Drugs 11 (SuppI.1): 100-111 (1976) © ADIS Press 1976
Session V: Pharmacology of I3-Adrenoreceptor Blocking Drugs Chairman: Professor M.J. Rand (Melbourne)
Some Aspects of the Pharmacology of I3-Adrenoreceptor Blockers B. Ablad, E. Carlsson, C. Dahliif and L. Ek Research Laboratories, AB Hassle, Molndal
Summary
The pharmacodynamic properties of a /3-blocker are mainly determined by its affinity to /3, and /3 2 -receptors respectively and by its intrinsic activity. It is suggested that there is no absolute organ separation of the two receptor sub-types. Instead both /3, and /3 2 -receptors are involved in the mediation of the same effect. The frequency distribution ratio of /3, //3 2 -receptors varies markedly among various effector responses. A non-selective and a /3, -selective blocker may have different haemodynamic effects when the levels of circulating adrenaline are high, because of their markedly different potency in inhibiting the /3 2 -mediated vasodilator effect of adrenaline. Data are presented which suggest the existence of a presynaptic /3, -receptor mediating a positive feedback mechanism on neuronal release of noradrenaline.
There is now abundant evidence indicating that {3-adrenoreceptors are not homogeneous but may be sub-divided into at least two groups. Lands et al. (l967) have suggested that one type, 131 , mediates for instance relaxation of vascular and bronchial smooth muscle. In apparent support of this concept, 3 classes of l3-blockers have been described: 131 -selective, 132 -selective and those that are relatively non-selective. Blockers that are 131 -selective or non-selective
have been found to be therapeutically useful in patients with, for instance: (l) angina pectoris, mainly because of inhibition of {3-adrenoreceptormediated increase of cardiac rate and contractility; (2) cardiac arrhythmias, predominantly because of inhibition of {3-adrenoreceptor-mediated effects on cardiac excitability and conductance; and (3) hypertension. The antihypertensive effect is due to {3-blockade, but otherwise the mode of action has not been clarified.
Pharmacology of j3-adrenoreceptor-blockers
1. Factors of Importance for Characterisation of {3-Blockers
Factors of importance for the characterisation of the pharmacological properties of a {3-blocker include pharmacodynamic properties such as 131 and/or 132 affinity, intrinsic sympathomimetic activity and other non-{3-receptor-mediated actions, and pharmacokinetic properties such as absorption, distribution, metabolism and excretion. The clinical effect pattern of one {3blocker can differ from that of another, mainly due to variations in selective affinity to 131 or 132 receptors and in intrinsic sympathomimetic activity. The most discussed 'non-specific' effect of {3-blockers is a membrane-stabilising action, one expression of which is cardio-depression. This action is exerted by compounds such as propranolol, alprenolol, oxprenolol and pindolol, but only at plasma levels that are at least 100 times higher than those associated with commonly used therapeutic doses (Gibson, 1974). It is therefore likely that the membrane stabilising action of 13-blockers is of clinical importance only in patients who have taken huge doses, e.g. for purposes of suicide. Differences in the clinical effect patterns of t3-blockers may also be due to variations in pharmacokinetic properties such as distribution to the brain and formation of biologically active metabolites. Practolol has been reported to cross the blood brain barrier to a smaller extent than propranolol (Scales and Cosgrove, 1970) but the functional Significance of this difference is not clear. The functional significance of the biotransformation products of most 13-blockers is incompletely elucidated, but 131 -blocking metabolites have been identified in plasma after oral administration of propranolol (Cleaveland and Shand, 1972) and alprenolol (Ablad et aI., 1974a). Table I shows comparative data for some {3blockers as regards inhibition of the cardiac chronotropic (mainly 131 -mediated) and the peripheral vasodilator (mainly 132 -mediated)
101
Table I. Comparative data for some j3-blockers 1 lin anaesthetised cats pre-treated with reserpine) Compound
Blockade of isoprenaline responses (ED 50; mg/kg IV)2 Heart rate
Metoprolol Atenolol (lCI 66082) Practolol Tolamolol Propranolol Timolol Alprenolol Oxprenolol Pindolol
0.3 0.3 0.5 0.1 0.1 0.01 0.1 0.1 0.005
Intrinsic activity (% of iso· prenaline)
Peripheral vascular resistance 5 5 35 1.5 0.1 0.01 0.1 0.1 0.005
0 0 25 15 0 0 25 30 50
1 Approximate comparative data for some {3-blockers as regards their potency in inhibiting the cardiac chronotropic and peripheral vasodilator responses to isoprenaline and as regards intrinsic activity on {3-receptors mediating heart rate increase. 2 The ED50 blockade values indicate the dose of the /l-blocker producing a 50% reduction of a submaximal control response to isoprenaline. Intrinsic activity is expressed as the maximal chronotropic response of a compound in relation to that of isoprenaline (for details on the experimental technique, see Ablad et aI., 1973).
responses to isoprenaline in the anaesthetised cat pre-treated with reserpine, and the 'intrinsic' sympathomimetic activity on the heart rate. The results in table I indicate that {3-blockers can be divided into two groups, those with t31 selectivity of varying degree and those with no significant selectivity for either of the two 13adrenoreceptor sub-types. Within each group there are compounds devoid of intrinsic activity and others that possess such activity to a varying extent. This paper will be concerned mainly with some comparative studies of the pharmacodynamic properties of the non-selective blocker propranolol and the 131 -selective blocker metoprolol, especially
Symposium on hypertension
102
(1) their interaction with various {3-adrenoreceptor agonists; (2) the mechanisms underlying their acute general haemodynamic effects; and (3) their influence on the vascular adrenergic neuro-effector system. 2. Pharmacodynamic properties of Metoprolol and Propranolol
The pharmacodynamic properties of metoprolol (structure, fig. 1) have been compared with
OH yH3 I OCH2cHCH2NHyH
00
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~H3
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~
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Inhibition of
Substance
Propranolol Metoprolol
Cardiac responses to symp. nerve stirn. (ED 5 0; rng/kg)
Peripheral vascular dilator response to adrenaline (ED 50 ; mg/kg)
0.1 0.1
0.1 5
Fig. 1. Comparative potency data for propranolol and metoprolol in anaesthetised dogs as regards inhibition of: (1) the cardiac chronotropic and inotropic responses to electrical stimulation of cardiac sympathetic nerves; and (2) the vasodilator response to intra-arterially injected adrenaline in a gracilis muscle pre-treated with phenoxybenzamine. The EDs 0 values indicate the dose of J3·blocker required to reduce submaximal responses to the agonist by 50%.
those of propranolol in animal studies. Stimulant effects of isoprenaline were markedly inhibited by metoprolol in doses that only slightly influenced the vasodilator and bronchodilator effects of isoprenaline. Propranolol, on the other hand, produced no marked differential blockade of these responses to isoprenaline. Metoprolol was somewhat less active than propranolol as regards inhibition of the cardio-stimulant response of isoprenaline (table I). As regards inhibition of the cardio-stimulant responses to exogenous or neuron ally released noradrenaline, however, metoprolol was practically equipotent to propranolol (fig. 1; see also section 3). The two {3blockers were further found to be approximately equipotent inhibitors of renin release induced by electrical stimulation of the renal sympathetic nerves and of FF A release induced by IV infused noradrenaline. Metoprolol differed from propranolol in being a very weak inhibitor of the peripheral vasodilator effect of adrenaline (fig. 1). When given to reserpinised cats both compounds were found to be devoid of intrinsic sympathomimetic activity on the heart. In high dosage, propranolol produced a direct cardiodepressant effect; this effect was less pronounced with metoproioi. The results of toxicological and general pharmacological studies with metoprolol indicate that the compound is a highly specific {3-blocker. Combined pharmacokinetic-effect studies indicate that the action of metoprolol is due to the unchanged molecule. Metoprolol is eliminated at about the same rate as propranolol, mainly by bio-transformation in the liver. The results of animal studies have thus shown that metoprolol is a {31 -selective adrenoreceptor blocker devoid of intrinsic activity. Studies in man (survey by Ablad et aI., 1975) have confirmed the pharmacodynamic effect pattern found for metoprolol in animals. It would appear that metoprolol and propranolol should be suitable tools for elucidating {31 receptor mediated mechanisms.
Pharmacology of (3-adrenoreceptor-blockers
103
3. Are the (31 and (32 Receptors Characterised by Absolute Organ Separation?
The results of Lands et al. (1967) indicated that the three catecholamines noradrenaline, isoprenaline and adrenaline had different (31/(32 affinity ratios. Noradrenaline had the highest relative affInity to (31 receptors. During the pharmacological characterisation of selective antagonists, we obtained differential blockade patterns which were not consonant with the absolute organ separation of (31 and (32 receptors as suggested by Lands et al. (1967). It was found (Carlsson, 1972) that (31selective blockers inhibited, for example, the cardiac response to noradrenaline more than that to isoprenaline, which in turn was blocked more than the response to adrenaline (fig. 2). The (32 -blocker H35/25 produced a differential blockade of the reverse order, while the non-selective blocker propranolol inhibited the effects of the agonists to about the same degree. Corresponding differentiated blockade patterns have been obtained with selective antagonists in studies of (3receptor mediated cardiac stimulation in the cat, dog and man, bronchial smooth muscle relaxation in the cat and man, and adipose tissue lipolysis in the dog and man (Carlsson, 1972; Carlsson et al., 1972; Ablad et al., 1974b; Carlsson and Carlsson, 1976;Abladetal.,1975). A differential blockade of the type described is not consonant with competitive interaction at one type of receptor, e.g. (31 in the heart. The results could, however, be explained by assuming: (1) that there are both (31 - and (32 -receptors mediating one and the same response; and (2) that the relative frequencies or concentrations of (31 - and (32receptors vary in different effector organs (Carlsson, 1972; Carlsson et al., 1972; Carlsson and Carlsson, 1976). Thus in, for example, bronchial and vascular smooth muscles there are mainly (32 -receptors. The number of each type of receptor stimulated for a certain response depends on the relative affinities of the agonist to (31 - and (32 -receptors and the relative concentrations of the
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Fig. 2. Chronotropic responses of the isolated cat heart to injected noradrenaline (NA) (0.1-0.2f.Lg), adrenaline (Adr) (0.2-0.3f.Lg), isoprenaline (lpr) (0.01f.Lg) and salbutamol (Salb) (0.7-1f.Lg) before and during perfusion with propranolol (0.1f.Lg/ml perfusate), practolol (0.1 f.Lg/mll and H 35/25 (0.1 f.Lg/mll (after Carlsson et aI., 'j 972)
two types of receptors. The cardiac response to noradrenaline for instance, seems to be more or less a result of (31 -receptor stimulation, depending both on the relatively high concentration of (31receptors in the heart and the selective affmity of noradrenaline for (31 -receptors (Carlsson and Carlsson, 1976). Our results also indicate that for the same cardiac response to adrenaline, a considerable number of (32 -receptors are involved. The concept appears also to be applicable to human (3-receptors. Thus the (31 -selective blocker metoprolol was a more potent inhibitor of the inotropic response to noradrenaline than of the response to adrenaline in isolated human atrial tissue, while the non-selective blocker propranolol showed no such differential blockade (fig. 3) (Ablad et al., 1974b). The differentiated potency of (31 -selective blockers as regards inhibition of a given response to noradrenaline and adrenaline may turn out to be of clinical interest. A (31 -selective blocker may
Symposium on hypertension
104
be expected to inhibit a 13-receptor mediated effect induced by noradrenaline released from adrenergic nerves to a much greater extent than if the same effect is instead induced by adrenaline released from the adrenal medulla. It is evident that much work remains to be done in order to clarify the significance of this modified i3-receptor concept. One important task is to elucidate the relative frequency of {31 - and 132receptors in a given organ in different species as well as to study individual variations, especially in man. Such studies might explain individual variations in the clinical response to 131 -selective blockers. The bronchospastic effect of the highly selective blocker practolol in certain
patients, for example (Waal-Manning and Simpson, 1971), might be due to the fact that 131-receptors are of great importance in the mediation of the relaxation of bronchial smooth muscle in these patients. This modified receptor concept might furthermore explain why patients with occlusive bronchial disease can tolerate 131 -blocker treatment when they are given a 131 -blocker combined with a 132 -agonist, as reported by F ormgren (personal communication, 1975). One consequence of the present concept, moreover, is that it may be impossible to develop i3-receptor agonists or antagonists with absolute organ selectivity, the concentration of the subordinate receptor in the organ being the limiting factor for the selectivity ..
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Fig. 3. Isolated muscle strips of the right atrial appendage from man suspended in an organ bath and stimulated electrically with 1amp/sec. Strips pre-treated with 6-0H-dopamine (17/-1g/ml for 30min) followed by cocaine (6/-1g/mil added throughout the experiment. Effects of propranolol (0.02/-1g/mil and metoprolol (0.2/-1g/mi) on the inotropic responses to noradrenaline (NA) and adrenaline (Add. Agonist dose-response curves from one experiment and KB values with SEM from four experiments (after fu,lad et aI., 1974b).
105
Pharmacology of /3-adrenoreceptor-blockers
4. Acute Haemodynamic Effects of Metopro101 and Propranolol in Conscious Dogs
Metoprolol and propranolol have been found to be approximately equipotent as regards inhibition of the cardiac chronotropic and inotropic responses to sympathetic nerve stimulation (Ablad et al., 1973; see also fig. 1). This action of the {J-blockers probably represents the main determinant of their acute haemodynamic effects in the intact organism. The inhibition of the sympathetic activation of the heart should result in reductions of the heart rate, cardiac contractility and cardiac output, the magnitude of which will depend upon the prevailing discharge rate in the cardiac adrenergic nerves. In situations with Significant release of adrenaline from the adrenal medulla, the haemodynamic effects of a {J-blocker might in part be due to inhibition of the vasodilator action of adrenaline in e.g. skeletal muscle. Propranolol is a potent inhibitor of the peripheral vasodilator effect of adrenaline (fig. 1), while metoprolol is a very weak antagonist of this response, which is mainly mediated by {J2 receptors. Propranolol and metoprolol might therefore be expected to produce different haemodynamic effects when circulating adrenaline contributes to the control of the peripheral circulation. The haemodynamic effects of metoprolol and propranolol have been compared in conscious dogs pre-treated with methscopolamine and studied at rest, during treadmill exercise, during adrenaline infusion and during electrical stimulation of the hypothalamic defence area (Ek et aI., 1973, 1976; Ablad et aI., 1974b). In dogs studied at rest and during submaximal exercise, metoprolol and propranolol, when given in equal doses (0.1 or O.5mgjkg IV) were found to produce equal reductions of the heart rate, left ventricular contractility and cardiac output (Ablad et al., 1974b). Fig. 4 shows some of the results that were recorded. The {J-blockers reduced cardiac output more markedly during
exercise when the sympathetic activation of the heart could be expected to be more intense than at rest. The reduced cardiac output was accompanied by an increased vasoconstrictor nerve activity elicited via baroreceptur reflex mechanisms. It is likely that the effects of the two /3-blockers observed at rest and during exercise were primarily due to blockade of the cardio-stimulant effect of sympathetic nerve activity. Fig. 5 shows how the /3-blockers influenced the haemodynamic responses to IV infused adrenaline. In control experiments, adrenaline tended to reduce the mean arterial blood pressure due to reduced total peripheral vascular resistance. This indicates that a predominant effect of adrenaline was dilatation of peripheral
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_ MetoproiollO,5 mg/kg i.v.1 .Propranolol 10,5 mg/kg i.v.1
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Fig. 4. Haemodynamic effects of metoprolol and propranolol in conscious dogs pre-treated with methscopolamine at rest and during treadmill exercise. Mean values from four experiments with the two /3-blockers and saline control.
Symposium on hypertension
106
resistance vessels and the cardio-stimulation after adrenaline might largely be a secondary phenomenon elicited via the baroreceptor reflex mechanism. After propranolol (O.5mg/kg), adrenaline caused a marked increase of the blood pressure by about 60mm Hg due to increased total peripheral vascular resistance. Propranolol had evidently inhibited the 132 -receptor-mediated vasodilator effect of adrenaline and 'unmasked' the a-receptor mediated vasoconstrictor effect of the catecholamine. Metoprolol (O.5mg/kg) did not greatly influence the effects of adrenaline on the blood pressure and the total peripheral vascular resistance, indicating no significant inhibition of the vasodilator effect of adrenaline. In a study on
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Session V: Pharmacology of I3-Adrenoreceptor Blocking Drugs Chairman: Professor M.J. Rand (Melbourne)
Some Aspects of the Pharmacology of I3-Adrenoreceptor Blockers B. Ablad, E. Carlsson, C. Dahliif and L. Ek Research Laboratories, AB Hassle, Molndal
Summary
The pharmacodynamic properties of a /3-blocker are mainly determined by its affinity to /3, and /3 2 -receptors respectively and by its intrinsic activity. It is suggested that there is no absolute organ separation of the two receptor sub-types. Instead both /3, and /3 2 -receptors are involved in the mediation of the same effect. The frequency distribution ratio of /3, //3 2 -receptors varies markedly among various effector responses. A non-selective and a /3, -selective blocker may have different haemodynamic effects when the levels of circulating adrenaline are high, because of their markedly different potency in inhibiting the /3 2 -mediated vasodilator effect of adrenaline. Data are presented which suggest the existence of a presynaptic /3, -receptor mediating a positive feedback mechanism on neuronal release of noradrenaline.
There is now abundant evidence indicating that {3-adrenoreceptors are not homogeneous but may be sub-divided into at least two groups. Lands et al. (l967) have suggested that one type, 131 , mediates for instance relaxation of vascular and bronchial smooth muscle. In apparent support of this concept, 3 classes of l3-blockers have been described: 131 -selective, 132 -selective and those that are relatively non-selective. Blockers that are 131 -selective or non-selective
have been found to be therapeutically useful in patients with, for instance: (l) angina pectoris, mainly because of inhibition of {3-adrenoreceptormediated increase of cardiac rate and contractility; (2) cardiac arrhythmias, predominantly because of inhibition of {3-adrenoreceptor-mediated effects on cardiac excitability and conductance; and (3) hypertension. The antihypertensive effect is due to {3-blockade, but otherwise the mode of action has not been clarified.
Pharmacology of j3-adrenoreceptor-blockers
1. Factors of Importance for Characterisation of {3-Blockers
Factors of importance for the characterisation of the pharmacological properties of a {3-blocker include pharmacodynamic properties such as 131 and/or 132 affinity, intrinsic sympathomimetic activity and other non-{3-receptor-mediated actions, and pharmacokinetic properties such as absorption, distribution, metabolism and excretion. The clinical effect pattern of one {3blocker can differ from that of another, mainly due to variations in selective affinity to 131 or 132 receptors and in intrinsic sympathomimetic activity. The most discussed 'non-specific' effect of {3-blockers is a membrane-stabilising action, one expression of which is cardio-depression. This action is exerted by compounds such as propranolol, alprenolol, oxprenolol and pindolol, but only at plasma levels that are at least 100 times higher than those associated with commonly used therapeutic doses (Gibson, 1974). It is therefore likely that the membrane stabilising action of 13-blockers is of clinical importance only in patients who have taken huge doses, e.g. for purposes of suicide. Differences in the clinical effect patterns of t3-blockers may also be due to variations in pharmacokinetic properties such as distribution to the brain and formation of biologically active metabolites. Practolol has been reported to cross the blood brain barrier to a smaller extent than propranolol (Scales and Cosgrove, 1970) but the functional Significance of this difference is not clear. The functional significance of the biotransformation products of most 13-blockers is incompletely elucidated, but 131 -blocking metabolites have been identified in plasma after oral administration of propranolol (Cleaveland and Shand, 1972) and alprenolol (Ablad et aI., 1974a). Table I shows comparative data for some {3blockers as regards inhibition of the cardiac chronotropic (mainly 131 -mediated) and the peripheral vasodilator (mainly 132 -mediated)
101
Table I. Comparative data for some j3-blockers 1 lin anaesthetised cats pre-treated with reserpine) Compound
Blockade of isoprenaline responses (ED 50; mg/kg IV)2 Heart rate
Metoprolol Atenolol (lCI 66082) Practolol Tolamolol Propranolol Timolol Alprenolol Oxprenolol Pindolol
0.3 0.3 0.5 0.1 0.1 0.01 0.1 0.1 0.005
Intrinsic activity (% of iso· prenaline)
Peripheral vascular resistance 5 5 35 1.5 0.1 0.01 0.1 0.1 0.005
0 0 25 15 0 0 25 30 50
1 Approximate comparative data for some {3-blockers as regards their potency in inhibiting the cardiac chronotropic and peripheral vasodilator responses to isoprenaline and as regards intrinsic activity on {3-receptors mediating heart rate increase. 2 The ED50 blockade values indicate the dose of the /l-blocker producing a 50% reduction of a submaximal control response to isoprenaline. Intrinsic activity is expressed as the maximal chronotropic response of a compound in relation to that of isoprenaline (for details on the experimental technique, see Ablad et aI., 1973).
responses to isoprenaline in the anaesthetised cat pre-treated with reserpine, and the 'intrinsic' sympathomimetic activity on the heart rate. The results in table I indicate that {3-blockers can be divided into two groups, those with t31 selectivity of varying degree and those with no significant selectivity for either of the two 13adrenoreceptor sub-types. Within each group there are compounds devoid of intrinsic activity and others that possess such activity to a varying extent. This paper will be concerned mainly with some comparative studies of the pharmacodynamic properties of the non-selective blocker propranolol and the 131 -selective blocker metoprolol, especially
Symposium on hypertension
102
(1) their interaction with various {3-adrenoreceptor agonists; (2) the mechanisms underlying their acute general haemodynamic effects; and (3) their influence on the vascular adrenergic neuro-effector system. 2. Pharmacodynamic properties of Metoprolol and Propranolol
The pharmacodynamic properties of metoprolol (structure, fig. 1) have been compared with
OH yH3 I OCH2cHCH2NHyH
00
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Metoprolol
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Inhibition of
Substance
Propranolol Metoprolol
Cardiac responses to symp. nerve stirn. (ED 5 0; rng/kg)
Peripheral vascular dilator response to adrenaline (ED 50 ; mg/kg)
0.1 0.1
0.1 5
Fig. 1. Comparative potency data for propranolol and metoprolol in anaesthetised dogs as regards inhibition of: (1) the cardiac chronotropic and inotropic responses to electrical stimulation of cardiac sympathetic nerves; and (2) the vasodilator response to intra-arterially injected adrenaline in a gracilis muscle pre-treated with phenoxybenzamine. The EDs 0 values indicate the dose of J3·blocker required to reduce submaximal responses to the agonist by 50%.
those of propranolol in animal studies. Stimulant effects of isoprenaline were markedly inhibited by metoprolol in doses that only slightly influenced the vasodilator and bronchodilator effects of isoprenaline. Propranolol, on the other hand, produced no marked differential blockade of these responses to isoprenaline. Metoprolol was somewhat less active than propranolol as regards inhibition of the cardio-stimulant response of isoprenaline (table I). As regards inhibition of the cardio-stimulant responses to exogenous or neuron ally released noradrenaline, however, metoprolol was practically equipotent to propranolol (fig. 1; see also section 3). The two {3blockers were further found to be approximately equipotent inhibitors of renin release induced by electrical stimulation of the renal sympathetic nerves and of FF A release induced by IV infused noradrenaline. Metoprolol differed from propranolol in being a very weak inhibitor of the peripheral vasodilator effect of adrenaline (fig. 1). When given to reserpinised cats both compounds were found to be devoid of intrinsic sympathomimetic activity on the heart. In high dosage, propranolol produced a direct cardiodepressant effect; this effect was less pronounced with metoproioi. The results of toxicological and general pharmacological studies with metoprolol indicate that the compound is a highly specific {3-blocker. Combined pharmacokinetic-effect studies indicate that the action of metoprolol is due to the unchanged molecule. Metoprolol is eliminated at about the same rate as propranolol, mainly by bio-transformation in the liver. The results of animal studies have thus shown that metoprolol is a {31 -selective adrenoreceptor blocker devoid of intrinsic activity. Studies in man (survey by Ablad et aI., 1975) have confirmed the pharmacodynamic effect pattern found for metoprolol in animals. It would appear that metoprolol and propranolol should be suitable tools for elucidating {31 receptor mediated mechanisms.
Pharmacology of (3-adrenoreceptor-blockers
103
3. Are the (31 and (32 Receptors Characterised by Absolute Organ Separation?
The results of Lands et al. (1967) indicated that the three catecholamines noradrenaline, isoprenaline and adrenaline had different (31/(32 affinity ratios. Noradrenaline had the highest relative affInity to (31 receptors. During the pharmacological characterisation of selective antagonists, we obtained differential blockade patterns which were not consonant with the absolute organ separation of (31 and (32 receptors as suggested by Lands et al. (1967). It was found (Carlsson, 1972) that (31selective blockers inhibited, for example, the cardiac response to noradrenaline more than that to isoprenaline, which in turn was blocked more than the response to adrenaline (fig. 2). The (32 -blocker H35/25 produced a differential blockade of the reverse order, while the non-selective blocker propranolol inhibited the effects of the agonists to about the same degree. Corresponding differentiated blockade patterns have been obtained with selective antagonists in studies of (3receptor mediated cardiac stimulation in the cat, dog and man, bronchial smooth muscle relaxation in the cat and man, and adipose tissue lipolysis in the dog and man (Carlsson, 1972; Carlsson et al., 1972; Ablad et al., 1974b; Carlsson and Carlsson, 1976;Abladetal.,1975). A differential blockade of the type described is not consonant with competitive interaction at one type of receptor, e.g. (31 in the heart. The results could, however, be explained by assuming: (1) that there are both (31 - and (32 -receptors mediating one and the same response; and (2) that the relative frequencies or concentrations of (31 - and (32receptors vary in different effector organs (Carlsson, 1972; Carlsson et al., 1972; Carlsson and Carlsson, 1976). Thus in, for example, bronchial and vascular smooth muscles there are mainly (32 -receptors. The number of each type of receptor stimulated for a certain response depends on the relative affinities of the agonist to (31 - and (32 -receptors and the relative concentrations of the
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Salb
120 80
cL
H 35/25
Fig. 2. Chronotropic responses of the isolated cat heart to injected noradrenaline (NA) (0.1-0.2f.Lg), adrenaline (Adr) (0.2-0.3f.Lg), isoprenaline (lpr) (0.01f.Lg) and salbutamol (Salb) (0.7-1f.Lg) before and during perfusion with propranolol (0.1f.Lg/ml perfusate), practolol (0.1 f.Lg/mll and H 35/25 (0.1 f.Lg/mll (after Carlsson et aI., 'j 972)
two types of receptors. The cardiac response to noradrenaline for instance, seems to be more or less a result of (31 -receptor stimulation, depending both on the relatively high concentration of (31receptors in the heart and the selective affmity of noradrenaline for (31 -receptors (Carlsson and Carlsson, 1976). Our results also indicate that for the same cardiac response to adrenaline, a considerable number of (32 -receptors are involved. The concept appears also to be applicable to human (3-receptors. Thus the (31 -selective blocker metoprolol was a more potent inhibitor of the inotropic response to noradrenaline than of the response to adrenaline in isolated human atrial tissue, while the non-selective blocker propranolol showed no such differential blockade (fig. 3) (Ablad et al., 1974b). The differentiated potency of (31 -selective blockers as regards inhibition of a given response to noradrenaline and adrenaline may turn out to be of clinical interest. A (31 -selective blocker may
Symposium on hypertension
104
be expected to inhibit a 13-receptor mediated effect induced by noradrenaline released from adrenergic nerves to a much greater extent than if the same effect is instead induced by adrenaline released from the adrenal medulla. It is evident that much work remains to be done in order to clarify the significance of this modified i3-receptor concept. One important task is to elucidate the relative frequency of {31 - and 132receptors in a given organ in different species as well as to study individual variations, especially in man. Such studies might explain individual variations in the clinical response to 131 -selective blockers. The bronchospastic effect of the highly selective blocker practolol in certain
patients, for example (Waal-Manning and Simpson, 1971), might be due to the fact that 131-receptors are of great importance in the mediation of the relaxation of bronchial smooth muscle in these patients. This modified receptor concept might furthermore explain why patients with occlusive bronchial disease can tolerate 131 -blocker treatment when they are given a 131 -blocker combined with a 132 -agonist, as reported by F ormgren (personal communication, 1975). One consequence of the present concept, moreover, is that it may be impossible to develop i3-receptor agonists or antagonists with absolute organ selectivity, the concentration of the subordinate receptor in the organ being the limiting factor for the selectivity ..
Propranolol 0.02 J.'9/ml
Metoprolol 0.2/-1g/ml
CI)
5l §
en
c:
8.
e
"
NA
Nil b.for.
100
e
'0 50
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8.
before
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50
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~
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.-----1"/;%
'5,
t:
NA
c.
after
: : : ' ;:'::::
oL..::::::=--~----:-----====--~~ oIL_ _ _-.----::=====__'
0.01 ",g/ml
0.1
10
enCl)
0.01 ",g/ml
0.1
10
'"jO" r------,r: J7b~.fO"
Adr
IE ' :
~./ml
~
Ad,
/bO 10
Adr
°,
Adr
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_
~
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U
••
l
0
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/-Ig/ml
10
100
l
0
200 m
II:
10. 9 M
4211109
L::~-_--=-_~=='='=:::-,
0.01 ",g/ml
0.1
10
Fig. 3. Isolated muscle strips of the right atrial appendage from man suspended in an organ bath and stimulated electrically with 1amp/sec. Strips pre-treated with 6-0H-dopamine (17/-1g/ml for 30min) followed by cocaine (6/-1g/mil added throughout the experiment. Effects of propranolol (0.02/-1g/mil and metoprolol (0.2/-1g/mi) on the inotropic responses to noradrenaline (NA) and adrenaline (Add. Agonist dose-response curves from one experiment and KB values with SEM from four experiments (after fu,lad et aI., 1974b).
105
Pharmacology of /3-adrenoreceptor-blockers
4. Acute Haemodynamic Effects of Metopro101 and Propranolol in Conscious Dogs
Metoprolol and propranolol have been found to be approximately equipotent as regards inhibition of the cardiac chronotropic and inotropic responses to sympathetic nerve stimulation (Ablad et al., 1973; see also fig. 1). This action of the {J-blockers probably represents the main determinant of their acute haemodynamic effects in the intact organism. The inhibition of the sympathetic activation of the heart should result in reductions of the heart rate, cardiac contractility and cardiac output, the magnitude of which will depend upon the prevailing discharge rate in the cardiac adrenergic nerves. In situations with Significant release of adrenaline from the adrenal medulla, the haemodynamic effects of a {J-blocker might in part be due to inhibition of the vasodilator action of adrenaline in e.g. skeletal muscle. Propranolol is a potent inhibitor of the peripheral vasodilator effect of adrenaline (fig. 1), while metoprolol is a very weak antagonist of this response, which is mainly mediated by {J2 receptors. Propranolol and metoprolol might therefore be expected to produce different haemodynamic effects when circulating adrenaline contributes to the control of the peripheral circulation. The haemodynamic effects of metoprolol and propranolol have been compared in conscious dogs pre-treated with methscopolamine and studied at rest, during treadmill exercise, during adrenaline infusion and during electrical stimulation of the hypothalamic defence area (Ek et aI., 1973, 1976; Ablad et aI., 1974b). In dogs studied at rest and during submaximal exercise, metoprolol and propranolol, when given in equal doses (0.1 or O.5mgjkg IV) were found to produce equal reductions of the heart rate, left ventricular contractility and cardiac output (Ablad et al., 1974b). Fig. 4 shows some of the results that were recorded. The {J-blockers reduced cardiac output more markedly during
exercise when the sympathetic activation of the heart could be expected to be more intense than at rest. The reduced cardiac output was accompanied by an increased vasoconstrictor nerve activity elicited via baroreceptur reflex mechanisms. It is likely that the effects of the two /3-blockers observed at rest and during exercise were primarily due to blockade of the cardio-stimulant effect of sympathetic nerve activity. Fig. 5 shows how the /3-blockers influenced the haemodynamic responses to IV infused adrenaline. In control experiments, adrenaline tended to reduce the mean arterial blood pressure due to reduced total peripheral vascular resistance. This indicates that a predominant effect of adrenaline was dilatation of peripheral
AControl
_ MetoproiollO,5 mg/kg i.v.1 .Propranolol 10,5 mg/kg i.v.1
Heart rate beats/min
Cardiac output liter/min
5
•• Control
200
4
150
3 2
100 Rest
... Propranolol
~
Rest
ExerCise
Mean artenal
..
Metoprolol
Exercise
Calculated total peripheral
blood pressure
vascular resistance
::1
H9
100
140
75
::1~ Rest
ExerCise
50
==----:1 A•
..........•
Rest
Exercise
Fig. 4. Haemodynamic effects of metoprolol and propranolol in conscious dogs pre-treated with methscopolamine at rest and during treadmill exercise. Mean values from four experiments with the two /3-blockers and saline control.
Symposium on hypertension
106
resistance vessels and the cardio-stimulation after adrenaline might largely be a secondary phenomenon elicited via the baroreceptor reflex mechanism. After propranolol (O.5mg/kg), adrenaline caused a marked increase of the blood pressure by about 60mm Hg due to increased total peripheral vascular resistance. Propranolol had evidently inhibited the 132 -receptor-mediated vasodilator effect of adrenaline and 'unmasked' the a-receptor mediated vasoconstrictor effect of the catecholamine. Metoprolol (O.5mg/kg) did not greatly influence the effects of adrenaline on the blood pressure and the total peripheral vascular resistance, indicating no significant inhibition of the vasodilator effect of adrenaline. In a study on
• ContrOl .Metoprolol (0,5 mg/kg Lv.) .Propranolol (D,S mg/kg Lv.)
Heart rate beats/min 200
150
Heart rate beats/mm
1.\1 )
Cardiac output liter/min
5
....... ...•
150
.. ' ....•
......
-_ ....... ::.::---
~
During adrenaline infUSion
Mean artenal
120
, I
I
I
,,
~...
Before
Dunng ddrenallne InfUSion
,,• ,, ,
vascular resistance
,,
140
Before
Calculated total peripheral
• ,,
160
100
Metoprolol
..................... Propranolol
blood pressure mm Hg
I
,
I
units
100
75
,, ,, , ,
~
u.:t
.'
.... Control
~ Metoprolol
Before
DUring defence area stim
Before
Propranolol
DUring defence area stlm
Mean arterial blood pressure mm Hg
Calculated total peripheral vascular reSistance units
t60
100
140
tOO
/
, ,,
,,
' .'
