Comparison of the effects of xamoterol,atenolol and propranolol on breathlessness,fatigue and plasma electrolytes during exercise in healthy volunteers

Summary The influence of clinical doses of drugs that affect -adrenoceptors has been examined on heart rate, blood pressure, duration of exercise, and on electrolyte concentrations (Na, K, Ca and Mg) during recovery from exercise in healthy volunteers. The drugs used were a ₁-adrenoceptor antagonist atenolol, a nonselective -adrenoceptor antagonist propranolol, and a cardioselective, partial ₁-adrenoceptor agonist with 43% ISA activity, xamoterol.The duration of exercise was smaller on propranolol. Maximum exercise heart rate and blood pressure were reduced significantly by propranolol and atenolol. Xamoterol reduced maximum exercise heart rate and had no effect on blood pressure. The degree of breathlessness and fatigue revealed no differences between treatments.Recent evidence has suggested an association between hyperkalaemia and hypomagnesaemia with an increase in the occurrence of arrythmias following acute myocardial infarction. Exercise-induced hyperkalaemia has been suggested as a factor in sudden death. The results confirmed a rise in serum potassium during exercise and attenuation of the fall during recovery under -adrenoceptor blockade. Xamoterol was no different from placebo in these respects. Exercise also produced a rise in magnesium levels and during recovery the level fell below baseline. Both these effects were attenuated by propranolol. Calcium levels were not affected by any of the treatments.     

The influence of hyperthyroidism on β-adrenoceptor-mediated relaxation of isolated small mesenteric arteries

We investigated the influence of hyperthyroidism on relaxant responses of small mesenteric resistance arteries to -adrenoceptor agonists and to compounds stimulating the corresponding second-messenger system. Hyperthyroidism was induced by feeding rats for 28 days with 5 mg/kg L-thyroxine (T4)-containing rat chow. This treatment produced a stable hyperthyroid state, as indicated by several biochemical/metabolic and haemodynamic parameters. Preparations of small mesenteric arteries were mounted in an isometric wire myograph. Subsequently, concentration-effect curves were determined for isoproterenol, noradrenaline and salbutamol as well as for forskolin, dibutyryl-cAMP and theophylline. We also determined concentration-effect curves to the -adrenoceptor agonists in the presence of ICI 118,551 and CGP 20712A (i.e., in the presence of a selective ₂- and ₁-adrenoceptor antagonist, respectively). Apparent pA₂-values were calculated to determine which -adrenoceptor subtype causes vasodilation. These experiments indicate that -adrenoceptor-mediated vasodilation involves both ₁- and ₂-adrenoceptors in mesenteric resistance vessels of both hyperthyroid and control rats. In our experiments hyperthyroidism has a sensitizing influence on vascular responses induced by the -adrenoceptor agonist isoproterenol and the selective ₂-adrenoceptor agonist salbutamol. Sensitization to isoproterenol was abolished in the presence of ICI 118,551, whereas it was emphasized in the presence of CGP 20712A. Although this was not fully supported by the results obtained with noradrenaline, these results indicate that the sensitization to -adrenoceptor agonists is probably limited to the ₂-adrenoceptor/G-protein complex and not associated with alterations of the corresponding second messenger system.     

Differentiation of cardiac chronotropic and inotropic effects of β-adrenoceptor agonists

Summary The relative inotropic and chronotropic activity of -adrenoceptor agonists was studied in the noradrenaline-depleted, anaesthetized cat. Terbutaline, a selective ₂-adrenoceptor agonist, gave at a certain dose a more pronounced chronotropic than inotropic response, while a new ₁-selective adrenoceptor agonist (–)-H 80/62 produced the same degree of chronotropic and inotropic stimulation. The results indicate that there is some difference between the -adrenoceptors in the sinus node mediating chronotropic stimulation and -adrenoceptors in the ventricular myocardium mediating stimulation of the contractile force. It has been shown that there are both ₁- and ₂-adrenoceptors in the heart (Carlsson et al., 1972). In the light of this finding it is hypothetized that there are differences in the relative distribution of ₁- and ₂-adrenoceptors in the sinus node and in the myocardium. Although ₁ is the predominant type of -adrenoceptor in both regions, the ₁: ₂ concentration ratio seems to be higher in the myo-cardium, than in the sinus node.     

Reflex epicardial coronary vasoconstriction elicited by nicotine in anaesthetized dogs

Summary The effects of arterial chemoreceptor activation by nicotine on coronary artery diameter was studied in anaesthetized, artificially ventilated dogs. Left circumflex coronary artery diameter, coronary blood flow, calculated mean coronary resistance, systemic arterial blood pressure and heart rate were measured. In control dogs (n = 10) the injection of nicotine (100 g) into the carotid artery evoked an increase of arterial pressure (+22 ±9 mm Hg) and a decrease in heart rate (– 36 + 13 beats/min), and tended to increase coronary blood flow (+7 ±4ml/min). Intracarotid nicotine had no effect on large coronary artery diameter (+ 0.02 ±0.03 mm) or total coronary resistance (+ 0.04 ±0.09 mm Hg min/ml) under these conditions. When heart rate was controlled by (1)-adrenoceptor blockade (propranolol, 1 mg/kg i. v.) plus pacing of the right ventricle (n = 4) or (2)-adrenoceptor blockade plus bilateral vagotomy (n = 7), the chemoreflex-induced constriction of the large coronary artery (–0.07 ±0.02 mm and –0.12 ± 0.03 mm, respectively;p < 0.05). In contrast, there was no chemoreflex-induced change in total coronary resistance after -adrenoceptor blockade plus pacing (+0.01 ±0.09 mm Hg min/ml, but after -adrenoceptor blockade plus vagotomy coronary resistance was increased (+0.75 ±0.31 mm Hg min/ml;p < 0.05). The constriction of both large and small coronary arteries was abolished by phentolamine (0.5 mg/kg i. v.). These results suggest that carotid body chemoreceptor stimulation by nicotine can produce reflex -adrenoceptor-mediated constriction of both large and small coronary arteries, and that the constriction of the small vessels is balanced by vagally-mediated dilatation.     

Both β1- and β2-adrenoceptors mediate catecholamine-evoked arrhythmias in isolated human right atrium

Summary The involvement of ₁- and ₂-adrenoceptors in catecholamine-evoked arrhythmias was investigated in isolated human right atrial appendages obtained from 22 patients chronically treated with blockers (usually ₁-selective) and 9 patients not treated with blockers. A simple experimental model that assesses the incidence of arrhythmic contractions as a function of heart rate (pacing) is introduced. ₁-adrenoceptors were activated by (–)-noradrenaline during ₂-adrenoceptor blockade with 50 nmol/l ICI 118551. ₂-adrenoceptors were activated by (–)-adrenaline during ₁-adrenoceptor blockade with 300 nmol/l CGP 20712A. Both (–)noradrenaline and (–)-adrenaline caused arrhythmic contractions whose incidence was greater at low than at high pacing rates. CGP 20712A (300 nmol/l) blocked the (–)-noradrenaline-evoked contractions in 1/1 atrial strip from 1/1 patient not treated with a blocker and 17/17 atrial strips from 15/15 patients chronically treated with blockers. ICI 118551 (50 nmol/l) blocked the (–)-adrenaline-evoked contractions in 3/4 atrial strips from 3/4 patients not treated with blockers and 17/20 atrial strips from 15/18 patients chronically treated with blockers. The incidence of arrhythmic contractions evoked by both (–)-noradrenaline and (–)-adrenaline was higher in chronically blocked patients than in non blocked patients. We conclude that both ₁- and ₂-adrenoceptors mediate atrial arrhythmias and that the generation of these arrhythmias is facilitated by chronic ₁-adrenoceptor blockade. Correspondence to: A. J. Kaumann at the Clinical Pharmacology Unit, University of Cambridge, as above     

Distinct pathways for β-adrenoceptor-induced up-regulation of muscarinic acetylcholine receptors and inhibitory G-protein α-subunits in chicken cardiomyocytes

Summary Exposure of cardiomyocytes from chicken embryos for 3 days to the -adrenoceptor agonist, isoproterenol, lead to a down-regulation of -adrenoceptors by about 70% and to a decrease in isoproterenol-stimulated adenylyl cyclase activity by about 40% (homologous desensitization). In addition, the isoproterenol treatment induced an increase in the level of muscarinic acetylcholine receptors by about 30% and an increase in pertussis toxin-catalyzed ADP-ribosylation of two about 40 kDa proteins, most probably -subunits of the inhibitory G-protein (G_i), by about a factor of two (heterologous desensitization). The purpose of the present study was to characterize the role of -adrenoceptor-dependent and -independent mechanisms in heterologous desensitization of adenylyl cyclase. Therefore, the effect of pretreatment with the -adrenoceptor antagonist, propranolol, with the partial agonists, celiprolol and xamoterol, and with the -adrenoceptor-independent adenylyl cyclase activators, prostaglandin E₁ and forskolin, on -adrenoceptors, muscarinic acetylcholine receptors and pertussis-toxin-catalyzed ADP-ribosylation of G-protein -subunits was studied.Pretreatment of the cardiomyocytes for 3 days with xamoterol or celiprolol, but not with propranolol, induced a small decrease in -adrenoceptor number and in isoproterenol-stimulated adenylyl cyclase activity by about 15–20%. Exposure to prostaglandin E₁ and forskolin lead to a more pronounced decrease in -adrenoceptor binding and in isoproterenol-mediated adenylyl cyclase stimulation by about 40–60% (heterologous desensitization). An increase in the level of muscarinic acetylcholine receptors, similar to that induced by isoproterenol exposure, was only observed after pretreatment with the partial agonists, celiprolol and xamoterol, but not after pretreatment with the -adrenoceptor-independent agonists, prostaglandin E₁ and forskolin, nor after pretreatment with propranolol. In contrast, prostaglandin E₁ and forskolin exposure lead to a similar increase in pertussis toxin-catalyzed ADP-ribosylation of about 40 kDa G-proteins as isoproterenol exposure whereas treatment with propranolol, celiprolol and xamoterol had no or only a very small effect on pertussis toxin substrates. In summary, the data suggest that, similar as shown for homologous desensitization, cyclic AMP-dependent and -independent mechanisms are also involved in heterologous desensitization of adenylyl cyclase stimulation. The -adrenoceptor-induced upregulation of muscarinic acetylcholine receptors and of the -subunits of pertussis toxin-sensitive G-proteins, most probably of G_i, seem to be mediated via distinct pathways. Send offprint requests to C. Reithmann at the above address     

Chronic β1-adrenoceptor blockade sensitises the H1 and H2 receptor systems in human atrium: role of cyclic nucleotides

We have reported that chronic treatment of patients with ₁-adrenoceptor blockers sensitises isolated atrial preparations to adrenaline, noradrenaline and 5-HT. We have now examined the effect of chronic treatment with -adrenoceptor blockers on responses to histamine of human right atrial appendages. We compared the effects of histamine on contractile force, cyclic AMP and cyclic GMP levels as well as cyclic AMP-dependent protein kinase (PKA) activity and explored the arrhythmogenic effects of histamine in preparations obtained from patients chronically treated or not treated with -adrenoceptor blockers.Histamine increased contractile force in paced preparations; the effects were blocked by the H₂ receptor antagonist famotidine (0.1–30 mol/1). The maximum inotropic response to histamine was doubled and the inotropic potency of histamine 0.4 log units greater in atria from -adrenoceptor blocker-treated compared to non -adrenoceptor blocker-treated patients. Histamine elicited frequency-dependent arrhythmias that were blocked by famotidine (30 mol/1) but not by mepyramine (1 mol/1). The incidence of arrhythmias was higher in atria from -adrenoceptor blocker-treated compared to untreated patients. Histamine increased both cyclic AMP and cyclic GMP levels, as well as PKA activity, significantly more in atria from -adrenoceptor blocker-treated compared to those from untreated patients. Mepyramine 1 mol/l prevented the histamine-evoked increase in cyclic GMP levels, reduced the inotropic hyperresponsiveness and abolished the hyperresponsiveness in cyclic AMP levels and PKA activity observed in patients chronically treated with blockers. Sodium nitroprusside 10 mol/l caused smaller increases of cyclic GMP levels than histamine and restored the contracile force depressed by mepyramine to its original level in atria from -adrenoceptor blocker-treated patients.The evidence is consistent with sensitisation of both the histamine H₁ and histamine H₂ receptor systems by chronic ₁-adrenoceptor blockade. H₁ receptor-mediated increases in cyclic GMP, enhanced through an as yet unknown mechanism by chronic ₁-adrenoceptor blockade, may inhibit phosphodiesterase 3 activity, thereby causing enhanced histamine-evoked increases in cyclic AMP levels and PKA activity, and accounting partially for the increased inotropic responses to histamine through H₂ receptors.     

In vitro demonstration of the existence of β-adrenoceptors in human saphenous and canine femoral veins

Summary Helical strips of human saphenous (normal and varicose tissues) and canine femoral veins relaxed in response to isoproterenol when there was pre-existing tone. This effect was antagonised by the -adrenoceptor blocking drugs pronethalol and pindolol demonstrating the presence of -adrenoceptors. Using the canine femoral vein, dose-response curves for isoproterenol were determined in the presence of phenoxybenzamine and a depolarising concentration of potassium. Under these conditions, both -adrenoceptor blocking agents caused a parallel shift to the right of the dose-response curves. Approximately one hundred times more pronethalol than pindolol was needed to produce a similar degree of blockade.     

Calcium channel function and regulation in β<Subscript>1</Subscript>- and β<Subscript>2</Subscript>-adrenoceptor transgenic mice

Cardiac effects of catecholamines on the L-type calcium channel depend on -adrenoceptor subtype (₁- vs. ₂-adrenoceptor). Chronic overexpression of these receptors leads to hypertrophy and early death at moderate (₁) or excessive (₂) levels of overexpression respectively. In order to examine the role of L-type calcium channels in altered cardiomyocyte calcium homeostasis found with ₁-adrenoceptor overexpression, and to understand the quantitative differences between -adrenoceptor subtypes regarding calcium channel regulation, we examined single channels in myocytes obtained from ₁- and ₂-adrenoceptor transgenic mice. The effects of the agonist isoproterenol were investigated and compared with acute receptor stimulation in the respective non-transgenic littermates.Channels from ₁-adrenoceptor transgenic mice have normal baseline activity, and channel number is not reduced. This contrasts to previous findings with ₂-adrenoceptor transgenic mice, where channel activity is depressed. Isoproterenol is unable to stimulate channel activity in both transgenic models.In conclusion, the L-type calcium channel is not likely to be involved in alterations of calcium handling of ₁-adrenoceptor transgenic myocytes. Furthermore, chronic ₁-adrenoceptor overexpression does not depress channel activity, giving another example of the difference between ₁- and ₂-adrenoceptor signal transduction.K.F. and T.K. equally contributed to this work     

Differential Effects of Sulfate and Sulfobutyl Ether of β-Cyclodextrin on Erythrocyte Membranes in Vitro

The hemolytic activity of -cyclodextrin (-CyD) on rabbit erythrocytes was reduced by the introduction of negatively-charged groups onto the hydroxyls of -CyD; the membrane disrupting abilities decreased in the order of -CyD > 2-hydroxypropyl--CyD (HP--CyD) > sulfobutyl--CyD (SB--CyD) >> -CyD sulfate (S--CyD). Under pre-hemolytic concentrations, both -CyD and SB--CyD induced shape changes of membrane invagination on the erythrocytes. In sharp contrast, S--CyD showed biphasic effect on the shape of the erythrocytes; i.e. the crenation at relatively low concentrations and the invagination at higher concentrations. The S--CyD-induced membrane crenation arose from a direct action on the membranes rather than cell metabolism-mediated effects. Unlike -CyD, S--CyD was found to bind to the erythrocytes and may be confined to the outer surface of the membrane bilayer, which may expand the exterior layer relative to the cytoplasmic half, thereby inducing the cells to crenate. On the other hand, the membrane invagination mediated by the three - CyDs was initiated by extracting specific membrane lipids from the cells, depending upon their inclusion abilities, subsequently leading to the lysis of the cells. These results indicate that SB--CyD and S--CyD interact with the erythrocyte membranes in a differential manner and possess lower membrane disrupting abilities than the parent -CyD and HP--CyD.     

β-Adrenoceptor studies

Summary Propranolol, pindolol, practolol and metoprolol were investigated for -adrenoceptor blocking activities in the guinea-pig right atrium and tracheal strip preparation, both in the absence and presence of 2.8% bovine serum albumin. Similarly, the influence of 2.8% albumin on the antagonism of ouabain-induced arrhythmias in the guinea-pig right atrium was studied. Local anesthetic activities were measured on the isolated, partially desheathed, frog sciatic nerve.Incubation with albumin decreased the in vitro atrial -adrenoceptor blocking potency of propranolol against (-)-isoprenaline-induced positive chronotropism by a factor of 12 whereas the activity on tracheal receptors was 4.5 times lower. The activities of pindolol, practolol and metoprolol both on atrial and tracheal -receptors were not significantly influenced by the presence of albumin. The results demonstrate the important role of albumin binding in causing differences in the in vivo and in vitro cardiac -adrenoceptor blocking potency ratios of propranolol compared to the other -receptor antagonists studied.The large difference between -adrenoceptor blocking and minimal antiarrhythmic concentrations, the approximately 1000 times lower antiarrhythmic activity of practolol compared to propranolol and the very significant correlation between the antiarrhythmic and local anesthetic activities demonstrate that the antagonism of ouabain-induced arrhythmias in the isolated right atrium of the guinea pig is solely due to the membrane-stabilizing properties of the -receptor antagonists. The moderate decrease of the antiarrhythmic potency of propranolol by 2.8% albumin was concluded to have no relevance for the in vivo situation.Binding to 2.8% albumin was investigated using the ultracentrifugation technique. For propranolol a linear relationship was found between log concentration and percent binding which amounted to 88.2% at 10^–6 M. In contrast, protein binding of pindolol, practolol and metoprolol was low and concentration independent.     

Involvement of central β-adrenoceptors in the regulation of yawning responses

Summary A behavioral study was performed in an attempt to understand the role of central -adrenoceptors in yawning in rats. Yawning was evoked by apomorphine and piribedil, mixed dopamine D₁/D₂-receptor agonists, but not by SK&F 38393 [1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8diol], a dopamine Dr-receptor angonist. The apomorphine-induced yawning was increased by pindolol, propranolol, indenolol, alprenolol and bukumolol which block the central -adrenoceptors, but not by the peripheral -adrenoceptor antagonists, carteolol and atenolol. These -adrenoceptor antagonists given alone did not elicit yawning. Conversely, the yawning was inhibited by salbutamol, a -adrenoceptor agonist, without being affected by prazosin, an -adrenoceptor antagonist. The combined administration of SK&F 38393 and the -adrenoceptor antagonists did not induce yawning. The yawning elicited by either apomorphine or piribedil in combination with pindolol was suppressed by spiperone and YM-09151-2 [cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide], dopamine D₂-receptor antagonists, and scopolamine, a muscarinic receptor antagonist, but not by SCH 23390 [R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol], a dopamine D₁-receptor antagonist. Physostigmine or pilocarpine induced yawning, which was also enhanced by pindolol and propranolol. This enhanced yawning was inhibited by scopolamine, but not by spiperone, YM-09151-2 and SCH 23390. The present results suggest that the \-adrenoceptor blockade facilitates the occurrence of yawning induced by dopaminergic and cholinergic agonists. Therefore, the central adrenergic neuron systems may participate in the regulation of yawning responses.Send offprint requests to K. Yamada at the above address     

The mechanism of the drinking response to some hypotensive drugs: Activation of the renin-angiotensin system by direct or reflex-mediated stimulation of β-receptors

Summary The increase in water intake and plasma renin concentration (PRC) in response to the administration of the -receptor blocker phentolamine (10 mg/kg) were simultaneously diminished or abolished by ganglionic blockade with pempidine (10 mg/kg) or camphidonium (10 mg/kg) as well as by pretreatment with reserpine or 6-OH-dopamine. In contrast, the effects of the -mimetic agent, isoprenaline (250 g/kg), on both parameter remained unchanged. The (–)-isomer of propranolol (200 g/kg) selectively blocked the dipsogenic and PRC-raising effects of isoprenaline and phentolamine, thus demonstrating that a specific -receptor blockade antagonizes the drinking and increase in PRC induced by the drugs used.From these results it is concluded that the stimulation fo certain -receptors causes an increase in PRC. The -receptors may be stimulated either directly by -mimetic agents such as isoprenaline or indirectly by a reflex-mediated activation of the sympathetic nervous system brought about by hypotensive, drugs such as phentolamine.The activation of the renin-angiotensin system triggers off the drinking response.Some of the results were presented to the Deutsche Pharmakologische Gesellschaft (Meyer and Hertting, 1971).     

Brainβ-adrenoceptor binding sites in depressed suicide victims: effects of antidepressant treatment

-Adrenoceptor binding sites were measured by saturation binding of [³H]CGP 12177 in nine brain regions from 13 suicides, with a firm retrospective diagnosis of depression, who had been receiving antidepressant drugs, and 11 matched controls. Significantly lower numbers of-adrenoceptor binding sites were found in thalamus and temporal cortex (Brodmann area 38), but not in other brain regions, of antidepressant-treated suicides compared to controls. The lower number of-adrenoceptor binding sites in thalamus appeared to be related to drug treatment, whereas lower numbers of-adrenoceptors in temporal cortex were also found in antidepressant-free suicides.     

Comparative β-adrenoceptor blocking effect and pharmacokinetics of bucindolol and propranolol in man

Summary The -adrenoceptor blocking properties and pharmacokinetics of bucindolol 150 mg were compared to those of propranolol 80 mg and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures and peak expiratory flow rate (PEFR) at rest and during vigorous exercise, and plasma renin activity (PRA) at rest, were measured before and at intervals up to 24 h after oral administration of the drugs. Bucindolol reduced exercise tachycardia and decreased exercise PEFR, thus behaving as a non-selective -adrenoceptor blocking drug. In contrast to propranolol, bucindolol did not reduce resting HR and PRA, probably because of its intrinsic sympathomimetic activity. It decreased resting DBP in relation to its peripheral vasodilator properties. The effects of bucindolol developed as early as 30 min after administration and lasted up to 24 h, whereas its T_max and T_1/2 were 1.6 and 3.6 h respectively. Comparison of the time courses of plasma bucindolol and the cardiac -adrenoceptor blockade strongly suggests that in man bucindolol undergoes an extensive first-pass effect, leading to the formation of one or more active metabolites.     

Effect of prednisolone and ketotifen onβ 2-adrenoceptors in asthmatic patients receivingβ 2-bronchodilators

Summary In 13 patients with bronchial asthma, who were on ₂-adrenergic bronchodilator therapy, the effects of prednisolone and ketotifen on lymphocyte ₂-adrenoceptor density and -responsiveness were investigated. The mean lymphocyte ₂-adrenoceptor density and -responsiveness was significantly lower than in healthy controls, presumably due to the long-term ₂-adrenergic bronchodilator treatment. Both prednisolone 100 mg i.v. and ketotifen 1 mg b.d.p.o. for 6 days rapidly improved lymphocyte ₂-adrenoceptor function. 16 h after prednisolone and about 6 days after the first dose of ketotifen lymphocyte ₂-adrenoceptor density and-responsiveness had risen to values within the range in normal volunteers.The improvement of lymphocyte ₂-adrenoceptor function was accompanied by a significant increase in peak expiratory flow rate before and after inhalation of salbutamol.It is concluded that prednisolone and ketotifen may act beneficially on the recovery of ₂-adrenoceptor responsiveness to ₂-adrenergic bronchodilators in tolerant asthmatic patients.     

Beta-adrenoceptor subtype of the venous capacity system: Characterization by venous occlusion plethysmography

Summary In order to characterize the -adrenoceptor subtype of the venous vessel wall, venous occlusion plethysmograph studies were carried out in 7 healthy volunteers. Venous distensibility (VD) was considered to be a measure of venous tone. Infusion of the ₁- and ₂-adrenoceptor agonist isoproterenol (I), of the predominantly ₂-adrenoceptor agonist fenoterol (F) and of the predominantly ₁-adrenoceptor agonist dobutamine (D) in increasing doses led to a significant increase in VD by I and F but not by D. Administration of the ₁-adrenoceptor antagonists betaxolol (B) and metoprolol (M) did not significantly change VD. Neither -adrenoceptor antagonist prevented the increase in VD provoked by subsequent administration of I or F. It is concluded that -adrenoceptors in the venous vessel wall belong to the ₂-adrenoceptor subtype.Dedicated to Professor K. D. Bock for his 60th birthday     

In kitten ventricular myocardium,the inotropic potency of an agonist is determined by both its intrinsic activity for the adenylyl cyclase and its affinity for the β-adrenoceptors

Summary Three -adrenoceptor-related parameters were measured for 23 agonists on kitten ventricular myocardium: inotropic potencies (EC₅₀'s) on papillary muscles, intrinsic activities for stimulation of the adenylyl cyclase in membrane particles, and affinities for -adrenoceptors labelled with ³H-(–)-propranolol in membrane particles.For catecholamines a dissociation between inotropic potencies and -adrenoceptor affinities was observed. Inotropic potencies are 1.3–1.8 orders of magnitude higher than affinities. This dissociation between inotropic activation and binding is similar for (+)- and (–)-enantiomers of catecholamines, despite the higher affinities of the latter. The dissociation is considerably smaller for dopamine and dobutamine, which suggests a role of the -OH group in the phenomenon. The effect is also smaller with resorcinols than with catechols; it decreases further, or is not observed at all, when one of the ring hydroxyl groups is replaced or absent. With most agonists the degree of dissociation appears to be directly proportional to the degree of adenylyl cyclase stimulation. About 1/4 of maximum adenylyl cyclase stimulation suffices to activate the inotropic processes fully. It is suggested that both the magnitude of the dissociation and the degree of adenylyl cyclase activation are indicators of the degree of change induced by agonist in the conformation of the -adrenoceptor.The production of marked inotropic effects by noradrenaline and adrenaline with low -adrenoceptor occupancy and little adenylyl cyclase stimulation may permit the regulation of heart function. Conditions of desensitization that reduce maximum activation of the adenylyl cyclase may not necessarily reduce maximum inotropic effects of these catecholamines.The agonist (±)-hydroxybenzylpindolol caused positive inotropic effects only at high -adrenoceptor occupancy. This is consistent with the idea that sufficient conformational change occurs only near receptor saturation.     

Functional capacity in healthy volunteers before and following β-blockade with controlled-release metoprolol

The effects of the ₁-selective -adrenergic blocker metoprolol on physiological responses, exercise capacity and gas exchange parameters were measured in healthy men using different graded bicycle exercise protocols on separate days before and following administration of 200 mg controlled-release metoprolol. Eleven men performed in randomised order maximal cardiopulmonary exercise testing on 50-W/6-min stage, 50-W/3-min stage and ramp (15-W/min^–1) protocols. Peak heart rate and peak heart rate-blood pressure products were similar on all exercise protocols, and were significantly reduced by metoprolol. Submaximal and peak oxygen consumption were similar before and following -adrenoceptor blockade. Depending on the exercise protocol applied, an insignificant decrease of 4–10% in maximal cumulated exercise capacity (work-rate × time integral) was observed following administration of metoprolol. It is concluded that in healthy men evaluated with different exercise protocols the ₁-selective controlled-release -adrenoceptor blocker metoprolol does not influence exercise capacity despite a marked reduction of heart rate and rate-pressure product.     

Sympathomimetic Bronchodilators: Increased Selectivity with Lung-Specific Prodrugs

The development of selective bronchodilator -adrenoceptor agonists is reviewed with emphasis on a pharmacodynamic approach, which is directed to drugs with high specificity for the ₂-adrenoceptor, and on a pharmacokinetic approach in which known ₂-adrenoceptor agonists are converted to prodrugs with selectivity for the lung. The pharmacodynamic approach has produced drugs that display high specificity for the ₂-adrenoceptor but still suffer from side-effects including tremor and palpitations. This is due to the fact that the ₂-adrenoceptors present in skeletal muscle and blood vessel are indistinguishable from those in the airways. On the other hand, the prodrug pharmacokinetic approach offers a promising way to obtain selectively acting bronchodilators with significantly fewer side-effects.