and FIELD, M. (1982) Bradykinin receptormediated chloride secretion in intestinal function. Nature 299: 256-259. MANNING, D. C., VAVREK,R., STEWART,J. M. and SNYDER,S. H. (1986) Two bradykinin binding sites with picomolar affinities. J. Pharmac. exp. Ther. 237: 504-512. MANTIONE,C. L. and RODRIGUEZ,R. (1990) A bradykinin (BK)I receptor antagonist blocks capsaicin-induced ear inflammation in mice. Br. J. Pharmac. 99: 516-518. MARCEAU,F. and REGOLI,D. (1991) Kinin receptors of the B1 type and their antagonists. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 33-49, BURCI4, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hong Kong. MARCEAU,F. and TREMBLAY,B. (1986) Mitogenic effect of bradykinin and of des-Arg9-bradykinin on cultured fibroblasts. Life Sci. 39: 2351-2358. MARCEAU,F., BARABI~,J., ST. PIERRE,S and REGOLI,O. (1980) Kinin receptors in experimental inflammation. Can. J. Physiol. Pharmac. 58: 536-542. MARCEAU, F., LUSSIER,A., REGOLI,O. and GIROUD,J. P. (1983) Pharmacology of kinins: their relevance to tissue injury and inflammation. Gen. Pharmac. 14: 209-229. MARCEAU, F., LUSS1ER,A. and ST. PIERRE, S. (1984) Selective induction of cardiovascular responses to des-Arg9-bradykinin by bacterial endotoxin. Pharmacology 29: 70-74. MARGOLIUS,H. S. (1989) Tissue kallikreins and kinins: regulation and roles in hypertensive and diabetic diseases. A. Rev. Pharmac. Toxic. 29: 343-364. MARTINS,D. Z. O., FIOR, D. R., NAKAIE,C. R. and LINDSEY,C. J. (1991) Kinin receptors of the central nervous system of spontaneously hypertensive rats related to the pressor response to bradykinin. Br. J. Pharmac. 103: 1851-1856.


185

McEACHERN,A. E., SI-IELTON,E. R., BHAKTA,S., OBERNOLTE,R., BACH,C., ZUPPAN,P., FUJISAKA,J., ALDRICH, R. W. and JARNAGIN,K. (1991) Expression cloning of a rat B2 receptor. Proc. natn. Acad. Sci. U.S.A. 88: 7724-7728. MILLER, R. J. (1987) Bradykinin highlights the role of phospholipid metabolism in the control of nerve excitability. Trends Neurosci. 10: 226-228. MIZRAHI,J., D'ORLI~ANS-JusTE,P., CARANIKAS,S. and REGOLI,n. (1982) Effects of peptides and amines on isolated guinea-pig tracheae as influenced by inhibitors of the metabolism of arachidonic acid. Pharmacology 25: 320-326. MIZUMURA,K., MINAGAWA,M., TsuJII, Y. and KUMAZAWA,T. (1990) The effects of bradykinin agonists and antagonists on visceral polymodal receptor activities. Pain 40: 221-227. MODf~ER, T., LJUNGGREN, O. and LERNRER, U. H. (1990) Bradykinin-2 receptor-mediated release of [3H]arachidonic acid and formation of prostaglandin E2 in human gingival fibroblasts. J. Periodont. Res. 25: 358-363. MOMBOULI,J.-V. and VANHOUTTE,P. M. (1992) Kinins mediate kallikrein-induced endothelium-dependent relaxations in isolated canine coronary arteries. Biochem. biophys. Res. Commun. 185: 693~97. MOUSLI, M., BULB,J.-L., BRONNER,C., ROUOT,B. and LANDRY,Y. (1990) G protein activation: a receptorindependent mode of action for cationic amphiphilic neuropeptides and venom peptides. Trends Pharmac. Sci. I1: 358-362. MURRAY,M. A., HEISTAD,D. n. and MAYI-IAN,W. G. (1991) Role of protein kinase C in bradykinin-induced increases in microvascular permeability. Circ. Res. 68: 1340-1348. MUSCH, M. W., KACHUR, J. F., MILLER, R. J., FIELD, M. and STOFF, J. S. (1983) Bradykinin-stimulated electrolyte secretion in rabbit and guinea-pig intestine. Involvement of arachidonic acid metabolites. J. clin. Invest. 71: 1073-1083. NACLERIO, R. M., PROUD, D., TOGIAS,A. G., ADKINSON,N. F., JR, MEYERS, D. A., KAGEY-SOBOTKA,A., PLAUT,M., NORMAN,P. S. and LICHTENSTEIN,L. M. (1985) Inflammatory mediators in late antigen-induced rhinitis. New Engl. J. Med. 313: 65-70. NACLERIO,R. M., PROUD, O., LICHTENSTEIN,L. M., KAGEY-SOBOTKA,A., HENDLEY,J. O., SORRENTINO,J. and GWALTNEYJ. M., JR (1987) Kinins are generated during experimental rhinovirus colds. J. Infect. Dis. 157: 133-142. NEWBALL,H. H., KEISER,H. R. and PISANO,J. J. (1975) Bradykinin and human airways. Resp. Physiol. 24: 139-146. ODYA, C. E. and GOODERIEND,T. L. (1973) Bradykinin binding by tissues. Fed. Proc. 32: 766. ODYA,C. E., GOODFRIEND,T. L. and PEUA,C. (1980) Bradykinin receptor-like binding studied with iodinated analogues. Biochem. Pharmac. 29: 175-185. OKAMOTO,H. and GREENBAUM,L. M. (1983) Isolation and structure of T-kinin. Biochem. biophys. Res. Commun. 112: 701-708. OLSEN, R., SANTONE,K., MELDER,D., OAKES,S. G., ABRAHAM,R. and PowIs, G. (1988) An increase in intracellular free Ca 2÷ associated with serum-free growth stimulation of Swiss 3T3 fibroblasts by epidermal growth factor in the presence of bradykinin. J. biol. Chem. 263: 18030-18035. O'NEILL, L. A. J. and LEWIS,G. P. (1989) Interleukin-1 potentiates bradykinin- and TNF~-induced PGE2 release. Eur. J. Pharmac. 166: 131-137. ORCE, G. G., CARRETERO,O. A., SCICLI,G. and SCICLI,A. G. (1989) Kinins contribute to the contractile effect of rat glandular kallikrein on the isolated rat uterus. J. Pharmac. exp. Ther. 249: 470--475. OSUGI, T., IMAIZUMI,T., MIZUSHIMA,A., UCHIDA,S. and YOSHIDA,H. (1987) Role of a protein regulating guanine nucleotide binding in phosphoinositide breakdown and calcium mobilization by bradykinin in neuroblastoma X glioma hybrid NG108-15 cells: effects of pertussis toxin and cholera toxin on receptormediated signal transduction. Eur. J. Pharmac. 137: 207-218. PAEGELOW,I., REISSMANN,S., VIETINGHOFF,G., REMER,W. and AROLD,H. (1977) Bradykinin action in the rat duodenum through the cyclic AMP system. Agents Actions 7: 447451. PAIVA,A. C. M., PAIVA,T. B., PEREIRA,C. C. and SHIMUTA,S. I. (1989) Selectivity of bradykinin analogues for receptors mediating contraction and relaxation of the rat duodenum. Br. J. Pharmac. 98: 206-210. PARRIES,G., HOEBEL,R. and RACKER,E. (1987) Opposing effects of a ras oncogene on growth factor-stimulated phosphoinositide hydrolysis. Desensitization to platelet-derived growth factor and enhanced sensitivity to bradykinin. Proc. hath. Acad. Sci. U.S.A. 84: 2648-2652. PATEL,K. V. and SCHREY,M. P. (1992) Inhibition of DNA synthesis and growth in human breast stromal cells by bradykinin: evidence for independent roles of Bl and B2 receptors in the respective control of cell growth and phospholipid hydrolysis. Cancer Res. 52: 334-340. PEREIRA,C. C. and PAIVA,T. B. (1989) Characterization of the receptors responsible for the diphasic effect of bradykinin in rat duodenum. Braz. J. reed. Biol. Res. 22:1137-1140. PERKINS, M. N., FORSTER,P. L. and DRAY,A. (1988) The involvement of afferent nerve terminals in the stimulation of ion transport by bradykinin in rat isolated colon. Br. J. Pharmac. 94: 47-54. PERKINS, M. N., BURGESS,G. M., CAMPBELL,E. A., HALLETT,A., MURPHY, R. J., NAEEM,S., PATEL,I. A., PATEL,S., RUEFF,A. and DRAY,A. (1991) HOEI40: a novel bradykinin analogue that is a potent antagonist at both B2 and B3 receptors in vitro. Br. J. Pharmac. 102: 171. PERKINS,M. N., CAMPBELL,E. A., DAVIS,A. and DRAY,A. 0992) Anti-nociceptive activity of bradykinin Bt and B2 antagonists in two models of persistent hyperalgesia in the rat. Br. J. Pharmac. 107: 237.

186

J.M. HALL

PERRY,D. C. and SNYDER,S. H. (1984) Identification of bradykinin in mammalian brain. J. Neurochem. 43: 1072-1080.

PETTIBONE,D. J., CLINESCHMIDT,B. V., Lis, E. V., RANSOM,R. W., TOTARO,J. A., YOUNG,G. S., BOCK, M. G., FREIDINGER,R. M., VEBER,D. F. and WILLIAMS,P. D. (1991) Bradykinin agonist activity of a novel, potent oxytocin antagonist. Eur. J. Pharmac. 196: 233-237. PHILLIPS,E., CONDER,M. J., BEVAN,S., MCINTYRE,P. and WEBB,M. (1992) Expression of functional bradykinin receptors in Xenopus oocytes. J. Neurochem. 58:243 249. PHILLIPS, J. A. and HOULT, J. R. S. (1988) Secretory effects of kinins on colonic epithelium in relation to prostaglandins released from cells of the lamina propria. Br. J. Pharmac. 95: 701-712. P1SANO,J. J. (1979) Kinins in nature. In: Handbook of Experimental Pharmacology: Bradykinin, Kallidin and Kallikrein, pp. 273-285, ERDOS, E. G. (ed.) Springer-Verlag, Berlin, Heidelberg, New York. PLEVIN, R. and OWEN, P. J. (1988) Multiple B2 kinin receptors in mammalian tissues. Trends Pharmac. Sci. 9: 387-389. PONGRACIC,J. A., CHURCHILL,L. and PROUD,D. (1991a) Kinins in rhinitis. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 237 259, BURCH, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hong Kong. PONGRAC1C,J. A., NACLEIRO,R. M., REYNOLDS,C. J. and PROUD, D. (1991b) A competitive kinin receptor antagonist [o-Arg°,Hyp3,o-Phe7]-bradykinin does not effect the response to nasal provocation with bradykinin. Br. J. clin. Pharmac. 31: 287-294. PROUD, D. and KAPLAN,A. P. (1988) Kinin formation: mechanisms and role in inflammatory disorders. A. Rev. Immun. 6: 49-83. PROUD, D., TOGIAS,A., NACLERIO,R. M., CRUSH, S. A., NORMAN,P. S. and LICHTENSTEIN,L. M. (1983) Kinins are generated in vivo following nasal airway challenge of allergic individuals with allergen. J. clin. Invest. 72:1678 1685. PROUD, D., REYNOLDS, C. J., LA CAPRA, S., KAGEY-SOBOTKA,A., LICHTENSTEIN,L. M. and NACLEROI,R. M. (1988) Nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat. Am. Rev. Resp. Dis. 137: 613-616. PURKISS, J., MURRIN,R. A., OWEN,P. J. and BOARDER,M. R. (1991) Lack of phospholipase D activity in chromaffin cells: bradykinin-stimulated phosphatidic acid formation involves phospholipase C in chromarlin cells but phospholipase D in PCl2 cells. J. Neurochem. 57: 1084-1087. RAJAKULASINGAM,K., POLOSA,R., HOLGATE,S. T. and HOWARTH,P. H. (1991) Comparative nasal effects of bradykinin, kallidin and [des-Argq]-bradykinin in atopic rhinitic and normal volunteers. J. Physiol. 437: 577-587. RANGACHARI,P. K., DONOEE,B., VAVREK,R. J. and STEWART,J. M. (1990) Luminal responses to bradykinin on the isolated canine tracheal epithelium: effects of bradykinin antagonists. Regul. Pept. 30: 221-230. RANSOM, R. W., GOODMAN,C. B. and YOUNG, G. S. (1992a) Bradykinin stimulation of phosphoinositide hydrolysis in guinea-pig ileum longitudinal muscle. Br. J. Pharmac. 105: 919-924. RANSOM, R. W., YOUNG, G. S., SCHNECK,K. and GOODMAN,C. I. (1992b) Characterization of solubilized B2 receptors from smooth muscle and mucosa of guinea-pig ileum. Biochem. Pharmac. 43: 1823-1827. REGOLI,D. and BARABI~,J. (1980) Pharmacology of bradykinin and related kinins. Pharmac. Rev. 32: 1-46. REGOLI, D., BARABI~,J. and PARK, W. K. (1977) Receptors for bradykinin in rabbit aortae. Can. J. Physiol. Pharmac. 55: 855-867. REGOLI,D., MARCEAU,F. and BARABI~,J. (1978) De novo formation of vascular receptors for bradykinin. Can. J. Physiol. Pharmac. 56: 674-677. REGOLI,O. C., MARCEAU,F. and LAVIGNE,J. (1981) Induction of B~-receptors for kinins in the rabbit by a bacterial lipopolysaccharide. Fur. J. Pharmac. 71: 105-115. REGOLI, D., DRAPEAU,G., ROVERO,P., DION, S., D'ORLI~ANS-JUSTE,P. and BARABI~,J. (1986a) The actions of kinin antagonists on B~ and B2 receptor systems. Eur. J. Pharmac. 123: 61~5. REGOLI, O., DRAPEAU, G., ROVERO, P., DION, S., RHALEB, N.-E., BARABI~,J., D'ORLI~ANS-JUSTE,P. and WARD,P. (1986b) Conversion of kinins and their antagonists into B~ receptor activators and blockers in isolated vessels. Eur. J. Pharmac. 127: 219-224. REGOLI,D., RHALEB,N.-E., DION,S. and DRAPEAU,G. (1990a) New selective bradykinin receptor antagonists and bradykinin B2 receptor characterization. Trends Pharmac. Sci. 11: 156-161. REGOLI, D., RHALEB,N. -E., DRAPEAU, G. and DION, S. (1990b) Kinin receptor subtypes. J. Cardiovasc. Pharmac. 15: $30-$38. REGOLI,D., RHALEB,N.-E., TOUSIGNANT,C., ROUISSI,N., NANTEL,F., JUKIC, D. and DRAPEAU,G. (1991) New highly potent bradykinin B2 receptor antagonists. Agents Actions 34: 138-141. REGOLI,D., JUKIC,D., TOUSIGNANT,C. and RHALEB,N.-E. (1992) Kinin receptor classification. In: Recent Progress on Kinins, Vol. 38/I, pp. 475-485, BONNER,G., FRITZ, H., UNGER,TH., ROSCHER,A. and LUPPERTZ, K. (eds.) Birkhafiser Verlag, Basel, Boston, Berlin. REISER,G., BINMOLLER,F.-J., STRONG,P. N. and HAMPRECHT,B. (1990) Activation of a K + conductance by bradykinin and by inositol-l,4,5-trisphosphate in rat glioma cells: involvement of intracellular and extracellular Ca 2+ . Brain Res. 506: 205-214. REISSMANN,S., PAGELOW,I., L1EBMANN,C., STEINMETZGER,H., JANKOVA,T. and AROLD, H. (1977) Investigations on the mechanism of bradykinin action on smooth muscles. In: Physiology and Pharmacology of Smooth Muscle, pp. 208-217, PAPASOVA,M. and ATANASSOVA,E. (eds.) Bulgarian Academy of Science, Sofia.


187

RHALEB,N.-E., DION,S., D'ORLI~ANS-JUSTE,P., DRAPEAU,G., REGOLI,D. and BROWNE,R. G. (1988) Bradykinin antagonism: differentiation between peptide antagonists and antiinflammatory agents. Fur. J. Pharmac. 151: 275-279. RHALEB,N.-E., DRAPEAU,G., DION, S., JUKIC,D., ROUISSI,N. and REGOLI,D. (1990a) Structure-activity studies on bradykinin and related peptides; agonists. Br. J. Pharmac. 99: 445-448. RHALES, N.-E., ROUISSI,N., DRAPEAU,G., JUKIC, D. and REGOLI,D. (1990b) Characterization of bradykinin receptors in peripheral organs. Can. J. Physiol. Pharmac. 69: 938-943. RHALEB,N.-E., ROUISSl,N., JUKIC, D., REGOLI,D., HENKE, S., BREIPOHL,G. and KNOLLE,J. (1992) Pharmacological characterization of a new highly potent B2 receptor antagonist (HOE 140: D-Arg-[Hyp3,ThiS,D TicT,OicS]bradykinin). Fur. J. Pharmac. 210: 115-120. RIFO, J., POURRAT,M., VAVREK,R. J., STEWART,J. M. and HUIDOBRO-ToRo,J. P. (1987) Bradykinin receptor antagonists used to characterize the heterogeneity of bradykinin-induced responses in rat vas deferens. Eur. J. Pharmac. 142: 305-312. RINDERKNECHT,H., HAVERBACK,B. J. and ALADJEM,F. (1967) Radioimmunoassay of bradykinin. Nature 213: 1130-1131. RITTER, J. M., DOKTOR,H. S. and CRAGOE,E. J. (1989) Actions of bradykinin and related peptides on rabbit coeliac artery rings. Br. J. Pharmac. 96: 23-28. ROBERTS,R. A. (1989) Bradykinin receptors: characterization, distribution and mechanisms of signal transduction. Prog. Growth Factor Res. 1: 237-252. ROBERTS,R. A. and GUILLICK,W. J. (1989) Bradykinin receptor number and sensitivity to ligand stimulation of mitogenesis is increased by expression of a mutant ras oncogene. J. Cell Sci. 94: 527-535. ROCH-ARVEILLER,M., REGOLI,D. and GIROUD,J.-P. (1981) Effect of bradykinin and various synthetic analogues on rat polymorphonuclear chemotaxis. Agents Actions 11: 499-502. ROCH-ARVEILLER,M., GIROUD,J. P. and REGOLI,D. (1985) Kinins and inflammation. Emphasis on interactions of kinins with various cell types. In: Progress in Applied Microcirculation. White Cells Rheology and Inflammation, pp. 81-95, KELLER, H. (ed.) Karger, Basel. ROCHAE SILVA,M. (1962) Definition of bradykinin and other kinins. Biochem. Pharmac. 10: 3-23. ROCHAE SILVA,M., BERALDO,W. T. and ROSENFELD,G. (1949) Bradykinin, hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venom and by trypsin. Am. J. Physiol. 156: 261-273. ROSCHER, A. A., KLIER, C., DENGLER,R., FAUBNER,A. and Mf0LLER-ESTERL,W. (1990) Regulation of bradykinin action at the receptor level. J. Cardiovasc. Pharmac. 15: $39-$43. RUGGIERO,M., SR1VASTAVA,S. K., FLEMING,T. P., RON, D. and EVA,A. (1989) NIH3T3 fibroblasts transformed by the dbl oncogene show altered expression of bradykinin receptors: effect on inositol lipid turnover. Oncogene 4: 767-771. SAHA,J. K., SENGUPTA,J. N. and GOYAL,R. K. (1990) Effect of bradykinin on opossum esophageal longitudinal smooth muscle: evidence for novel bradykinin receptors. J. Pharmac. exp. Ther. 252: 1012-1020. SAHA,J. K., SENGUPTA,J. N. and GOYAL,R. K. (1991) Effects of bradykinin and bradykinin analogues on the opossum lower esophageal sphincter: characterization of an inhibitory bradykinin receptor. J. Pharmac. exp. Ther. 259: 265-273. SAKAMOTO,T., ELWOOD,W., BARNES,P. J. and CHUNG,K. F. (1992) Effect of HOE 140, a new bradykinin receptor antagonist, on bradykinin- and platelet-activating factor-induced bronchoconstriction and airway microvascular leakage in guinea-pig. Eur. J. Pharmac. 213: 367-373. SARIA, A., MARTLING,C.-R., YAN, Z., THEODORSSON-NORHEIM,E., GAMSE, R. and LUNDBERG,J. M. (1988) Release of multiple tachykinins from capsaicin-sensitive sensory nerves in the lung by bradykinin, histamine, dimethylphenyl piperazinium and vagal nerve stimulation. Am. Rev. Resp. Dis. 137: 1330-1335. SCHACHTER,M. (1964) Kinins--a group of active peptides. A. Rev. Pharmac. 4: 281-292. SCHACHTER,M. (1980) Kallikreins (kininogenases)--A group of serine proteases with bioregulatory actions. Pharmac. Rev. 31: 1-17. SCUACnTER, M. (1983) Kallikreins and kinins, an overview: some thoughts old and new. In: Kinins III, Part A, pp. 13-27, FRITZ, H., BACK, N. and DIETZE, G. (eds.) Plenum Press, New York, London. SCHACHTER,M., UCHIDA,Y., LONGRIDGE,D. J., LABEDZ,T., WHALLEY,E. T., VAVREK,R. J. and STEWART,J. M. (1987) New synthetic antagonists of bradykinin. Br. J. Pharmac. 92: 851-855. SCHAFFEL,R., RODRIGUES,M. S. and ASSREUY,J. (1991) Potentiation of bradykinin effects and inhibition of kininase activity in isolated smooth muscle. Can. J. Physiol. Pharmac. 69: 904-908. SCHRODER,E. (1970) Structure-activity relationships of kinins. In: Handbook o f Experimental Pharmacology. Bradykinin, Kallidin and Kallikrein, pp. 324-350, ERDOS, E. G. (ed.) Springer, Berlin, Heidelberg, New York. SHARIF,N. A. and WHITING,R. L. (1991) Identification of B2-bradykinin receptors in guinea-pig brain regions, spinal cord and peripheral tissues. Neurochem. Int. 18: 89-96. SHARMA,J. N. (1988) Interrelationship between the kallikrein-kinin system and hypertension: a review. Gen. Pharmac. 19: 177-187. SHIBATA,M., OHKUBO,T., TAKAHASHI,H. and INOKI,R. (1986) Interaction of bradykinin with substance P on vascular permeability and pain response. Japan J. Pharmac. 41: 427-429. SHORLEY,P. G. and COLLIER,H. O. J. (1960) Bradykinin. Synthetic bradykinin: its biological identity with natural pure trypsin bradykinin. Nature 188: 999-1000.

188

J.M. HALL

SKIDGEL,R. A., JOHNSON,A. R. and ERDOS,E. G. (1984) Hydrolysis of opioid hexapeptides by carboxypeptidase N. Presence of carboxypeptidase in cell membranes. Biochem. Pharmac. 33: 3471-3478.

SLIVKA,S. R. and INSEL,P. A. (1988) Phorbol ester and neomycin dissociate bradykinin receptor-mediated arachidonic acid release and polyphosphoinositide hydrolysis in Madin-Darby canine kidney cells. J. biol. Chem. 263: 14640-14647. SMITH,K. A. (1980) T-cell growth factor. Immun. Rev. 51: 337-357. SNELL, P. H., PHILLIPS,E., BURGESS,G. M., SNELL,C. R. and WEBB,M. (1990) Characterization of bradykinin receptors solubilised from rat uterus and NG108-15 cells. Biochem. Pharmac. 39: 1921-1928. SNIDER,R. M. and RICHELSON,E. (1984) Bradykinin receptor-mediated cyclic GMP formation in a nerve cell population (murine neuroblastoma clone N1E-115). J. Neurochem. 43:1749-1754. SNIDER, R. M., CONSTANTINE,J. W., LOWE, J. A., LONGO, K. P., LEBEL,W. S., WOODY, H. A., DROZDA,S. E., DESAI,M. C., VINICK,F. J., SPENCER,R. W. and HESS,H.-J. (1991) A nonpeptide antagonist of the substance P (NKI) receptor. Science 251: 435-437. SPRAGG, J., AUSTEN,K. F. and HABER,F. (1966) Production of antibody against bradykinin: demonstration of specificity by complement fixation and radioimmunoassay. J. Immun. 96: 865-871. SPRAGG,J., VAVREK,R. J. and STEWART,J. M. (1988) The inhibition of glandular kallikrein by peptide analogue antagonists of bradykinin. Peptides 9: 203-206. SPRAGGS, C. F., MARGOLIUS,H. S. and CUTHBERT,A. W. (1983) Selective activity of cyclokinins. J. Pharm. Pharmac. 35: 266-268. STERANKA,L. R. and BURCH, R. M. (1991) Bradykinin antagonists in pain and inflammation. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 191-211, BURCH, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hung Kong. STERANKA, L. R., DEHAAs, C. J., VAVREK, R. J., STEWART,J. M., ENNA, S. J. and SNYDER, S. H. (1987) Antinociceptive effects of bradykinin antagonists. Eur. J. Pharmac. 136: 261-262. STERANKA,L. R., MANNING,D. C., DEHAAS, C. J., FERKANY,J. W., BOROSKY,S. A., CONNOR,J. R., VAVREK, R. J., STEWART,J. M. and SNYDER,S. H. (1988) Bradykinin as a pain mediator: receptors are localized to sensory neurons and antagonists have analgesic actions. Proc. natn. Acad. Sci. U.S.A. 85: 3245-3249. STERANKA,L. R., FARMER,S. G. and BURCH, R. M. (1989) Antagonists of B2 bradykinin receptors. FASEB. J. 3: 2019-2025. STEWART,J. M. (1979) Chemistry and biologic activity of peptides related to bradykinin. In: Handbook o f Experimental Pharmacology: Bradykinin, Kallidin and Kallikrein, pp. 227-285, ERDt3S, E. G (ed.) SpringerVerlag, Berlin, Heidelberg, New York. STEWART,J. M. and VAVREK,R. M. (1991) Chemistry of peptide B2 bradykinin antagonists. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 51-96, BURCH, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hung Kong. STONER, J., MANGANIELLO,V. C. and VAUGHAN,M. (1973) Effects of bradykinin and indomethacin on cyclic GMP and cyclic AMP in lung slices. Proc. natn. Acad. Sci. U.S.A. 70: 3830-3833. SUNG, C.-P., ARLETH, A. J., SHIKANO,K. and BERKOWlTZ,B. A. (1988) Characterization and function of bradykinin receptors in vascular endothelial cells. J. Pharmac. exp. Ther. 247: 8-13. SUZUKI, K., ABICO,T. and ENDO, N. (1969) Synthesis of every kind of peptide fragments of bradykinin. Chem. Pharmac. Bull. 17: 1671-1678. SVANVlK, J., THORNELL,E. and ZETTERGREN,L. (1981) Gallbladder function in experimental cholecystitis. Surgery 89: 500-506. SZOLCS/~NYI,J. (1987) Selective responsiveness of polymodal nociceptors of the rabbit ear to capsaicin, bradykinin and ultra-violet irradiation. J. Physiol. 388: 9-23. TAMAOKI,J., KOBAYASHI,K., SAKAI,N., CHIYOTANI,A., KANEMURA,T. and TAKIZAWA,T. (1989) Effect of bradykinin on airway ciliary motility and its modulation by endopeptidase. Am. Rev. Resp. Dis. 140: 430-435. TERTOOLEN,L. G. J., TILLY,B. C., IRVlNE,R. F. and MOOLENAAR,W. H. (1987) Electrophysiological responses to bradykinin and microinjected inositol polyphosphates in neuroblastoma cells. FEBS Lett. 214: 365-369. TIFFANY,C. W. and BURCH,R. M. (1989) Bradykinin stimulates tumor necrosis factor and interleukin-l release from macrophages. FEBS Lett. 247: 189-192. TODA, N., BAIN, K., AKIBA,T. and OKAMURA,T. (1987) Heterogeneity of bradykinin action in canine isolated blood vessels. Eur. J. Pharmac. 135: 321-329. TOGO, J., BURCH, R. M., DEHAAS,C. J., CONNOR,J. R. and STERANKA,L. R. (1989) n-PheT-substituted peptide bradykinin antagonists are not substrates for kininase II. Peptides 10:109-112. TOUSIGNANT,C., DION, S., DRAPEAU,G. and REGOLI,D. (1987) Characterization of pre- and postjunctional receptors for neurokinins and kinins in the rat vas deferens. Neuropeptides 9: 333-343. TOUSIGNANT,C., GUILLEMETTE,G., BARABI~,J., RHALEB,N.-E. and REGOLI,D. (1991) Characterization of kinin binding sites: identity of B2 receptors in the epithelium and the smooth muscle of the guinea-pig ileum. Can. J. Physiol. Pharmac. 69: 818-825. TOUSIGNANT,C., REGOLI,D., RHALEB,N.-E., JUKIC,D. and GUILLEMETTE,G. (1992) Characterization of a novel binding site for ~25I-Tyr-D-Arg-[Hyp3,n-Phe7,Leu 8]bradykinin on epithelial membranes of guinea-pig ileum. Eur. J. Pharmac. (Molec. Pharmac.) 225: 235-244. TRFILIEFF,A., HADDAD,E.-B., LANDRY,Y. and GIES, J.-P. (1991) Evidence for two high-affinity bradykinin binding sites in the guinea-pig lung. Eur. J. Pharmac. (Molec. Pharmac.) 207: 129-134.


189

UEDA, N., MURAMATSU,I. and FUJIWARA,M. (1984) Capsaicin and bradykinin-induced substance P-ergic responses in the iris sphincter muscle of the rabbit. J. Pharmac. exp. Ther. 230: 469-473. f3FKES,J. G. R. and VANDERMEER,C. (1975) The effect of catecholamine depletion on the bradykinin-induced relaxation of isolated smooth muscle. Fur. J. Pharmac. 33: 141-144. VANE,J. R. (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 231: 232-235. VAVREK,R. J. and STEWART,J. M. (1980) Bradykinin analogs containing ~t-aminoisobutyric acid (Aib). Peptides 1: 231-235. VAVREK,R. J. and STEWART,J. M. (1985) Competitive antagonists of bradykinin. Peptides 6: 161-164. VAVREK,R. J. GERA, L. and STEWART,J. M. (1992) Pseudopeptide analogues of bradykinin and bradykinin antagonistst. In: Recent Progress on Kinins, Vol. 38/I, pp. 564-570, BONNER,G., FRITZ, H., UNGER,TH., ROSCHER, A. and LUPPERTZ, K. (eds.) Birkhatiser Verlag, Basel, Boston, Berlin. VOYNO-YASENETSKAYA,T. A., TKACHUK,V. A., CHEKNYOVA,E. G., PANCHENKO,M. P., GRIGORIAN,G. Y., VAVREK, R. J., STEWART,J. M. and RYAN, U. S. (1989) Guanine nucleotide-dependent, pertussis toxininsensitive regulation of phosphoinositide turnover by bradykinin in bovine pulmonary artery endothelial cells. FASEB J. 3: 44-51. WAHLESTEDT,C., BYNKE,G. and H~KANSON,R. (1985) Pupillary constriction by bradykinin and capsaicin" mode of action. Eur. J. Pharmac. 106: 577-583. WALKER,R. and WILSON,K. A. (1979) Prostaglandins and the contractile action of bradykinin on the longitudinal muscle of rat isolated ileum. Br. J. Pharmac. 67: 527-533. WARD, P. E. (1991) Metabolism of bradykinin analogues. In: Bradykinin Antagonists. Basic and Clinical Research, pp. 147-170, BURCH, R. M. (ed.) Marcel Dekker, Inc., New York, Basel, Hong Kong. WARNER,S. J. C. and LIBBY,P. (1989) Human vascular smooth muscle cells. Target for and source of tumor necrosis factor. J. Immun. 142: 100-109. WARNER,S. J. C., AUGER,K. R. and Lmnv, P. (1987) Human interleukin- l induces interleukin- l gene expression in human vascular smooth muscle cells. J. exp. Med. 165: 1316-1331. WEINBERG, J., DINIZ, C. R. and MARES-GUIA,M. (1976) Influence of sex and sexual hormones in the bradykinin-receptor interaction in the guinea-pig ileum. Biochem. Pharmac. 25: 433-437. WEINREICH, D. (1986) Bradykinin inhibits a slow after-hyperpolarization in visceral sensory neurons. Eur. J. Pharmac. 132: 61-63. WE1PERT,J., HOffMANN,H., SIEBECK,M. and WHALLEY,E. T. (1988) Attenuation of arterial blood pressure fall in endotoxin shock in the rat using the competitive bradykinin antagonist Lys-Lys-[Hyp2,ThiS.S,o-PheT]bradykinin (B4148). Br. J. Pharmac. 94: 282-284. WHALLEY,E. T. (1978) The action of bradykinin and oxytocin on the isolated whole uterus and myometrium of the rat in oestrous. Br. J. Pharmac. 64: 21-28. WHALLEY,E. T. (1987) Receptors mediating the increase in vascular permeability to kinins: comparative studies in rat, guinea-pig and rabbit. Naunyn-Schmiedeberg's Arch. Pharmac. 336: 99-104. WHALLEY,E. T., FRITZ,H. and GEIGER,R. (1983) Kinin receptors and angiotensin converting enzyme in rabbits basilar arteries. Naunyn-Schmiedeberg's Arch. Pharmac. 324: 296-301. WHALLEY,E. T., AMURE,Y. O. and LYE,R. H. (1987a) Analysis of the mechanism of action of bradykinin on human basilar artery in vitro. Naunyn-Schmiedeberg's Arch. Pharmac. 335: 433-437. WHALLEY, E. T., CLEGG, S., STEWART,J. M. and VAVREK,R. J. (1987b) The effect of kinin agonists and antagonists on the pain response of the human blister base. Naunyn-Schmiedeberg's Arch. Pharmac. 336: 652-655. WHALLEY,E. T., NWATOR,I. A., STEWART,J. M. and VAVREK,R. J. (1987c) Analysis of the receptors mediating vascular actions of bradykinin. Naunyn-Schmiedeberg's Arch. Pharmac. 336: 43(~433. WHALLEY, E. T., LOY, S. D., MODIFERRI,D., BLODGETT,J. K. and CI-mRONlS,J. C. (1992) A novel potent bis(succinimido)hexane peptide heterodimer antagonist (CP-0364) of bradykinin BK~ and BK2 receptors: in vitro and in vivo studies. Br. J. Pharmac. 107: 257p. WHITELEY,P. J. and NEEDLEMAN,P. (1984) Mechanisms of enhanced fibroblast arachidonic acid metabolism by mononuclear cell factor. J. clin. Invest. 74: 2249-2253. WIEMER,G. and WIRTH,K. (1992) Production of cyclic GMP via activation of Bl and B2 kinin receptors in cultured bovine aortic endothelial cells. J. Pharmac. exp. Ther. 262: 729-733. WILSON,D. D., DE GARAVILLA,L., KUHN, W., TOGO, J., BURCH, R. M. and STERANKA,L. R. (1989) D-Arg[Hyp3,D-Phe7]-BK, a bradykinin antagonist, reduces mortality in a rat model of endotoxic shock. Circ. Res. 27: 93-101. WIRTH, K., BREIPOHL,G., STECHL,J., KNOLLE,J., HENKE, S. and SCH()LKENS,B. (1991a) Des-Arga-D-Arg [Hyp3,ThiS,o-TicT,OicS]bradykinin (des-Argl°-[Hoel40]) is a potent bradykinin B1 receptor antagonist. Eur. J. Pharmac. 205:217-218. WIRTH, K., HOCK, F. J., ALBUS, U., LINZ, W., ALPERMANN,H. G., ANAGNOSTOPOULOS,H., HENKE, ST., BREIPOHL,G., KONIG,W., KNOLLE,J. and SCHOLKENS,B. A. (1991b) HOE140 a new potent and long acting bradykinin-antagonist: in vivo studies. Br. J. Pharmac. 102: 774-777. WIRTH, K. J., WIENER, G. and SCH6LKENS,B. A. (1992) Des-Arg'°[HOE140] is a potent Bt bradykinin antagonist. In: Recent Progress on Kinins, Vol. 38/II, pp. 406-413, B6NNER, G., FRITZ, H., UNGER,TH., ROSCHER, A. and LUPPERTZ, K. (eds.) Birkhatiser Verlag, Basel, Boston, Berlin.

190

J.M. HALL

WOLSING, D. H. and ROSENBAUM,J. S. (1991) Bradykinin-stimulated inositol phosphate production in NG108-15 cells is mediated by a small population of binding sites which rapidly desensitize. J. Pharmac. exp. Ther. 257: 621-633. WOODS, M. and BAIRD,A. W. (1992) Endogenous peptidases attenuate bradykinin-evoked ion transport in guinea-pig gallbladder. Br. J. Pharmac. in press. YANG, H. Y. T., ERDOS, E. G. and LEVIN,Y. (1970) A dipeptidyl carboxypeptidase that converts angiotensin l and inactivates bradykinin. Biochem. biophys. Acta 214: 374-376. YAU, W. M., DORSETT,J. A. and YOUTHER,M. L. (1986) Bradykinin releases acetylcholine from myenteric plexus by a prostaglandin-mediated mechanism. Peptides 7: 289-292. YOSHIMURA,Y., ESPEY, L., HosoI, Y., ADACHI, T., ATLAS, S. J., GHODGAONKER,R. B., DUBIN, N. H. and WALLACH,E. E. (1988) The effect of bradykinin on ovulation and prostaglandin production by the perfused rabbit ovary. Endocrinology 122: 2540-2546. ZEITLIN,I. J. and SMITH,A. N. (1973) Mobilization of tissue kallikrein in inflammatory disease of the colon. Gut 14: 133-138. ZETLER, G. and KAMPMANN,E. (1979) An attempt to differentiate the effects of angiotensin II, substance P and bradykinin on the field-stimulated guinea-pig vas deferens. Eur. J. Pharmac. 56: 21-29.

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