Effects of adrenergic beta-receptor blocking drugs on brain catecholamine concentrations in spontaneously hypertensive rats (SHR) (author's transl)

To acquire data on the mechanism of central effects of adrenergic beta-blockers as antihypertensive agents, experiments were done on spontaneously hypertensive rats (SHR). Each group included 5 animals. Propranolol (5 mg/kg), pindolol (0.3 mg/kg), alprenolol (5 mg/kg) or bupranolol (5 mg/kg) were given subcutaneously to the respective groups, once daily for 7 days, while the control group were given no treatment. All the rats were sacrificed 12 hours after the last injection, and the concentrations of the following materials were measured: noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the brain; NA in the heart muscle; adrenaline and NA in the adrenal glands. As compared with the control group, all rats on the beta-blockers showed an increase in NA concentration in the brain. Both pindolol and alprenolol, which have an intrinsic sympathomimetic action (ISA), increased DA concentrations in the brain. Both propranolol and bupranolol, which have no ISA, either decreased DA concentrations or showed no effect. No marked change was seen in 5-HT concentration in the brain and of NA in the heart muscle. Catecholamine concentrations in the adrenal glands showed a tendency toward decrease. These results suggest that the mechanism of antihypertensive effects of beta-blockers may be due to depression of the peripheral sympathetic activity, as induced by the central inhibitory effects of beta-blockers.     

Effect of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the blood pressure in rats (author's transl)]

The effects of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the systolic blood pressure and heart rate were investigated in conscious Kyoto Wistar normotensive rats (WKY), spontaneously hypertensive rats (SHR) and DOCA-NaCl hypertensive rats (DOCA rats) and the results compared with those of propranolol and practolol. In WKY and DOCA rats, the intraperitoneal administration of acebutolol, propranolol and practolol (0.5 approximately 20 mg/kg) produced a hypotensive action, however, these effects were observed only with restricted doses and there was no evidence of a dose-dependency. The heart rate was decreased by acebutolol and propranolol, but was increased by practolol which possesses an intrinsic sympathomimetic activity. In SHR, propranolol produced a dual action, a slight rise followed by a slight fall, the change not being significant, while practolol induced a slight hypertension. On the other hand, acebutolol in high doses induced a dose-dependent hypotensive action. The heart rate was markedly and dose-dependently decreased by these three agents. Thus, while propranolol and practolol produced hypotensive effects in WKY and DOCA rats, acebutolol produced hypotensive effects in WKY, SHR and DOCA rats. These results suggest that acebutolol is a beta-adrenoceptor blocking agent which possesses hypotensive activity in hypertensive rats.     

A new series of cardioselective adrenergic beta-receptor blocking compounds. 1-(2-Acyl-4-acylaminophenoxy)-3-isopropylaminopropan-2-ols.

A series of 1-(2-acyl-4-acylaminophenoxy)-3-isopropylaminopropan-2-ols has been synthesized and examined for beta-receptor blocking and antiarrhythmic activity. Several of these compounds are more than 20 times as active in blocking cardiac beta-receptors than vascular beta-receptors when given intravenously to anesthetized cats. The activities have been correlated quantitatively with partition and steric substitution constants. The observed relationships are consistent with a tentative proposal that the vascular receptor is situated in a more lipophilic environment than the cardiac receptor so that there is a differential transport effect between the two types of receptor.     

Antihypertensive action of adrenergic beta-receptor blockers and its effect on the entire sympathetic outflow in spontaneously hypertensive rats

Three kinds of beta-adrenoceptor blocking agents were orally administered to spontaneously hypertensive rats (SH rats) from 5 to 13 weeks of age, and their effects on the development of hypertension and on peripheral sympathetic nervous system were investigated. In SH rats treated with the vehicle (2% Tween 80) for 8 weeks, systolic blood pressure increased from 132 +/- 1.3 to 179 +/- 2.7 mmHg (n = 10). Treatment with propranolol (2 X 50 mg/kg/day p.o., n = 8), pindolol (2 X 15 mg/kg/day p.o., n = 8) and D-32 (2 X 15 or 2 X 50 mg/kg/day p.o., n = 9) for 8 weeks slightly but definitely depressed the aforesaid development of hypertension, and their average reduction in systolic blood pressure was approximately 15 mmHg. In the pressor response to electrical stimulation of pre-ganglionic sympathetic nerves, there was not any difference between SH rats treated with vehicle and beta-adrenoceptor blocking agents (propranolol and D-32). P.o. administration of guanethidine or phentolamine, however, caused a slight hypotension and produced a significant reduction in the pressor response to electrical stimulation. SH rats treated with propranolol showed a leftward shift of the pressor response curve not to norepinephrine but to angiotensin II as compared with that obtained from vehicle treated SH rats. This phenomenon is probably due to the decreased renin release by the prolonged-treatment with drug. On the basis of these results, we could not obtain any clear evidence that the antihypertensive action exerted by beta-adrenoceptor blocking agents resulted from some interference with the function of the peripheral sympathetic nervous system.     

Electrophysiologic effects of calcium channel blocking agents on the sinus node function in anesthetized dogs (author's transl)

The electrophysiologic effects of calcium channel blocking agents, diltiazem, verapamil and nifedipine, on the sinus node function were examined in 43 anesthetized closed-chest dogs in comparison with the effects of propranolol. The parameters of sinus node function, i.e. sinus cycle length (SCL), sinus node recovery time determined by overdrive suppression (SRT), both of which are thought to reflect sinus node automaticity, and sinoatrial conduction time estimated by Strauss method (SACT), were evaluated. Intravenously administered diltiazem (0.2 mg/kg), verapamil (0.1 mg/kg) and propranolol (0.1 approximately 0.2 mg/kg) increased SCL and SRT significantly although the increase of these parameters induced by nifedipine (0.03 mg/kg) was not statistically significant. The calcium channel blocking agents did not significantly affect SACT in contrast with propranolol which showed a prolonging effect. Thus calcium channel blocking agents suppressed sinus node automaticity yet had little effect on sinoatrial conduction.     

葛根对β-肾上腺素能受体阻滞作用的研究

本文报告了葛根浸膏具有较为广泛而显著的β-受体阻滞效应。且对β₁-受体的作用强于β₂-受体。相当于0.5～5mg/ml或750mg/kg的葛根能分别对抗异丙肾上腺素0.17～1.7μg/ml或10μg/kg诱发的离体或在体心脏的兴奋作用。此外,相当于750mg/kg的葛根除能阻滞10μg/kg异丙肾上腺素及肾上腺素舒血管(β-受体效应)所致的降压作用外,尚能降低正常心率(平均下降43.7%)及血压(平均下降40±6mmHg)的作用,这些结果为葛根用来缓解心绞痛,治疗快速型心律失常及高血压等提供了根据。将葛根(750mg/kg)与心得宁(0.1mg/kg)抗异丙肾上腺素(10μg/kg)所致的β-受体效应加以比较,表明两者作用大体相似,减慢心率的作用心得宁似乎稍强于葛根。降压作用葛根略优于心得宁,且葛根无明显的抑制心脏的作用。根据上述事实,可以认为葛根是一种有效的β-受体阻滞剂。     

The effects of oxprenolol on cardiac function during hypovolemic shock in dogs (author's transl)

Effects of beta-receptor blockade by oxprenolol, which significantly prevented subendocardial necroses during hemorrhagic shock in dogs, on shock tolerance and myocardial function were analyzed. Overall mortality was not altered by beta-receptor blockade. Cardiac output and contractility (dp/dtmax) before, during and after a hypovolemic period of 120 to 210 min with mean arterial pressure = 40 +/- 5 mmHg showed no significant difference with or without oxprenolol treatment. Increase of heart rate during hemorrhage was abolished completely by oxprenolol and as a consequence of this duration of the diastolic filling period was about three times longer (p less than 0.001) and stroke volumes were greater. Stress metabolism was improved. Hyperglycemia and metabolic acidosis were diminished and arterial oxygen tension was higher in the treated group. Incidence of lethal ventricular fibrillation was higher and pulsus alternans found only in the control group. The beneficial effects of beta-receptor blockage on the course of hemorrhagic shock are explained by the prevention of the catecholamine induced tachycardia and thereby increased coronary perfusion and decreased myocardial oxygen consumption and by the intrinsic sympathicomimetic activity of oxprenolol.     

Influence of the beta-receptor blocker nifenalol on insulin secretion in normal subjects and diabetic patients (author's transl)

In 10 insulin-independent diabetic patients and 5 healthy volunteers the basal and glucose-stimulated insulin secretion was tested before and during oral treatment with the beta-blocker 1-(4-nitrophenyl)-2-isopropylaminoethanol (nifenalol, Inpea). In diabetic patients the insulin secretion was not changed by Inpea. The fasting blood sugar levels were slightly elevated in 8 of these patients. This result, which could not be ascertained statistically, may be due to a slight intrinsic activity of this beta-blocker. The normal subjects showed different responses. In one person the glucose tolerance deteriorated by Inpea.