The selectivity of the beta-adrenoceptor for ventilation in man.

1 Minute ventilation, alveolar PCO2, CO2 production and heart rate were measured in eight normal subjects before and during infusions of noradrenaline 0.2, 1.0 and 5.0 micrograms min-1 and isoprenaline 0.04, 0.2 and 1.0 microgram min-1. 2 These measurements were repeated after propranolol 3.5 mg, atenolol 8 mg or metoprolol 7 mg by intravenous injection. 3 Noradrenaline 5.0 micrograms min-1 and isoprenaline 1.0 microgram min-1 significantly increased ventilation and CO2 production and decreased alveolar PCO2. These changes were attenuated by propranolol, atenolol and metoprolol. There was no significant difference between the blocking effects of the three beta-adrenoceptor blockers for these three variables but propranolol was more effective than atenolol or metoprolol in blocking isoprenaline induced tachycardia (P less than 0.001). 4 The hyperventilatory response to catecholamines is predominantly a beta1-effect.     

A comparison of the cardioselectivity of five beta-adrenoceptor blocking drugs

The cardioselectivities of five beta-adrenoceptor antagonists were compared. Six normal subjects received, in a double-blind random order, 200 mg acebutolol, 50 mg atenolol, 10 mg betaxolol, 100 mg metoprolol, 80 mg propranolol, and placebo. All beta-adrenoceptor antagonists produced a similar reduction in exercise tachycardia. Isoprenaline infusions in incremental doses were given. Dose-response curves were constructed and the doses of isoprenaline required to increase heart rate by 25 beats/min (I25), forearm blood flow by 3 ml/100 ml/min (IF3), and finger tremor by 200% (IT200), and decrease diastolic blood pressure by 25 mm Hg (ID25), after each treatment were compared. After propranolol, I25, ID25, IF3, and IT200 were greater (p less than 0.02) than after atenolol, betaxolol, and metoprolol; I25, ID25, and IT200 were greater than after acebutolol. After acebutolol I25, ID25, and IF3 were greater than after atenolol and betaxolol; IT200 was greater than after betaxolol. Atenolol and betaxolol caused less reduction in the isoprenaline-induced changes in blood glucose, plasma potassium, lactate, renin activity, and serum insulin than propranolol. Acebutolol caused less attenuation of blood glucose and plasma lactate, and metoprolol less attenuation of plasma renin activity, than propranolol. It is concluded that acebutolol, atenolol, betaxolol, and metoprolol cause less blockade of beta 2-adrenoceptors than propranolol, and atenolol and betaxolol are more cardioselective than acebutolol.     

Observations on the mechanism underlying the differences in exercise and isoprenaline tachycardia after cardioselective and non-selective beta-adrenoceptor antagonists

1 Differences in ability to attenuate isoprenaline tachycardia between the cardioselective beta-adrenoceptor antagonist atenolol and the non-selective drug propranolol, when administered in equivalent anti-exercise tachycardia oral doses, were measured in four normal volunteers. 2 Propranolol at all dose comparisons showed a greater potency in antagonism of isoprenaline tachycardia than atenolol; this ranged from 6 at the lowest doses (40 and 50 mg respectively) to 13 at the highest doses (320 and 400 mg respectively). 3 After doses of each drug which produced equal inhibition of exercise tachycardia, isoprenaline induced a greater increase in heart rate and greater decrease in diastolic blood pressure after pre-treatment with atenolol than after propranolol. 4 The contribution of this isoprenaline induced vasodilatation to the reduced tachycardia response, 1 h after 25 mg oral atenolol, was measured in the same four subjects by correction of the hypotension with an intravenous angiotensin infusion. Reversal by angiotensin of the 17 mm Hg average fall in diastolic blood pressure during the sustained isoprenaline infusion did not reduce the tachycardia. 5 The hypotension that results from isoprenaline stimulation of unblocked vasodilator beta 2-adrenoceptors in normal subjects pre-treated with atenolol appears to make a negligible contribution to the tachycardia response and does not explain the different abilities of cardioselective and non-selective beta-adrenoceptor blocking drugs to antagonise isoprenaline tachycardia. Our results are compatible with the presence of beta 2-adrenoceptors in human atria.     

A comparative study of the activity of beta-adrenoceptor antagonists in man.

1. In healthy subjects the plasma concentration of unchanged drug, heart rate response to excerise and attenuation of isoprenaline tachycardia were maximal at one hour after ingestion of a range of doses of propranolol, oxprenolol, practolol, tolamolol, atenolol and metoprolol. 2. There was a within-drug relationship between plasma concentration of unchanged drug and the attenuation of exercise and iosprenaline tachycardia. There was no similar between-drug relationship. 3. There was a similar exponential relationship between oral dose and reduction of exercise tachycardia for all six drugs. 4. The linear relationship between oral dose and antagonism of infused isoprenaline was significantly greater for oxprenolol and propranolol than for the other four drugs. 5. "Cardioselective" activity was the only ancillary pharmacological property which differentiated the activity of these drugs in normal subjects.     

The selectivity of beta-adrenoceptor antagonists on isoprenaline-induced changes in heart rate, blood pressure, soleus muscle contractility and airways function in anaesthetized cats

The beta-adrenoceptor antagonist of propranolol, metoprolol, atenolol and butoxamine in anaesthetized cats has been measured and compared with the activity of four synthetic phenylethanolamine derivatives. The effects of isoprenaline on four parameters in the anaesthetized cat: heart rate, blood pressure, soleus muscle contractility and airway reactance, were measured and the modification of the isoprenaline dose-response relation by each of the antagonist drugs assessed. Parallel shifts in log dose-response curves for isoprenaline were caused by propranolol for all parameters, by metoprolol and atenolol for each parameter except blood pressure, and butoxamine for each except soleus muscle and heart rate. Selectivity of action of the antagonists between different organs was measured by comparing DR10 values, computed from isoprenaline dose-ratios. Propranolol was the most potent antagonist and showed slight selectivity of action on soleus muscle compared with heart. Atenolol and metoprolol were approximately equipotent and were cardioselective at low doses only. Butoxamine was the least potent antagonist and possessed non-beta-adrenoceptor effects on the parameters measured. Each of the new compounds, 4'-bromo-2'-methoxy-N-isopropyl phenylethanolamine, the 4'-chloro- and 4'-methyl analogues, and 4'-methoxy-N-t-butyl phenylethanolamine, was a potent antagonist but did not exhibit any selectivity of action. The results suggest no clear separation of beta-adrenoceptors into beta 1- and beta 2-subclasses in organs of the cat. There is no apparent separation of beta-adrenoceptor-mediated effects on skeletal muscle and airways.     

Enhancement of physiological finger tremor by intravenous isoprenaline infusions in man: evaluation of its role in the assessment of beta-adrenoceptor antagonists.

Graded intravenous isoprenaline infusions produce dose-related increases in finger tremor. The dose-response curves constructed with intra-arterial or intravenous isoprenaline behave similarly in the presence of both atenolol 50 mg and propranolol 40 mg. In Five subjects, practolol 120 mg, atenolol 50 mg, propranolol 40 mg and sotalol 200 mg reduced exercise heart rate by 20.2 +/- 2.3, 21.4 +/- 1.8, 17.4 +/- 2.5, 23.9 +/- 3.6% respectively: the differences were not significant. The corresponding dose-ratios for reduction of an isoprenaline tachycardia were 2.8, 2.3, 19.1 and 16.9 respectively. At doses which had comparable effects on an exercise tachycardia, the non-selective beta-adrenoceptor antagonists, propranolol 40 mg and sotalol 200 mg, attenuated the finger response to isoprenaline (dose ratios 33.3 and greater than 25.0 respectively) more than the beta 1-selective adrenoceptor antagonists, practolol 120 mg and atenolol 50 mg (dose ratios 1.0 and 2.3 respectively). In two out of five subjects, dose-response curves could not be constructed with sotalol, either at a dose of 200 or 100 mg. The enhancement of physiological finger tremor by intravenous infusions of isoprenaline may be useful in the investigation of beta 2-adrenoceptors and their antagonists in man.     

Inverse agonist activities of beta-adrenoceptor antagonists in rat myocardium.

1. Negative inotropic effects of several beta-adrenoceptor (betaAR) antagonists on electrically-stimulated right atria, left atria, right ventricles and left ventricular papillary muscles from reserpine-treated rats were used as a measure of their inverse agonist activities. 2. Beta1AR antagonists acebutolol, atenolol and metoprolol, beta2AR antagonist ICI-181,551 and nonselective betaAR antagonists alprenolol, nadolol, propranolol and timolol produced negative inotropic effects, which were most marked on the right atria. 3. The nonselective betaAR antagonist pindolol did not exhibit inverse agonist activity but inhibited the negative inotropic activities of ICI-118,551, atenolol and propranolol. 4. The negative inotropic effects of lidocaine, nifedipine and pentobarbitone were similar on all the four myocardial preparations. 5. The positive inotropic efficacy of salbutamol on right and left atria but not on right ventricles and papillary muscles was comparable to that of isoprenaline. The antagonist activity of ICI-118,551 against isoprenaline was greater on right atria than on other cardiac regions. 6. Beta1AR proteins were expressed in all regions of the heart but of beta2AR were primarily localized in the right atrium. 7. It is concluded that beta2AR play a greater role in right atria than in other cardiac regions and almost all betaAR antagonists behave as inverse agonists.     

Interaction of orally administered metoprolol,practolol and propranolol with isoprenaline in asthmatics

Summary In a single-blind study eight patients with asthma received on five different days, in randomized order, doses of: propranolol 40 mg, metoprolol 50 mg and 100 mg (a new selective beta₁-blocking agent with no intrinsic activity), practolol 200 mg or placebo. The beta₁-blocking potency of the selective drugs at these dose levels was higher than or equal to that of propranolol. The effects on heart rate, blood pressure, ventilatory capacity (FEV₁) and skeletal muscle tremor were studied at rest and during infusion of increasing doses of isoprenaline. There was a slight decrease in FEV₁ after propranolol and both doses of metoprolol. After the placebo, isoprenaline produced a dose-dependent increase in heart rate, systolic blood pressure, FEV₁ and tremor, and lowered the diastolic blood pressure. Propranolol almost completely blocked the effects of all doses of isoprenaline on heart rate, FEV₁ and tremor, and, to a lesser extent, any change in systolic and diastolic pressure. The two doses of metoprolol and practolol did not inhibit the effect of isoprenaline on FEV₁. The effect of metoprolol and practolol on the isoprenaline-induced increase of heart rate indicated their selectivity for beta₁-receptors. The increase in tremor during infusion of isoprenaline was blocked by propranolol, but not by the selective beta₁-blockers, which implies that the induction of tremor was a beta₂-effect. The effect of isoprenaline on FEV₁ was not inhibited by selective beta₁-blocking agents, and so, when combined with beta₂-stimulators, they may be given to asthmatic patients.     

The use of Doppler ultrasound techniques to study the effects of isoprenaline and beta-adrenoceptor blocking drugs on peripheral blood vessels in man.

A Doppler ultrasound technique has been used in six volunteers to determine the effects of intravenous isoprenaline on blood velocity and volume blood flow in the femoral artery and to investigate the effects of single oral doses of atenolol (50 mg) and propranolol (40 mg) on these effects and on heart rate changes. Isoprenaline increased the blood velocity and volume blood flow which was attenuated by propranolol and not by atenolol; the tachycardia of isoprenaline was inhibited by both drugs. The results show that the Doppler ultrasound measurements in the femoral artery can identify pharmacologically induced changes in peripheral blood vessels in the leg and warrants further investigation as a tool to study the pharmacology of peripheral blood vessels in man.     

Comparison of beta-adrenoceptor selectivity of acebutolol and its metabolite diacetolol with metoprolol and propranolol in normal man

Summary 1. The beta-adrenergic selectivity of diacetolol, the major metabolite of acebutolol, has been compared with that of acebutolol, metoprolol and propranolol in 11 normal subjects.2. Bronchial and cardiac beta-adrenoceptor blockade were assessed on separate occasions after diacetolol 600 mg, acebutolol 400 mg, metoprolol 200 mg, propranolol 80 mg and placebo.3. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose response curve to inhaled isoprenaline after each beta blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta-adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the 5th minute of exercise at 70% of the subject's maximum work rate.4. There was a significant reduction in exercise heart rate with all 4 beta-blocking drugs when compared with placebo, 22% for diacetolol, 24% for acebutolol, 25% for propranolol and 28% for metoprolol. The reduction with metoprolol was significantly greater than the reduction with the other three beta-adrenoceptor antagonists.5. Mean dose ratios for the airway isoprenaline dose response curves after each of the 4 beta-blocking drugs were 2.4 for diacetolol, 2.7 for metoprolol, 8 for acebutolol and 72 for propranolol. The difference between diacetolol and metoprolol was not significant.6. Thus diacetolol appears to be more cardioselective than acebutolol and both are more cardioselective than propranolol in man. Metoprolol is probably more cardioselective than diacetolol though interpretation of the differences in exercise heart rate is complicated by the fact that diacetolol has some intrinsic sympathomimetic activity.     

Human pharmacokinetic and pharmacodynamic studies on the atenolo (ICI 66,082), a new cardioselective beta-adrenoceptor blocking drug.

The beta-adrenoceptor blocking effects of orally administered atenolol on tachycardia induced by intravenous isoprenaline or by exercise have been studied in normal volunteers, and compared with the effects of similar doses of propranolol. The blood levels of atenolol at various times after oral administration were determined by g.l.c. and correlated with the degree of inhibition of tachycardia. Atenolol was shown to be a beta-adrenoceptor blocker in man, as in animals, in that it antagonized the chronotropic effects of isoprenaline and of exercise. The inhibitory effect of atenolol on exercise-induced tachycardia was evident at a concentration in blood of 0.2 mug/ml and virtually complete at 0.5 mug/ml. Higher concentrations than this did not produce significantly greater blockade. The effects of atenolol on exercise-induced tachycardia were similar to those of propranolol but it was less effective in blocking the rise in heart rate and fall in diastolic blood-pressure induced by intravenous infusion of isoprenaline. This separation of effects is considered characteristic of drugs causing preferential blockade of cardiac beta-adrenoreceptors. The half-life of atenolol in blood was calculated to ablut 9 hours.     

Effects of ICI 141,292 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

The beta-adrenoceptor blocking properties and cardioselectivity of ICI 141, 292 were investigated in healthy male subjects. Seven subjects received in random order oral doses of ICI 141,292 20, 50, 100, 200 and 400 mg, atenolol 50 and 100 mg and placebo. ICI 14 292 had no effect on supine heart rate which was reduced by atenolol 100 mg. ICI 141,292 50, 100 and 200 mg had no effect on standing heart rate which was reduced by 400 mg at 2 h. Both doses of atenolol caused greater reductions. The maximum percent reduction of an exercise tachycardia after ICI 141,292 200 mg (23.9 +/- 3.7%) and 400 mg (24.3 +/- 5.2%) were similar to atenolol 50 mg (27.3 +/- 4.7%) but less than atenolol 100 mg (30.8 +/- 2.9%) (P less than 0.02). Six subjects received in random order single oral doses of ICI 141,292 100, 200 and 400 mg, atenolol 50 mg, propranolol 40 mg and placebo. Following each dose each subject received graded infusions of isoprenaline sulphate until heart rate increased by 40 beats min-1. Dose-response curves were constructed for the changes in heart rate, finger tremor, blood pressure and forearm blood flow produced by each infusion. At the 4 micrograms min-1 dose of isoprenaline, ICI 141,292 200 mg caused more attenuation than atenolol 50 mg but less than propranolol 40 mg in the changes of heart rate, diastolic blood pressure and finger tremor (P less than 0.02). ICI 141,292 400 mg caused more attenuation of the changes of all parameters than atenolol 50 mg but less attenuation of the changes in diastolic blood pressure and finger tremor than propranolol 40 mg (P less than 0.02). These results indicate that ICI 141,292 is a cardioselective beta-adrenoceptor antagonist with partial agonist activity.     

Comparison of the anti-hypertensive response to beta-adrenoceptor blocking drugs in intact and adrenal-demedullated spontaneously hypertensive rats.

1 The beta-adrenoceptor blocking drugs atenolol, metoprolol, practolol, propranolol, timolol and oxrenolol (as racemates) were administered acutely at three dose levels (0.01, 0.03 and 0.1 mmol/kg i.p. or s.c.) to spontaneously hypertensive rats with intact adrenal glands (SH-rats) and following unilateral adrenalectomy and contralateral adrenal-demedullation (SHAD-rats). Changes in mean arterial pressure and heart rate were determined via an indwelling aortic catheter, with the animals placed in a quiet environment. 2 All drugs significantly lowered the blood pressure of SHAD-rats, and these responses were not always associated with changes in basal heart rate. 3 With the exception of metoprolol and atenolol, the beta-adrenoceptor blocking drugs were less effective as anti-hypertensives in SH- than in SHAD-rats. Notably, timolol and oxprenolol lowered the blood pressure of SH-rats at low doses only, whereas propranolol evoked a pressor response in this model. 4 Whilst (+)-propranolol lowered the blood pressure of SHAD-rats only at a dose which caused myocardial depression, the anti-hypertensive response to (--)-propranolol did not parallel changes in heart rate and was preceded by a pressor response. 5 The results imply that adrenal catecholamine release contributes towards masking the anti-hypertensive effects of some beta-adrenoceptor antagonists in SH-rats.     

Beta-adrenoceptor blockade and hypoglycaemia. A randomised, double-blind, placebo controlled comparison of metoprolol CR, atenolol and propranolol LA in normal subjects.

1. The effect of 1 week of treatment with propranolol LA (160 mg), atenolol (100 mg) and metoprolol CR (100 mg) on awareness of and the physiological responses to moderate hypoglycaemia were compared with placebo using a randomised, cross-over design in 12 healthy volunteers. 2. All three beta-adrenoceptor antagonists reduced resting heart rate, systolic blood pressure and heart rate responses to submaximal exercise compared with placebo. 3. Under hyperinsulinaemic (60 mu m-2 min-1) clamp conditions, at a blood glucose of 2.5 mmol l-1, atenolol prevented the rise in systolic and atenolol and metoprolol CR prevented the fall in diastolic blood pressure usually associated with hypoglycaemia. At this level of hypoglycaemia, the expected increase in heart rate was inhibited by atenolol but not metoprolol CR. Pre-treatment with propranolol LA resulted in a significant pressor response and a bradycardia during hypoglycaemia. In addition the normal increase in finger tremor was abolished by propranolol LA. 4. During hypoglycaemia all three beta-adrenoceptor blockers augmented sweating compared with placebo but hypoglycaemic symptoms, awareness and slowing of reaction time were the same with drugs and placebo. 5. The rise in plasma adrenaline and other counter-regulatory hormones during hypoglycaemia was enhanced by beta-adrenoceptor blockade. 6. We conclude that beta-adrenoceptor antagonists modify the physiological and hormonal responses to, but do not adversely affect awareness of, moderate hypoglycaemia in healthy volunteers.     

Beta 1-selectivity of bisoprolol, a new beta-adrenoceptor antagonist, in anesthetized dogs and guinea pigs

The beta-adrenoceptor activity of the newly synthesized antagonist bisoprolol [+/-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2- propranol, hemifumarate), has been compared with the effect of several reference compounds in anesthetized dogs and guinea pigs. In anesthetized, bivagotomized dogs, isoprenaline dose-response relations for increase in heart rate and decrease in diastolic blood pressure were established. Bisoprolol had the largest beta 1/beta 2 ratio, i.e., 147 (102-292). Practolol showed a beta 1/beta 2 ratio greater than 17; betaxolol 6-15; acebutolol, atenolol, and metoprolol 1.1-3.2; mepindolol 0.6-1 and propranolol 0.2. In artificially ventilated guinea pigs, the activity of bisoprolol on histamine-induced increase in tracheal lateral pressure (TLP) and basal heart rate (HR) was tested: using doses taken at TLP (30 mm Hg) and HR (250 beats/min), bisoprolol exhibited the most pronounced ratio TLP/HR of 124 +/- 59, followed by atenolol 33 +/- 23, metoprolol 25 +/- 15, betaxolol 12 +/- 4, propranolol 1 +/- 0.3, and celiprolol 0.23 +/- 0.19. These experiments indicate that bisoprolol possesses a pronounced beta 1-selectivity, which seems to be superior to that of known beta 1-selective antagonists.     

Beta-adrenoceptor blockers and the blood-brian barrier.

1 This study on 21 neurosurgical patients was set up to investigate the extent to which four chronically administered beta-adrenoceptor blockers, propranolol, oxprenolol, metoprolol and atenolol, cross and blood-brain barrier and enter the cerebrospinal fluid (CSF) and brain tissue. The concentration in the CSF of the three lipophilic beta-adrenoceptor blockers, propranolol, oxprenolol and metoprolol, approximated to the free drug concentration in the plasma, and was a poor predictor of brain concentration. These three lipophilic beta-adrenoceptor blockers appeared in brain tissue at concentrations 10-20 times greater than that of hydrophilic atenolol. The approximate brain/plasma ratio for propranolol was 26, for oxprenolol 50, for metoprolol 12 and for atenolol 0.2. 2 The low concentration of atenolol in brain tissue is possibly responsible for the low incidence of central nervous system-related side effects in patients on this agent compared to lipophilic beta-adrenoceptor blockers.     

Selective manipulation of neurohumoral control of the cardiac pacemaker by drugs given intrapericardially

A technique of intrapericardial administration of β-adrenoceptor and muscarinic cholinergic receptor antagonist drugs has been tested in conscious rabbits. Intrapericardial propranolol or atenolol (50 μg/kg) had the same effect on isoprenaline heart rate dose-response curves and on the sympathetic component of the arterial baroreceptor-heart rate reflex as did conventional, 5-fold greater, intravenous doses of the drugs. The action of intrapericardial propranolol was attributable to its (−)isomer. Intrapericardial propranolol (50 μg/kg) had little effect on ventricular contractility. Plasma levels of propranolol and atenolol after intrapericardial administration were, respectively, 7- and 40-fold less than after the usual intravenous doses. Intrapericardial hyoscine methyl bromide (10 μg/kg) abolished baroreflex vagal effects on heart rate as effectively as did the conventional, 5-fold greater, intravenous dose. The duration of receptor blockade by both classes of drugs when given intrapericardially was at least 2 hr. We conclude that the rapid diffusion of β-adrenoceptor and muscarinic cholinergic receptor blocking drugs from the pericardial sac to receptors on the sinoatrial cardiac pacemaker, and their prolonged actions, provides a useful technique for preventing the actions of the sympathetic and vagus nerves, and of circulating catecholamines, on the chronotropic functions of the heart.     

Controlled release metoprolol formulations. A review of their pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and ischaemic heart disease.

Conventional formulations of metoprolol have become well established in cardiovascular medicine and are particularly useful in the management of hypertension and ischaemic heart disease. Recently developed controlled release metoprolol delivery systems (metoprolol CR/ZOK and metoprolol OROS) were designed to overcome the drug delivery problems of matrix-based sustained release forms by releasing the drug at a relatively constant rate over a 24-hour period, and thus producing sustained and consistent metoprolol plasma concentrations and beta 1-blockade while retaining the convenience of once daily administration. Clinically and statistically significant reductions in blood pressure have been observed with metoprolol CR/ZOK and metoprolol OROS 24 hours after administration in mildly or moderately hypertensive patients. Studies in patients with mild to moderate hypertension have demonstrated that a similar or higher percentage of patients achieved a goal response with metoprolol CR/ZOK compared with matrix-based sustained release formulations of metoprolol, or conventional atenolol or bisoprolol, while metoprolol OROS achieved an equal or greater response rate compared with conventional or matrix-based sustained release metoprolol preparations. In patients with stable effort angina pectoris, once daily administration of metoprolol CR/ZOK provided at least equal antianginal efficacy as conventional metoprolol in divided doses, while metoprolol OROS reduced the mean number of anginal attacks by the same margin as atenolol. Controlled release metoprolol formulations have been well tolerated in clinical trials. Metoprolol CR/ZOK was associated with a similar or lesser degree of adverse effects related to the central nervous system compared with atenolol or long acting propranolol. Metoprolol CR/ZOK also demonstrated less pronounced beta 2-mediated bronchoconstrictor effects than atenolol in asthmatics, and less general fatigue and leg fatigue in healthy subjects. Metoprolol OROS produced less pronounced bronchoconstrictor effects than atenolol, matrix-based sustained release metoprolol or long acting propranolol in patients with asthma or obstructive airways disease, and healthy volunteers. These results are presumably due to the beta 1-selectivity of metoprolol in addition to the relatively low plasma concentrations maintained by metoprolol CR/ZOK and metoprolol OROS, and the avoidance of high peak plasma concentrations with these agents. Despite the relative safety of the controlled release forms of metoprolol, the use of all beta-adrenoceptor antagonists should be avoided in patients with a history of bronchospasm. Thus, controlled release metoprolol formulations offer the potential to maximise the confirmed benefits of this agent in the management of hypertension and angina, by maintaining clinically effective plasma concentrations within a narrow therapeutic range over a 24-hour dose interval.     

Characterization of the beta-adrenoreceptors which mediate the isoprenaline-induced changes in finger tremor and cardiovascular function in man

Summary We have studied the contribution of beta₁- and beta₂-adrenoceptors to the isoprenaline-induced changes in heart rate, blood pressure, forearm blood flow, peripheral vascular resistance, and finger tremor. This was achieved by a comparison of the effects of atenolol 50 mg, ICI 118551 25 mg, propranolol 80 mg, atenolol 50 mg combined with ICI 118551 25 mg, propranolol 80 mg combined with ICI 118551 25 mg, and placebo.Atenolol 50 mg and ICI 118551 25 mg caused similar attenuations in the isoprenaline-induced changes in heart rate and diastolic blood pressure, but the responses after the combination of atenolol and ICI 118551 were similar to those after propranolol 80 mg.There was no difference in the forearm blood flow responses to isoprenaline after atenolol 50 mg and ICI 118551, but atenolol 50 mg did not reduce peripheral vascular resistance compared with placebo. Both responses after treatment with atenolol combined with ICI 118551 were similar to those after propranolol 80 mg.Finger tremor responses to isoprenaline were antagonized by ICI 118551 alone and in combination with propranolol and atenolol but not by atenolol alone, suggesting that the response is beta₂-adrenoceptor-mediated.We conclude that the cardiovascular responses to isoprenaline are mediated by both beta₁- and beta₂-adrenoceptors, whereas the finger tremor response is mediated by beta₂-adrenoceptors.     

Effects of the beta 2-adrenoceptor antagonist ICI 118,551 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

ICI 118,551, 5 to 80 mg orally, did not significantly alter resting heart rate or blood pressure. In doses less than 40 mg the reduction in exercise tachycardia was under 10 beats/min. ICI 118,551, 10 to 40 mg, did not appear to reduce the maximum rise in systolic pressure with isoprenaline but did attenuate the changes in diastolic pressure, forearm blood flow and finger tremor. It also attenuated the isoprenaline-induced changes in serum glucose, insulin and potassium. On these observed changes, the effect of ICI 118,551 20 mg was similar to that of 40 mg and of propranolol 10 mg, but greater than that of atenolol 25 mg. An isoprenaline tachycardia was attenuated by all doses of ICI 118,551 studied. After atropine (0.04 mg/kg) ICI 118,551 20 mg still significantly reduced the effects of isoprenaline suggesting that functional beta 2-adrenoceptors may be present in the human heart. In doses less than 40 mg, ICI 118,551 appears to be a selective and competitive antagonist of beta 2-adrenoceptors in man.