BLOOD PRESSURE
1992; 1: 68-7 1
PERSONAL VIEW
The Cholinergic Nervous System in Hypertension: A Neglected Issue P. A. VAN ZWIETEN From the Departments of Pharmacotherapy and Cardiology, Academic Medical Centre, University of Amsterdam, The Netherlands
Blood Press Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
INTRODUCTION Ever since the recognition of essential hypertension (EHT) as an important disease and major risk factor attempts have been made to establish the role of the autonomic nervous system in the pathogenesis and maintenance of high blood pressure and its sequelae. Although many questions remain unanswered it is now widely accepted that the sympathetic nervous system plays an important role in hypertensive disease and its treatment. The “excitatory psychoemotional influences” proposed by Folkow [I] to be an important stimulus that may reinforce or sometimes precipitate primary hypertension in persons with a genetic predisposition are now being linked to episodic increases in plasma adrenaline [2]. Accordingly, the role of adrenaline released from the adrenal medulla in the genesis of EHT has become an acceptable hypothesis [2]. More recently, increased sympathetic firing in the neurons of persons with EHT has been established, as well as increased spillover of noradrenaline into the circulating blood of such persons [3-61. Recently, the hypothesis was put forward [6] that this process is governed by the central nervous system and possibly deranged in hypertensives. Finally, the vascular system of hypertensive humans and animals is known to be hypersensitive to various categories of pressor agents, including ~ 1 adrenoceptor stimulants [7]. Long before such delicate phenomena could be measured in humans and in animal models drug treatment of EHT was to a major degree founded on pharmacodynamic suppression of the sympathetic nervous system. It is no exaggeration to state that we are now able to influence any element of the sympathetic system we wish with drugs: at the central nervous level (central az-adrenoceptor stimulants which depress peripheral sympathetic activity, such as clonidine and amethyl-DOPA); at the sympathetic ganglia (ganglioplegic agents); at postganglionic sympathetic neurons (peripheral neuron blockers like guanethidine, etc.); by depletion of the intracellular noradrenaline stores (reserpine); and at the level of peripheral adrenoceptors (a- and P-adrenoceptor blocking agents) [8]. Speaking of the autonomic nervous system it is generally assumed without much further thought that
those derangements which are associated with EHT are limited to the sympathetic neurons and the (dys) regulation of their activities. This is understandable for a variety of reasons. First, sympathetic activation has been known for a long time to be a hypertensive mechanism. Secondly, the sympathetic system and its various components and elements, including neurotransmitters, adrenoceptors and even neuronal activity can be investigated with great sophistication. Finally, as stated above, classical drug therapy of EHT is to a major degree based on compounds which somehow depress sympathetic activation and its sequelae-it is only for a decade now that drugs with other mechanisms such as calcium antagonists or ACE-inhibitors have played an important role in antihypertensive treatment, and even these newer drugs may interact with certain elements of the sympathetic system in addition to their primary modes of action [9]. In spite of this it should be realized that the autonomic nervous system comprises both the sympathetic and the parasympathetic circuits which are assumed to maintain equilibrium and homeostasis by functionally counteracting each other. In this connection it is conceivable that a derangement of the parasympathetic system may play a role in cardiovascular diseases as well, possibly including EHT. Indeed, several elements of the cardiovascular system, in particular the heart, are subject to a substantial degree of parasympathetic innervation. Why has so little attention so far been paid to the parasympathetic system in the pathophysiology and treatment of EHT and other cardiovascular disorders? First of all, the obvious role of the sympathetic system and the numerous drugs targeting this system have (logically) focussed our interest on the sympathetic elements of the autonomic nervous system. In addition, it has been and still is notoriously difficult to obtain quantitative information on parasympathetic activity in vivo. Furthermore, drugs interacting with the parasympathetic system have not been developed in such a sophisticated manner as those targeting the sympathetic neurons and adrenoreceptors-no “parasympathetic” drug is known to be a useful antihypertensive. However, recent developments in research into the cholinergic system are changing this picture: our possibilities to study this system and its
The cholinergic nervous system in hypertension
Blood Press Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
receptors are rapidly improving. For these reasons it seems justified to discuss the modern developments in “cholinergic” research and to spend some thoughts and speculations on their possible implication for EHT.
MODERN DEVELOPMENTS IN RESEARCH ON THE CHOLINERGIC (PARASYMPATHETIC) SYSTEM What can be measured? As stated previously it is very difficult to obtain quantitative information on parasympathetic nervous activity in uiuo. Heart rate variability by means of spectral analysis [lo] and salivary secretion [l I] are probably the best we can offer at present as indirect measures for parasympathetic activity in vivo. In the adrenergic system, the fate of the neurotransmitters noradrenaline and adrenaline in the organism can be followed by analysing them in biological fluids. This is virtually impossible for acetylcholine (ACh), the neurotransmitter of the cholinergic (parasympathetic) system, which is subject to extremely rapid in vivo degradation via esterases. Indirect information concerning the functional activity of ACh and its possible alteration in disease can be obtained by studying the vasodilator effects of muscarinic receptor agonists in particular vascular beds. This vasodilator process requires the release of the endothelium derived relaxant factor (EDRF) which is now known to be identical with nitric oxide (NO) [12]. As such the vasodilation caused by muscarinic receptor stimulation should be considered as an important target of the parasympathetic nervous system. A major and probably the most important innovation in recent research on the cholinergic nervous Table I. Various types of muscarinic receptors in diferent tissues The effects of receptor stimulation and blockade by appropriate agonists and antagonists are also shown. Receptor type
Organ/Tissue
MI
Neurons, ganglia (sympathetic)
M2
Heart
M3
Glands Ileum
Stimulation (agonist)
Blockade (antagonist)
Excitation NA-releasef
Depression NA-releasel
Bradycardia Contractility1 Smooth muscle Contraction Secretionf Contraction
Tachycardia Contractilityf Relaxation Secretion1 Relaxation
69
Table 11. Selective antagonistsfor muscarinic receptor subtypes Receptor subtypes Antagonists MI
Pirenzepine Telenzepine
M1
AF-DX 116; AF-DX 237; AQ-RA 741 Himbacine Gallamine Pancuronium Methoctramine
M,
4-Diphenylacetoxy-N-methylpiperidine(4-DAMP) Hexahydro-Sila-difenidol (HHSiD)
system is the discovery of several subclasses of muscarinic cholinergic receptors. Cholinergic receptors have traditionally been subdivided into muscarinic and nicotinic subtypes owing to the classical work of Sir Henry Dale in the 1930’s. The parasympathetic system is intricately associated with muscarinic receptors, which are stimulated by ACh (the neurotransmitter) and synthetic parasympathomimetic drugs. It is now known that the muscarinic receptors are subdivided into at least 3 functional subtypes M I ,M2 and M3 [13161. Table I shows the functional aspects of the stimulation/blockade of the M-receptor subtypes, as well as the tissues and organs where they have been demonstrated to exist. The subdivision of M-receptors also implies that agonists and antagonists for these receptors should be defined more precisely with respect to their selectivity. Table I1 gives a few examples of the muscarinic receptor agonists and antagonists which are more or less selective for the various M-receptor subtypes. ACh and most of the classical synthetic muscarinic receptor agonists are non-selective with respect to the varous muscarinic receptor subtypes. This lack of selectivity is known for ACh, muscarine, carbachol, aceclidine, pilocarpine, arecoline and acetylP-metacholine. The experimental compounds McNA 343 and SDZ-ENS 163 appear to display selectivity towards MI-receptors, particularly those in the brain. Atropine is the best known, but a non-selective antagonist for the various M-receptor subtypes. Pirenzepine is moderately selective for the MI-subtype, whereas AFDX 116 and AQ-RA 741 are selective for the M2subtype. The compounds p-F-HHSiD and to a lesser degree 4-DAMP are selective antagonists for M3receptors. For reviews on M-receptors and associated drugs see [13-161. Biochemical studies have indicated that muscarinic receptors are coupled to adenylate cyclase. In contrast to P-adrenoceptors, which are also coupled to adeny-
70
P . A . uan Zwieten
Blood Press Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
late cyclase, the influence of muscarinic receptor stimulation is inhibitory, thus causing a decrease in the cellular concentration of CAMP, via an inhibitory Gi protein, As in the sympathetic system, the existence of presynaptic muscarinic receptors beside those at postsynaptic sites has been demonstrated. Presynaptic Mreceptors are assumed to modulate the release of ACh from the parasympathetic nerve endings. THE PARASYMPATHETIC SYSTEM, MUSCARINIC RECEPTORS AND HYPERTENSION It seems reasonable to assume that beside the sympathetic system its parasympathtic counterpart also plays a role in EHT. Even if there would be no change per se in the parasympathetic system associated with EHT, the ratio sympathetic/parasympathetic tone is bound to be altered in EHT. In subjects with EHT both heart rate variability, studied by means of spectral analysis, and salivary flow indicate moderate decreases in parasympathetic activity which are associated with the disorder [lo, 111. Isolated blood vessel preparations from EHT patients and from hypertensive animals usually show a decreased vasodilator response to ACh, indicating that the vasodilator and endothelium dependent protective role of EDRF is diminished in EHT [ 171. Unfortunately the data so far available are rather inhomogeneous and sometimes conflicting. The vasodilator response to ACh and to synthetic parasympathetic agents is assumed to be mediated by muscarinic receptors on the endothelium. It would therefore be of interest to identify the subtype of the M-receptor involved and to investigate whether the characteristics of such receptors may be altered by the hypertensive state. Such an analysis is now possible owing to the availability of the various selective M-receptor antagonists. In large conduit arteries (aorta, middle cerebral artery, etc.) the M3receptor appears to be the predominant M3-receptor subtype [I 81. Its characteristics are not clearly altered in spontaneously hypertensive rats [14]. Recently, we started a programme with the aim to investigate the M-receptor subtypes involved in endothelium dependent vasodilatation in rat small mesenteric arteries, which virtually approach resistance arteries. Again we found the dominant presence of the M3-receptorsubtypes, by means of a careful analysis of the vasodilatation caused by the agonist (non-selective) acetyl-/3-metacholine [ 181. This vasodilatation was counteracted most effectively by M3-receptor antagonists like p-FHHSiD and 4-DAMP, and much less so by pirenzepine (MI), AF-DX 116 (M2) or AQ-RA 741 (M2) 1181. In 18-week-old SHR the same pattern was found,
indicating that also in the mesenteric vascular bed of hypertensive animals the major M-receptor subtype present is the M3-type. Its functional responsiveness was not influenced by the hypertensive state [18].
CONCLUSIONS AND OUTLOOK After a thorough investigation of the various aspects of the sympathetic nervous system in EHT for several decades it now seems worth while to pay more attention to the parasympathetic system, its associated receptors and drugs acting thereupon. The evidence for a pathogenetic role of the parasympathetic system can well be imagined, but the experimental and clinical evidence for such a role is extremely meagre. However, even if there would be no role of the parasympathetic system on its own, the ratio sympathetic/parasympathetic tone is bound to be altered unfavourably by EHT. Methods are now becoming available which allow a more sophisticated analysis of the parasympathetic system and its receptors in uiuo as well as in isolated tissues and in biological fluids. A major innovation is the now possible analysis of M-receptors and their subtypes, in particular by means of selective receptor antagonists. Such experiments have so far pointed towards the dominant presence of M3- receptors in both conduit and resistance arteries, whereas the hypertensive state does not clearly change the characteristics of these M3-receptors. Such issues are of fundamental importance. A few therapeutic implications are rather old and well-known facts: (1) the mild antihypertensive effect of regular physical exercise is explained by the relative shift of sympathetic to parasympathetic tone; (2) several of the serious adverse reactions to the now obsolete ganglioplegic agents are caused by the suppression of parasympathetic activity, as a result of the blockade of the parasympathetic ganglia; (3) intense suppression of sympathetic activity by means of rather old drugs like reserpine, guanethidine, etc. will cause a pattern of side-effects (in particular nasal mucosal congestion and gastrointestinal problems) which reflect the relative increase of parasympathetic over sympathetic activity. New therapeutic options based on parasympathetic mechanisms are still extremely remote. This would require the development of extremely selective M3-receptor agonists and vasodilators. These are unavailable at present, but their design is not necessarily impossible. It will be essential to avoid the various unpleasant gastrointestinal, glandular and ocular side-effects caused by parasympathetic acti-
The cholinergic nervous system in hypertension vation, possibly by means of adding appropriate selective M-receptor antagonists which do not influence blood pressure.
Even without therapeutic options, the parasympathetic aspects of EHT deserve our attention a n d interest for fundamental reasons.
Blood Press Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
REFERENCES 1. Folkow B. Physiological aspects of primary hypertension. Physiol Rev 1982; 62: 347-504. 2. Floras JS. Epinephrine and the genesis of hypertension. Hypertension 1992; 19: 1-18. 3. Julius S, Johnson EH. Stress, autonomic hyperactivity and essential hypertension. An enigma. J Hypertens 1985; 3 (SUPPI4): S11-7. 4. Bohm RO, van Baak MA, van Hooff ME, Mooy J, Rahn KH. A long term study of plasma renin activity in borderline hypertension. J Hypertens 1987; 5: 655-61. 5. Julius S. Changing role of the autonomic nervous system. J Hypertens 1990; 8 (Suppl 7): S59-65. 6. Ferrier L, Esker MD, Eisenhofer G, et al. Increased norepinephrine spillover into the jugular veins in essential hypertension. Hypertension 1992: 19: 62-9. 7. Van Zwieten PA. Antihypertensive drugs interacting with the sympathetic nervous system and its receptors. In: Antonaccio MJ (Ed.). Cardiovasc. Drugs Ther., 3d edition. Raven Press New York, 1990; pp. 37-73. 8. Van Zwieten PA. General introduction: the classification of antihypertensive drugs. In: van Zwieten PA, ed. Handbook of hypertension. Amsterdam: Elsevier, 1984: 1-5.
9. Van Zwieten PA. Drugs interacting with cr-adrenoceptors. Cardiovasc Drugs Ther 1989; 3: 121-33. 10. Mancia G, Ferrari A, Gregorni L, et al. Blood pressure variabilities in normotensive and hypertensive human beings. Circ Res 1983; 53: 96-104.
71
11. Van Hooff M, van Baak MA, Schols M, Rahn KH. Studies of salivary flow in borderline hypertension: effects of drugs acting on structures innervated by the autonomic nervous system. Clin Sci 1984; 66: 599-604. 12. Plamer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothehum-derived relaxing factor. Nature 1987; 333: 664-6. 13. Doods HN, Mathy M-J, Davidesko D, van Charldorp KJ, de Jonge A, van Zwieten PA. Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative MI, M2 and M3-receptors. J Pharmacol exp Ther 1987; 246: 929-34. 14. Eglen RM, Whiting RL. Heterogeneity of vascular muscarinic receptors. J Auton Pharmacol 1990; 19: 23345. 15. Mutschler E, Moser U, Wess J, Lambrecht L. Muscarinic receptor subtypes: agonists and antagonists. Progr Pharmacol 1989; 7: 13-3 1 . 16. Goyal RK. Muscarinic receptor subtypes. Physiology and clinical implications. New Engl J Med 1989; 321: 1022-8. 17. Webb RC. Vascular changes in hypertension. In: Antonaccio MJ, ed. Cardiovasc. Pharmacol. 2nd ed. New York: Raven Press, 1984; 215-55. 18. Hendriks GC, Pfaffendorf M, van Zwieten PA. Characterization of the muscarinic receptors in the mesenteric vascular bed of spontaneously hypertensive rats. J Hypertens 1991; 9 (Suppl 6): S188-9. Submitted February 7, 1992; accepted February 14, I992 Address for correspondence: P. A. van Zwieten Depts. of Pharmacotherapy and Cardiology Academic Medical Centre Univ. of Amsterdam Meibergdreef 15 NL-1105 AZ Amsterdam The Netherlands
1992; 1: 68-7 1
PERSONAL VIEW
The Cholinergic Nervous System in Hypertension: A Neglected Issue P. A. VAN ZWIETEN From the Departments of Pharmacotherapy and Cardiology, Academic Medical Centre, University of Amsterdam, The Netherlands
Blood Press Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
INTRODUCTION Ever since the recognition of essential hypertension (EHT) as an important disease and major risk factor attempts have been made to establish the role of the autonomic nervous system in the pathogenesis and maintenance of high blood pressure and its sequelae. Although many questions remain unanswered it is now widely accepted that the sympathetic nervous system plays an important role in hypertensive disease and its treatment. The “excitatory psychoemotional influences” proposed by Folkow [I] to be an important stimulus that may reinforce or sometimes precipitate primary hypertension in persons with a genetic predisposition are now being linked to episodic increases in plasma adrenaline [2]. Accordingly, the role of adrenaline released from the adrenal medulla in the genesis of EHT has become an acceptable hypothesis [2]. More recently, increased sympathetic firing in the neurons of persons with EHT has been established, as well as increased spillover of noradrenaline into the circulating blood of such persons [3-61. Recently, the hypothesis was put forward [6] that this process is governed by the central nervous system and possibly deranged in hypertensives. Finally, the vascular system of hypertensive humans and animals is known to be hypersensitive to various categories of pressor agents, including ~ 1 adrenoceptor stimulants [7]. Long before such delicate phenomena could be measured in humans and in animal models drug treatment of EHT was to a major degree founded on pharmacodynamic suppression of the sympathetic nervous system. It is no exaggeration to state that we are now able to influence any element of the sympathetic system we wish with drugs: at the central nervous level (central az-adrenoceptor stimulants which depress peripheral sympathetic activity, such as clonidine and amethyl-DOPA); at the sympathetic ganglia (ganglioplegic agents); at postganglionic sympathetic neurons (peripheral neuron blockers like guanethidine, etc.); by depletion of the intracellular noradrenaline stores (reserpine); and at the level of peripheral adrenoceptors (a- and P-adrenoceptor blocking agents) [8]. Speaking of the autonomic nervous system it is generally assumed without much further thought that
those derangements which are associated with EHT are limited to the sympathetic neurons and the (dys) regulation of their activities. This is understandable for a variety of reasons. First, sympathetic activation has been known for a long time to be a hypertensive mechanism. Secondly, the sympathetic system and its various components and elements, including neurotransmitters, adrenoceptors and even neuronal activity can be investigated with great sophistication. Finally, as stated above, classical drug therapy of EHT is to a major degree based on compounds which somehow depress sympathetic activation and its sequelae-it is only for a decade now that drugs with other mechanisms such as calcium antagonists or ACE-inhibitors have played an important role in antihypertensive treatment, and even these newer drugs may interact with certain elements of the sympathetic system in addition to their primary modes of action [9]. In spite of this it should be realized that the autonomic nervous system comprises both the sympathetic and the parasympathetic circuits which are assumed to maintain equilibrium and homeostasis by functionally counteracting each other. In this connection it is conceivable that a derangement of the parasympathetic system may play a role in cardiovascular diseases as well, possibly including EHT. Indeed, several elements of the cardiovascular system, in particular the heart, are subject to a substantial degree of parasympathetic innervation. Why has so little attention so far been paid to the parasympathetic system in the pathophysiology and treatment of EHT and other cardiovascular disorders? First of all, the obvious role of the sympathetic system and the numerous drugs targeting this system have (logically) focussed our interest on the sympathetic elements of the autonomic nervous system. In addition, it has been and still is notoriously difficult to obtain quantitative information on parasympathetic activity in vivo. Furthermore, drugs interacting with the parasympathetic system have not been developed in such a sophisticated manner as those targeting the sympathetic neurons and adrenoreceptors-no “parasympathetic” drug is known to be a useful antihypertensive. However, recent developments in research into the cholinergic system are changing this picture: our possibilities to study this system and its
The cholinergic nervous system in hypertension
Blood Press Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
receptors are rapidly improving. For these reasons it seems justified to discuss the modern developments in “cholinergic” research and to spend some thoughts and speculations on their possible implication for EHT.
MODERN DEVELOPMENTS IN RESEARCH ON THE CHOLINERGIC (PARASYMPATHETIC) SYSTEM What can be measured? As stated previously it is very difficult to obtain quantitative information on parasympathetic nervous activity in uiuo. Heart rate variability by means of spectral analysis [lo] and salivary secretion [l I] are probably the best we can offer at present as indirect measures for parasympathetic activity in vivo. In the adrenergic system, the fate of the neurotransmitters noradrenaline and adrenaline in the organism can be followed by analysing them in biological fluids. This is virtually impossible for acetylcholine (ACh), the neurotransmitter of the cholinergic (parasympathetic) system, which is subject to extremely rapid in vivo degradation via esterases. Indirect information concerning the functional activity of ACh and its possible alteration in disease can be obtained by studying the vasodilator effects of muscarinic receptor agonists in particular vascular beds. This vasodilator process requires the release of the endothelium derived relaxant factor (EDRF) which is now known to be identical with nitric oxide (NO) [12]. As such the vasodilation caused by muscarinic receptor stimulation should be considered as an important target of the parasympathetic nervous system. A major and probably the most important innovation in recent research on the cholinergic nervous Table I. Various types of muscarinic receptors in diferent tissues The effects of receptor stimulation and blockade by appropriate agonists and antagonists are also shown. Receptor type
Organ/Tissue
MI
Neurons, ganglia (sympathetic)
M2
Heart
M3
Glands Ileum
Stimulation (agonist)
Blockade (antagonist)
Excitation NA-releasef
Depression NA-releasel
Bradycardia Contractility1 Smooth muscle Contraction Secretionf Contraction
Tachycardia Contractilityf Relaxation Secretion1 Relaxation
69
Table 11. Selective antagonistsfor muscarinic receptor subtypes Receptor subtypes Antagonists MI
Pirenzepine Telenzepine
M1
AF-DX 116; AF-DX 237; AQ-RA 741 Himbacine Gallamine Pancuronium Methoctramine
M,
4-Diphenylacetoxy-N-methylpiperidine(4-DAMP) Hexahydro-Sila-difenidol (HHSiD)
system is the discovery of several subclasses of muscarinic cholinergic receptors. Cholinergic receptors have traditionally been subdivided into muscarinic and nicotinic subtypes owing to the classical work of Sir Henry Dale in the 1930’s. The parasympathetic system is intricately associated with muscarinic receptors, which are stimulated by ACh (the neurotransmitter) and synthetic parasympathomimetic drugs. It is now known that the muscarinic receptors are subdivided into at least 3 functional subtypes M I ,M2 and M3 [13161. Table I shows the functional aspects of the stimulation/blockade of the M-receptor subtypes, as well as the tissues and organs where they have been demonstrated to exist. The subdivision of M-receptors also implies that agonists and antagonists for these receptors should be defined more precisely with respect to their selectivity. Table I1 gives a few examples of the muscarinic receptor agonists and antagonists which are more or less selective for the various M-receptor subtypes. ACh and most of the classical synthetic muscarinic receptor agonists are non-selective with respect to the varous muscarinic receptor subtypes. This lack of selectivity is known for ACh, muscarine, carbachol, aceclidine, pilocarpine, arecoline and acetylP-metacholine. The experimental compounds McNA 343 and SDZ-ENS 163 appear to display selectivity towards MI-receptors, particularly those in the brain. Atropine is the best known, but a non-selective antagonist for the various M-receptor subtypes. Pirenzepine is moderately selective for the MI-subtype, whereas AFDX 116 and AQ-RA 741 are selective for the M2subtype. The compounds p-F-HHSiD and to a lesser degree 4-DAMP are selective antagonists for M3receptors. For reviews on M-receptors and associated drugs see [13-161. Biochemical studies have indicated that muscarinic receptors are coupled to adenylate cyclase. In contrast to P-adrenoceptors, which are also coupled to adeny-
70
P . A . uan Zwieten
Blood Press Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
late cyclase, the influence of muscarinic receptor stimulation is inhibitory, thus causing a decrease in the cellular concentration of CAMP, via an inhibitory Gi protein, As in the sympathetic system, the existence of presynaptic muscarinic receptors beside those at postsynaptic sites has been demonstrated. Presynaptic Mreceptors are assumed to modulate the release of ACh from the parasympathetic nerve endings. THE PARASYMPATHETIC SYSTEM, MUSCARINIC RECEPTORS AND HYPERTENSION It seems reasonable to assume that beside the sympathetic system its parasympathtic counterpart also plays a role in EHT. Even if there would be no change per se in the parasympathetic system associated with EHT, the ratio sympathetic/parasympathetic tone is bound to be altered in EHT. In subjects with EHT both heart rate variability, studied by means of spectral analysis, and salivary flow indicate moderate decreases in parasympathetic activity which are associated with the disorder [lo, 111. Isolated blood vessel preparations from EHT patients and from hypertensive animals usually show a decreased vasodilator response to ACh, indicating that the vasodilator and endothelium dependent protective role of EDRF is diminished in EHT [ 171. Unfortunately the data so far available are rather inhomogeneous and sometimes conflicting. The vasodilator response to ACh and to synthetic parasympathetic agents is assumed to be mediated by muscarinic receptors on the endothelium. It would therefore be of interest to identify the subtype of the M-receptor involved and to investigate whether the characteristics of such receptors may be altered by the hypertensive state. Such an analysis is now possible owing to the availability of the various selective M-receptor antagonists. In large conduit arteries (aorta, middle cerebral artery, etc.) the M3receptor appears to be the predominant M3-receptor subtype [I 81. Its characteristics are not clearly altered in spontaneously hypertensive rats [14]. Recently, we started a programme with the aim to investigate the M-receptor subtypes involved in endothelium dependent vasodilatation in rat small mesenteric arteries, which virtually approach resistance arteries. Again we found the dominant presence of the M3-receptorsubtypes, by means of a careful analysis of the vasodilatation caused by the agonist (non-selective) acetyl-/3-metacholine [ 181. This vasodilatation was counteracted most effectively by M3-receptor antagonists like p-FHHSiD and 4-DAMP, and much less so by pirenzepine (MI), AF-DX 116 (M2) or AQ-RA 741 (M2) 1181. In 18-week-old SHR the same pattern was found,
indicating that also in the mesenteric vascular bed of hypertensive animals the major M-receptor subtype present is the M3-type. Its functional responsiveness was not influenced by the hypertensive state [18].
CONCLUSIONS AND OUTLOOK After a thorough investigation of the various aspects of the sympathetic nervous system in EHT for several decades it now seems worth while to pay more attention to the parasympathetic system, its associated receptors and drugs acting thereupon. The evidence for a pathogenetic role of the parasympathetic system can well be imagined, but the experimental and clinical evidence for such a role is extremely meagre. However, even if there would be no role of the parasympathetic system on its own, the ratio sympathetic/parasympathetic tone is bound to be altered unfavourably by EHT. Methods are now becoming available which allow a more sophisticated analysis of the parasympathetic system and its receptors in uiuo as well as in isolated tissues and in biological fluids. A major innovation is the now possible analysis of M-receptors and their subtypes, in particular by means of selective receptor antagonists. Such experiments have so far pointed towards the dominant presence of M3- receptors in both conduit and resistance arteries, whereas the hypertensive state does not clearly change the characteristics of these M3-receptors. Such issues are of fundamental importance. A few therapeutic implications are rather old and well-known facts: (1) the mild antihypertensive effect of regular physical exercise is explained by the relative shift of sympathetic to parasympathetic tone; (2) several of the serious adverse reactions to the now obsolete ganglioplegic agents are caused by the suppression of parasympathetic activity, as a result of the blockade of the parasympathetic ganglia; (3) intense suppression of sympathetic activity by means of rather old drugs like reserpine, guanethidine, etc. will cause a pattern of side-effects (in particular nasal mucosal congestion and gastrointestinal problems) which reflect the relative increase of parasympathetic over sympathetic activity. New therapeutic options based on parasympathetic mechanisms are still extremely remote. This would require the development of extremely selective M3-receptor agonists and vasodilators. These are unavailable at present, but their design is not necessarily impossible. It will be essential to avoid the various unpleasant gastrointestinal, glandular and ocular side-effects caused by parasympathetic acti-
The cholinergic nervous system in hypertension vation, possibly by means of adding appropriate selective M-receptor antagonists which do not influence blood pressure.
Even without therapeutic options, the parasympathetic aspects of EHT deserve our attention a n d interest for fundamental reasons.
Blood Press Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
REFERENCES 1. Folkow B. Physiological aspects of primary hypertension. Physiol Rev 1982; 62: 347-504. 2. Floras JS. Epinephrine and the genesis of hypertension. Hypertension 1992; 19: 1-18. 3. Julius S, Johnson EH. Stress, autonomic hyperactivity and essential hypertension. An enigma. J Hypertens 1985; 3 (SUPPI4): S11-7. 4. Bohm RO, van Baak MA, van Hooff ME, Mooy J, Rahn KH. A long term study of plasma renin activity in borderline hypertension. J Hypertens 1987; 5: 655-61. 5. Julius S. Changing role of the autonomic nervous system. J Hypertens 1990; 8 (Suppl 7): S59-65. 6. Ferrier L, Esker MD, Eisenhofer G, et al. Increased norepinephrine spillover into the jugular veins in essential hypertension. Hypertension 1992: 19: 62-9. 7. Van Zwieten PA. Antihypertensive drugs interacting with the sympathetic nervous system and its receptors. In: Antonaccio MJ (Ed.). Cardiovasc. Drugs Ther., 3d edition. Raven Press New York, 1990; pp. 37-73. 8. Van Zwieten PA. General introduction: the classification of antihypertensive drugs. In: van Zwieten PA, ed. Handbook of hypertension. Amsterdam: Elsevier, 1984: 1-5.
9. Van Zwieten PA. Drugs interacting with cr-adrenoceptors. Cardiovasc Drugs Ther 1989; 3: 121-33. 10. Mancia G, Ferrari A, Gregorni L, et al. Blood pressure variabilities in normotensive and hypertensive human beings. Circ Res 1983; 53: 96-104.
71
11. Van Hooff M, van Baak MA, Schols M, Rahn KH. Studies of salivary flow in borderline hypertension: effects of drugs acting on structures innervated by the autonomic nervous system. Clin Sci 1984; 66: 599-604. 12. Plamer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothehum-derived relaxing factor. Nature 1987; 333: 664-6. 13. Doods HN, Mathy M-J, Davidesko D, van Charldorp KJ, de Jonge A, van Zwieten PA. Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative MI, M2 and M3-receptors. J Pharmacol exp Ther 1987; 246: 929-34. 14. Eglen RM, Whiting RL. Heterogeneity of vascular muscarinic receptors. J Auton Pharmacol 1990; 19: 23345. 15. Mutschler E, Moser U, Wess J, Lambrecht L. Muscarinic receptor subtypes: agonists and antagonists. Progr Pharmacol 1989; 7: 13-3 1 . 16. Goyal RK. Muscarinic receptor subtypes. Physiology and clinical implications. New Engl J Med 1989; 321: 1022-8. 17. Webb RC. Vascular changes in hypertension. In: Antonaccio MJ, ed. Cardiovasc. Pharmacol. 2nd ed. New York: Raven Press, 1984; 215-55. 18. Hendriks GC, Pfaffendorf M, van Zwieten PA. Characterization of the muscarinic receptors in the mesenteric vascular bed of spontaneously hypertensive rats. J Hypertens 1991; 9 (Suppl 6): S188-9. Submitted February 7, 1992; accepted February 14, I992 Address for correspondence: P. A. van Zwieten Depts. of Pharmacotherapy and Cardiology Academic Medical Centre Univ. of Amsterdam Meibergdreef 15 NL-1105 AZ Amsterdam The Netherlands
