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.     

The effect of a week's beta-adrenoceptor antagonism on daytime heart-rates, subjective responses to exercise, and physical activity in normal subjects.

The effects on heart rate (HR) and physical activity of 1 week's treatment with three different beta-adrenoceptor antagonists (20 mg betaxolol (Lorex); 160 mg propranolol LA; or 100 mg atenolol daily) have been compared with placebo in a double-blind study of 12 normal men. On the fifth day of each treatment a body-borne tape-recorder was worn during waking hours for recording of ECG and footfall signals. Each record was calibrated in terms of the subject's response to laboratory ergometer exercise, and a computer analysis provided objective indices of physical activity. While on beta-adrenoceptor antagonists the subjects perceived standard exercise as significantly harder than on placebo and reported more side-effects (albeit mild and transient). Ambulatory monitoring of HR showed that subjects spent 13% of their waking day at heart rates below 50 beats min-1 while on propranolol, compared with 1% on placebo and 20% on atenolol and betaxolol. On these latter drugs, the group spent as much as 10% of their waking time with HR below 45 beats min-1. The lowest individual heart-rates recorded were below 35 beats min-1. Objective indices of physical activity, such as the duration of periods spent with heart rates above the HR found at 100 W in the ergometer test, showed no differences between the treatments. This negative finding was confirmed by pedometer step counts over the whole week.     

Inhibitory effect of a novel antianginal agent, E4080, on ST segment elevation induced by vasopressin in anesthetized guinea pigs.

We compared the antianginal effect of E4080, a novel bradycardiac agent with coronary vasodilating properties, with those of a bradycardiac agent and some coronary vasodilators in vasopressin-induced anginal model of guinea pigs. An i.v.-administration of vasopressin (0.2 IU/kg) produced an ST segment elevation on electrocardiograms (ECG) of 0.30 +/- 0.05 mV from the baseline within 30 sec in anesthetized guinea pigs. The ST segment elevation on ECG was used as an index of myocardial ischemia. E4080 and other drugs were injected i.v. 5 min before the administration of vasopressin. E4080 at 5 mg/kg depressed the ST segment elevation induced by vasopressin to 0.06 +/- 0.01 mV (20% of control, n = 6, P < 0.001). However, alinidine (5 mg/kg), which produced the same bradycardic action (reduction of heart rate by 50%) as that of E4080, tended to inhibit the ST segment elevation, but this was not statistically significant. On the other hand, other vasodilators such as isosorbide dinitrate (0.3 mg/kg), nifedipine (0.1 mg/kg) and lemakalim (1 mg/kg) also significantly reduced the ST segment elevation to 0.16 +/- 0.03, 0.08 +/- 0.04 and 0.09 +/- 0.03 mV, respectively. These results suggest that the inhibitory effect of E4080 on the ST segment elevation induced by vasopressin is due to the coronary vasodilating effect rather than the bradycardiac effect, and that E4080 would be useful as an antianginal agent.     

Effects of betaxolol on cardiohemodynamics and coronary circulation in anesthetized dogs: comparison with atenolol and propranolol

Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on cardiohemodynamics and coronary circulation were investigated in two kinds of anesthetized open-chest dog preparations in comparison with those of atenolol and propranolol. When administered intravenously, betaxolol, atenolol and propranolol produced dose-dependent decreases in the heart rate (HR), maximum left ventricular dP/dt [+)dP/dt), cardiac output (CO) and mean arterial pressure (MAP). Although all three drugs were almost equipotent in decreasing HR, betaxolol was much less potent than atenolol and propranolol in decreasing (+)dP/dt. Betaxolol decreased the total peripheral resistance (TPR), whereas atenolol and propranolol increased it. In another series of experiments, when administered intravenously, betaxolol, atenolol and propranolol all produced a decrease in the myocardial oxygen consumption (MVO2) and an increase in the atrioventricular conduction time (AVCT). All three drugs were nearly equipotent in decreasing MVO2, although betaxolol was less potent than the other two drugs at higher doses (greater than 300 micrograms/kg). Prolongation of AVCT with propranolol was stronger than those with betaxolol and atenolol. These results suggest that, unlike atenolol and propranolol, the decrease in TPR as well as beta 1-adrenoceptor blockade may be responsible for both the hypotensive effect of betaxolol and the decrease in MVO2 with betaxolol. The result that the cardiodepressant effect of betaxolol was much less potent than those of atenolol and propranolol suggests that betaxolol would be more beneficial than the others in the treatment of ischemic heart disease.     

The role of alpha- and beta-adrenoceptor subtypes in mediating the effects of catecholamines on fasting glucose and insulin concentrations in the rat.

1. The role of alpha- and beta-adrenoceptor subtypes in the regulation of plasma glucose and immunoreactive insulin (IRI) levels has been investigated in normal conscious fasted rats by employing selective agonists and antagonists. 2. Adrenaline (0.2 mg kg-1)-induced hyperglycaemia was abolished by the selective alpha 2-adrenoceptor antagonist idazoxan (1.0 mg kg-1), unaltered by non-selective beta-adrenoceptor blockade (propranolol, 1.0 mg kg-1) and potentiated by the selective alpha 1-adrenoceptor antagonist prazosin (0.3 mg kg-1). Adrenaline increased plasma IRI levels in the presence of idazoxan but not in the presence of either prazosin or propranolol. 3. The selective alpha 2-adrenoceptor agonists UK 14304 (0.1 and 0.3 mg kg-1) and BHT-920 (0.2 and 0.5 mg kg-1) elicited dose-dependent hyperglycaemic responses, but did not alter plasma IRI levels. UK 14304 (0.1 mg kg-1)-evoked hyperglycaemia was blocked by idazoxan but not by prazosin. 4. The selective alpha 1-adrenoceptor agonists methoxamine (0.3 mg kg-1) and phenylephrine (0.3 mg kg-1) failed to modify either plasma glucose or IRI levels. 5. Isoprenaline (0.2 mg kg-1) elicited hyperglycaemic and insulinotropic responses which were attenuated by propranolol (1.0 mg kg-1) and the selective beta 2-adrenoceptor antagonist ICI 118551 (1.0 mg kg-1), but not by the beta 1-selective antagonists atenolol (1.0 mg kg-1) and betaxolol (1.0 mg kg-1). 6. None of the antagonists per se affected basal plasma glucose or IRI concentrations, except prazosin (1.0 mg kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of NCO-700, an inhibitor of protease, on myocardial pH decreased by coronary occlusion in dogs

During myocardial ischemia in dogs effects of NCO-700, a protease inhibitor on myocardial pH, were investigated. Ischemia was produced for 90 min by partial occlusion of the left anterior descending coronary artery (LAD). Myocardial pH was measured by a micro glass pH electrode inserted in the subendocardium of the LAD area. Before partial occlusion, myocardial pH was 7.50-7.67. It decreased by 0.65 to 0.86 pH units after partial occlusion. NCO-700 was injected intravenously after 30 min partial occlusion. At a dose of 5 or 20 mg/kg NCO-700 increased myocardial pH, which had been decreased by LAD partial occlusion, by 0.26 or 0.31 pH units, respectively. In the nonischemic myocardium pH increased only 0.03 units. Drug-induced restoration of myocardial [H+] was then calculated. At a dose of 5 or 20 mg/kg NCO-700 restored myocardial [H+], which had been increased by partial occlusion. However, NCO-700 did not attenuate the ischemia-induced elevation of ST segment of the surface electrocardiogram. These observations demonstrate that NCO-700 attenuates myocardial pH depressed by partial occlusion of LAD.     

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.     

Response of plasma norepinephrine concentration to the vasodepression caused by beta-adrenoceptor antagonists in the conscious spontaneously hypertensive rat

The subcutaneous administration of a single dose of the beta-adrenoceptor antagonists atenolol, betaxolol, oxprenolol, pindolol, propranolol, or sotalol to conscious spontaneously hypertensive rats (SHR) lowered mean arterial pressure (MAP) by 15-20%, but this vaso-depression was not accompanied by a rise in plasma norepinephrine (NE) concentration. When MAP was decreased at the same rate and to the same extent with the vasodilator minoxidil, plasma NE concentration increased 50-75%. Atenolol, betaxolol, propranolol, and sotalol lowered heart rate, whereas oxprenolol, pindolol, and minoxidil elicited a tachycardia. Atenolol (-48%), betaxolol (-63%), and propranolol (-29%) significantly suppressed plasma renin activity (PRA), and minoxidil elevated PRA by 150-315%. Pindolol (+37%) caused a nonsignificant increase in PRA, and oxprenolol (-23%) and sotalol (-17%) produced nonsignificant decreases in PRA. Because the beta-adrenoceptor antagonists did not increase plasma NE concentration, whereas an equivasodepressor dose of minoxidil did, we conclude that plasma NE concentration is inappropriately low relative to the decrease in MAP caused by beta-adrenoceptor antagonists in the conscious SHR. In addition, the diverse effects of the beta-adrenoceptor antagonists on PRA in SHRs indicate that a suppression of renin release cannot account for either the decrease in MAP caused by these drugs or the failure of plasma NE concentration to increase when MAP is decreased by beta-adrenoceptor antagonists.     

Influence of environmental temperature and humidity on bronchial responses during assessment of selectivity of beta-adrenoceptor antagonists in man.

1 The effects of beta-adrenoceptor antagonists given intravenously in single doses were examined in a double-blind, placebo controlled study performed in six healthy volunteers. Heart rate and peak expiratory flow rate (PEFR) were measured at rest and during standardised exercise. 2 Atenolol 0.2 mg/kg, betaxolol 0.15 mg/kg, practolol 1 mg/kg and propranolol 0.2 mg/kg all reduced heart rate to a similar extent during exercise at 2 and 4 h after administration; betaxolol 0.6 mg/kg had a significantly greater effect than the other treatments at all times. Only betaxolol 0.15 and 0.6 mg/kg significantly inhibited exercise tachycardia at 24 h. 3 None of the treatments studied had any effect on PEFR at rest or during exercise. 4 A second study was performed to determine whether this lack of effect of propranolol on exercise PEFR could have been due to the warm and humid conditions prevailing during the experiment. Eight healthy men underwent a standardised exercise test under alternately 'warm and humid' and 'cool and dry' conditions before and after propranolol 0.2 mg/kg or saline placebo intravenously. 5 Propranolol treatment did not influence resting or exercise PEFR in either environment, but did reduce FEV1 immediately after exercise under the cool and dry conditions but not under the warm and humid conditions. 6 Comparison of the effects of beta-adrenoceptor antagonists on exercise heart rate and PEFR is not a reliable or sensitive method of measuring the cardioselectivity of these drugs. 7 Environmental temperature and humidity should ideally be controlled when the action of any drug on airflow resistance is being studied.     

Beta-adrenoceptor blockade in rats enhances the ambulation induced by 5-HT1A receptor agonists

The mixed beta-adrenoceptor and 5-HT1A receptor antagonists, (-)-pindolol and propranolol, enhance rather than inhibit the hyperlocomotion induced in rats by the 5-HT1A receptor agonist, 8-OH-DPAT. The mechanism of this effect was now investigated. The rats were pretreated with the beta-adrenoceptor antagonist or saline and with the agonist 45 min later. Ambulation was quantified as the number of quadrants entered during a 15 min observation period. (-)-Pindolol, alprenolol, betaxolol, ICI 118,551 and a combination of betaxolol and ICI 118,551 (all at 1 mg/kg) significantly enhanced the locomotion induced by 8-OH-DPAT (0.24 mg/kg). Timolol (1 and 10 mg/kg) given 45 min before 8-OH-DPAT was inactive; however, given at 10 mg/kg 15 min prior to 8-OH-DPAT, the compound enhanced locomotion. (-)-Pindolol (1 mg/kg) also enhanced the locomotion induced by the putative selective 5-HT1A receptor partial agonists, flesinoxan and ipsapirone, but not that induced by 5-OH-DPAT, a DA2 receptor agonist. These results suggest that beta 1- or beta 2-adrenoceptor antagonism can enhance the locomotion induced by 5-HT1A receptor agonists. In the case of mixed 5-HT1A and beta-adrenoceptor antagonists, the beta-adrenoceptor-mediated effect may mask the inhibition of locomotion expected from 5-HT1A receptor antagonism.     

Anti-ischemic effects of ivabradine, a selective heart rate-reducing agent, in exercise-induced myocardial ischemia in pigs

The effects of ivabradine, a novel heart rate-reducing agent that inhibits the cardiac pacemaker current If, were compared with those of the beta-adrenergic blocker propranolol, in a model of exercise-induced regional myocardial ischemia in pigs. Five Yucatan micropigs were chronically instrumented to measure hemodynamics, regional myocardial contractility, and local electrograms, and a fixed stenosis of the left anterior descending coronary artery was induced using a clip. Each animal underwent three experiments on different days, each consisting of two treadmill exercise sessions, 4 hours apart. Ivabradine 5 mg/kg, propranolol 5 mg/kg, or vehicle was administered orally 3 hours before the second exercise session. Exercises before treatment and after vehicle produced reproducible hemodynamic changes and regional myocardial ischemia in the area perfused by the stenosed coronary artery, indicated by ST segment shift and regional contractile dysfunction. Ivabradine and propranolol were equipotent in reducing heart rate at rest and limiting tachycardia during exercise. Ivabradine, unlike propranolol, did not reduce left ventricular contractility at rest or during exercise, and did not increase atrio-ventricular conduction time. Both compounds reduced the exercise-induced ST segment shift in the ischemic region by approximately 80%, but ivabradine preserved systolic shortening to a significantly greater degree than propranolol (P < 0.05).     

Effect of an orally active Na+/H+ exchange inhibitor, SMP-300, on experimental angina and myocardial infarction models in rats.

The effects of SMP-300, an orally active, potent, and selective Na+/H+ exchange inhibitor, were evaluated and compared with those of nifedipine, propranolol, and nicorandil on three experimental angina models and on myocardial infarction in rats. SMP-300 (0.1-1 mg/kg, p.o.) reduced isoproterenol-induced ST segment depression in a dose-dependent manner. Its maximal effect was comparable to that reported for propranolol and greater than that of nifedipine. SMP-300 (0.3-1 mg/kg) reduced vasopressin-induced ST segment depression in a dose-dependent manner, and its maximal effect was comparable to those of nifedipine and nicorandil. SMP-300 (0.3-1 mg/kg, p.o.) and propranolol (100 mg/kg, p.o.) inhibited coronary artery occlusion-induced T-wave elevation, but nifedipine (3 mg/kg, p.o.) did not. SMP-300 (1 mg/kg, p.o.) reduced myocardial infarct size after 40 min of coronary artery occlusion followed by 24 h of reperfusion, but nifedipine (3 mg/kg, p.o.) or propranolol (100 mg/kg, p.o.) did not. This study provides support for the future use of a Na+/H+ exchange inhibitor as an anti-anginal drug with a novel mode of action.     

Effects of beta-adrenoceptor antagonists on cardiac function in ischemic-reperfused myocardium of the isolated working rabbit heart

The effects of beta-adrenoceptor antagonists (dl-nebivolol, atenolol and propranolol) and of 1-nebivolol on cardiodynamics and mitochondrial oxidative phosphorylation were studied in the isolated working rabbit heart subjected to normothermic global ischemia, followed, in some cases, by reperfusion. The hearts were pretreated with the different drugs (0.32 mg/l) 30 min before the start of ischemia, dl-Nebivolol and propranolol provided protection for both cardiodynamic and mitochondrial functions, as did l-nebivolol, which lacks beta-adrenoceptor blocking properties, while atenolol failed to protect mechanical activity and cardiac mitochondria against the effects of ischemia and post-ischemic reperfusion. Catecholamine depletion with reserpine did not have a beneficial effect on the recovery of cardiodynamic and mitochondrial function during post-ischemic reperfusion. It is concluded that the beneficial effects of beta-blockers on the ischemic and reperfused myocardium can not be explained by a specific beta-blocking action alone.     

Effects of beta-adrenoceptor antagonists in the neural nitric oxide release induced by electrical field stimulation and sodium channel activators in the rabbit corpus cavernosum

Beta-Adrenoceptor antagonists may present receptor-independent mechanisms, such as blockade of voltage-gated sodium channels. This study aimed to investigate the effects of non-selective (propranolol), and selective beta1- (atenolol, metoprolol and betaxolol) and beta2-adrenoceptor (ICI 118,551) antagonists in the nitric oxide (NO)-mediated rabbit corpus cavernosum relaxations induced by either electrical field stimulation (EFS) or activators of voltage-gated sodium channels. The sodium channel blockers tetrodotoxin and saxitoxin abolished the relaxations induced by EFS or sodium channel activators of binding site-2 (aconitine and veratridine), site-3 (Ts3 toxin), site-4 (Ts1 toxin) and site-5 (brevetoxin-3). The beta-adrenoceptor antagonists failed to affect the relaxations induced by EFS, aconitine and veratridine. Relaxations induced by Ts3 and Ts1 toxins, as well as brevetoxin-3, were markedly reduced by prior addition of propranolol, betaxolol and ICI 118,551. During the established relaxation induced by Ts3 toxin, propranolol failed to restore the basal tone. In conclusion, beta-adrenoceptor antagonists may cause an allosteric inhibition at the binding site-3, -4 and -5 of voltage-gated sodium channels, leading to blockade of neural NO release.     

A possible involvement of oxygen free radicals in the development of myocardial acidosis during coronary occlusion in dogs

Summary The present study was designed to examine whether free radical scavengers attenuate myocardial acidosis induced by partial occlusion of the coronary artery in dogs. The myocardial pH was determined by a micro glass pH electrode inserted in the endocardial layers of the left ventricular wall perfused by the left anterior descending coronary artery. The left anterior'descending coronary artery was occluded for 90 min incompletely so that the flow would be 1/2–1/3 the original flow. The myocardial pH before partial occlusion was 7.54–7.55. Partial occlusion decreased the flow in the left anterior descending coronary artery by 49.3–64.9% and the myocardial pH by 0.71–0.76, and increased the ST segment (surface electrocardiogram) by 6.3–9.3 mV. Saline (0.5 ml/kg), recombinant human superoxide dismutase (70,000 or 210,000 U/kg), or catalase (55,000 or 165,000 U/kg) was injected intravenously 30 min after partial occlusion. The injection of recombinant human superoxide dismutase or catalase alone did not restore the myocardial pH that had been decreased by coronary occlusion. The combined injection of recombinant human superoxide dismutase (70,000 U/kg) + catalase (55,000 U/kg), however, restored the myocardial pH without restoration of ST segment. In conclusion, recombinant human superoxide dismutase + catalase attenuated myocardial acidosis during ischaemia, suggesting a possible involvement of oxygen free radicals in the development of myocardial acidosis (especially in the endocardial layers) during ischaemia. Send offprint requests to Y. Abiko at the above adress     

Cardiovascular and pharmacokinetic interactions between nicorandil and adjunctive propranolol, atenolol or diltiazem in conscious dogs

In support of clinical antianginal studies, the vasodilator nicorandil (NIC) was combined with the beta-adrenergic receptor antagonists propranolol (PRO) and atenolol (ATN) and with the calcium channel blocker diltiazem (DTZ) to determine their cardiovascular and pharmacokinetic interactions. Beagle dogs were chronically cannulated to record mean arterial pressure, heart rate, and the lead II electrocardiogram under conscious conditions. Oral NIC (1, 3, and 10 mg/kg) was coadministered with i.v. PRO (5.0 mg/kg) or ATN (7.5 mg/kg), both of which lessened NIC's reflex tachycardia. ECG rhythm remained normal, but both beta-blockers restricted high dose NIC's QTc prolongation and ST segment depression. Intravenous DTZ (5-23 micrograms/kg/min) did not affect i.v. NIC's hypotensive profile (10-80 micrograms/kg/min) but attenuated its tachycardia, whereas NIC-reversed DTZ's PR interval shortening and frequency of ectopic beats. Similar cardiovascular interactions were seen with chronic oral DTZ (10 mg/kg/day) + NIC (3.0 or 7.5 mg/kg). Plasma analysis confirmed that none of the adjuncts affected NIC's disposition nor its concentration-dependent hypotensive response profile. These studies establish the cardiovascular effects of NIC when combined with PRO, ATN or DTZ in dogs, and outline paradigms useful for evaluating such antianginal drug combinations.     

beta-adrenoreceptor blocking and antihypertensive activity of PP-24, a newly synthesized aryloxypropanolamine derivative

PP-24 is a newly synthesized putative beta-adrenoceptor antagonist. The objective of the study was to the evaluate beta-adrenoceptor blocking activity of PP-24 on isolated rat preparations: right atria, uterus and colon. Effects on the rat ECG and renal hypertension (induced by left renal artery ligation) were also investigated. Treatment with PP-24 (3 and 10 mg kg(-1)) for 7 days in rats with renal hypertension significantly reduced the mean atrial blood pressure. Single i.v. injections of isoprenaline (0.3, 1 and 3 microg kg(-1)) alone in normal anaesthetized rat caused hypotension and tachycardia, while PP-24 alone produced dose-dependent falls in mean aterial pressure and bradycardia. Pretreatment of anaesthetized rats with test compounds significantly blocked the hypotension response but not the tachycardia induced by isoprenaline (0.3, 1 and 3 microg kg(-1)). The pA(2) of PP-24 to beta(1)-, beta(2)- and beta(3)-adrenoceptors was 7.72 +/- 0.082, 7.40 +/- 0.082 and 6.39 +/- 0.16, respectively. The beta(1)/beta(2) selectivity ratio was 2.08, compared with 1.27 for propranolol and 39.17 for atenolol. It is concluded that PP-24 possesses beta-adrenoceptor blockade activity but with non-specific affinity for beta(1)- and beta(2)-adrenoceptor subtypes. The rank order of potency of the antagonists for beta(1)-adrenoceptors was atenolol > PP-24 > propranolol. The antihypertensive activity of PP-24 in rats with renal hypertension appears to be due to blockade of beta-adrenoceptors.     

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.     

Effect of dilazep on decrease in myocardial pH during ischemia in dogs

The present study was undertaken in order to examine whether dilazep (1,4-bis-[3-(3,4,5-trimethoxybenzoyloxy)propyl]perhydro-1, 4-diazepine dihydrochloride monohydrate) attenuates myocardial acidosis induced by coronary artery occlusion in dogs. In dogs with nonischemic normal heart, dilazep (300 or 500 micrograms/kg i.v.) increased blood flow in the left anterior descending coronary artery (LAD) with a decrease in heart rate and diastolic blood pressure. In other dogs, LAD flow was reduced by an occluder by 57 to 68% (partial occlusion) for 90 min. Partial occlusion for 30 min decreased myocardial pH by 0.67 to 0.87 pH units, increased ST segment of the surface electrocardiogram, and decreased regional myocardial contractile force. Dilazep was injected i.v. 30 min after partial occlusion. The decrease in myocardial pH induced by partial occlusion was attenuated by the injection of 300 micrograms/kg of dilazep insignificantly and by that of 500 micrograms/kg of dilazep significantly. Restoration of myocardial [H+] induced by dilazep was calculated from the myocardial pH data. Dilazep (500 micrograms/kg) restored myocardial [H+] induced by partial occlusion by 56.7%, and saline solution restored it by 27.4% 60 min after the drug injection, the actual restoration induced by dilazep being 29.3%. Dilazep, however, did not restore the ST segment elevation and contractile force decrease. It is concluded that dilazep attenuates myocardial acidosis during ischemia.     

In vivo evidence that isoproterenol may increase heart rate in the rat by mechanisms in addition to activation of cardiac beta(1)- or beta(2)-adrenoceptors

This study demonstrates that the tachycardia produced by systemic injections of the beta-adrenoceptor agonist, isoproterenol (10 microg/kg, i.v.), in conscious rats were not reduced after injection of the selective beta(1)-adrenoceptor antagonist, atenolol (1 mg/kg, i.v.), or after subsequent injection of the beta(1,2)-adrenoceptor antagonist, propranolol (1 mg/kg, i.v.). The hypotensive responses produced by isoproterenol were slightly diminished by atenolol and markedly diminished by propranolol. The tachycardia produced by catecholamines released for cardiac sympathetic nerve terminals were blocked by atenolol. These results suggest that the hypotensive actions of a 10 microg/kg dose of isoproterenol are mediated by activation of beta(1,2)-adrenoceptors whereas the increases in heart rate may be due to activation of another type of beta-adrenoceptor in cardiac pacemaker cells.