ICI 147,798: a slowly dissociable beta adrenoceptor antagonist that causes insurmountable beta-1 and surmountable beta-2 adrenoceptor antagonism in isolated tissues.

ICI 147,798 has been shown to exhibit both diuretic and beta-antagonist properties in vivo. The present study investigated the nature and selectivity of the beta-antagonism in a variety of isolated tissues. ICI 147,798 produced a concentration-dependent suppression of the maximum chronotropic response of norepinephrine in guinea pig right atria (beta-1 adrenoceptor). ICI 147,798 caused a concentration-dependent shift to the right of the salbutamol concentration-response curve in the guinea pig trachea (beta-2 adrenoceptor), and Schild analysis suggested competitive inhibition. Propranolol produced parallel shifts to the right of the norepinephrine concentration-response curve in guinea pig right atria, except at relatively high concentrations. The inhibitory effects of propranolol in guinea pig right atria were reversed by greater than 95%, whereas the effects of ICI 147,798 were only slightly reversed after a 6-hr washout period. Preincubation of propranolol with ICI 147,798 in guinea pig right atria prevented completely the suppression of the norepinephrine maximum chronotropic response. Postincubation of propranolol with ICI 147,798 partially reversed the suppression of the maximum chronotropic response. ICI 147,798 had no effect on the maximum chronotropic responses of either histamine (H2-receptor) or forskolin (adenylate cyclase activation) in guinea pig right atria and had no effect on agonist responses in a variety of other receptor systems. The insurmountable beta-1 adrenoceptor antagonism was evaluated based on the assumptions of irreversible competitive antagonism, mixed competitive and noncompetitive antagonism and slowly dissociating competitive antagonism ("hemi-equilibrium" conditions). Concentration-dependent changes in norepinephrine KA values suggested the first three possibilities were unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Insurmountable beta receptor blockade by ICI 147,798 in rabbits.

In rabbits, the characteristics of cardiac beta-1 receptor blockade produced by ICI 147,798, a novel beta receptor blocking agent with diuretic properties, were evaluated and compared with those of propranolol. In conscious rabbits, i.v. injections of 0.31, 1.0 and 3.1 mg/kg of ICI 147,798 and 1.0 mg/kg of propranolol caused significant bradycardia. ICI 147,798 produced a dose-dependent shift to the right of the dose-response (chronotropic) curve of isoproterenol with suppression of the maximal tachycardia, an effect characteristic of insurmountable beta receptor blockade. Propranolol also produced a shift to the right of the dose-response curve of isoproterenol without affecting the maximal tachycardia. ICI 147,798-induced antagonism was specific for beta adrenoceptors as it failed to modify the effects of acetylcholine, angiotensin II, phenylephrine, adenosine, histamine and prostaglandin E2 on mean arterial pressure and heart rate. In rabbits with prior autonomic blockade, ICI 147,798, like propranolol, failed to inhibit the positive chronotropic effects of theophylline which are mediated by postreceptor mechanisms. In reserpinized rabbits, ICI 147,798 was found to have no intrinsic sympathomimetic activity. Unlike the effects of propranolol, which were attenuated by first-pass through the hepatic vascular bed, the effects of ICI 147,798 were unaffected suggesting an absence of first-pass metabolism. The effects of propranolol (1.0 mg/kg i.v.) were not detectable at 24 hr after injection, whereas significant beta receptor blocking activity was still present at 24 hr after ICI 147,798 (1.0 mg/kg i.v.). The results suggest that ICI 147,798 is a specific, long-acting, insurmountable beta-1 receptor blocking agent without intrinsic sympathomimetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled beta-receptor blockade with flestolol: a novel ultrashort-acting beta-blocker.

The pharmacological properties of an ultrashort-acting beta-receptor blocking agent, flestolol, were evaluated in rabbits. Infusion of graded doses (1-100 micrograms/kg/min, i.v.) into conscious rabbits produced dose-dependent bradycardia without any significant effect on mean arterial pressure. A desired level of heart rate could be obtained by either increasing or decreasing the dose infused. Such titration could be done by changing the dose of flestolol at 20-min intervals. Infusion of 31 micrograms/kg/min of flestolol into reserpinized, conscious rabbits had no effect on mean arterial pressure or heart rate but produced significant inhibition of isoproterenol-induced hypotension and tachycardia. This dose had no effect on the chronotropic and vascular effects of norepinephrine (NE), angiotensin II, adenosine, or acetylcholine. In these rabbits, flestolol was greater than 10-fold as active as esmolol, another ultrashort-acting beta-blocking agent, in inhibiting the responses to isoproterenol. In rabbits under pentobarbital anesthesia, infusion of flestolol (3.1, 10, and 31 micrograms/kg/min) produced dose-dependent beta-receptor blockade. On termination of a 70-min infusion, recovery of the responses to isoproterenol occurred within 30 min. In a separate series of experiments, the effects of infusion of flestolol (10 micrograms/kg/min) into the portal vein were compared with the effects of infusion of the same dose of flestolol into the femoral vein of anesthetized rabbits. Infusion into the femoral vein produced bradycardia and inhibited the hypotensive as well as cardioaccelerator effects of isoproterenol. Infusion into the portal vein was devoid of either effect, suggesting extensive inactivation by the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic drugs and the modulation of autonomic control of heart rate in rabbits.

A model of the components of autonomic control of heart rate was developed and used for the evaluation of quantitative contribution of sympathetic and vagal tone to cardiac function. In conscious rabbits, sequential inhibition of muscarinic and beta receptors was produced and the relative contributions of vagal and sympathetic tone were characterized. Based on the model, the magnitude of presynaptic interaction between the vagal and sympathetic nerve endings was evaluated. From data in the literature, similar analysis of the control of heart rate was performed for the rat, dog, and human subject and compared with that of the rabbit. The results show that the resting rabbit heart is under less vagal tone than sympathetic tone as compared with other species. The effects of acute administration of amiodarone on the sympathetic and parasympathetic control of heart rate as well as intrinsic heart rate were investigated. Amiodarone decreased the heart rate, which resulted from a direct effect on the sinoatrial (SA) node. In addition, it attenuated the vagal as well as the sympathetic effects on the SA node. The effect on vagal component was greater. Further, the effects of other antiarrhythmic drugs on the electrocardiographic PP and PR intervals were studied. The usefulness of this model for the analysis of the effects of antiarrhythmic drugs is presented.

Cardiovascular and neuromuscular effects of esmolol during induction of anesthesia.

Sixteen subjects scheduled for surgical procedures under general anesthesia participated in an investigation of the effects of esmolol on the transient hypertension and tachycardia that was observed during endotracheal intubation and on the duration of succinylcholine-induced neuromuscular blockade. In eight subjects, infusion of esmolol was begun five minutes before induction of anesthesia and continued for 12 minutes after induction. In the remaining subjects, an equivalent volume of solvent (D5W) was infused for 12 minutes. Infusion of esmolol significantly attenuated the cardioacceleration observed during intubation without any significant effect on the pressor effects of the procedure. Esmolol delayed the recovery from succinylcholine-induced neuromuscular blockade by less than three minutes. The mechanism of this delay remains to be investigated, although such a delay does not have clinical significance. Esmolol-induced attenuation of the tachycardia seen during intubation may offer a protective effect on the myocardium, especially in elderly subjects and patients with coronary artery disease.

Esmolol and the adrenergic response to perioperative stimuli.

Esmolol, an ultra-short-acting, cardioselective, beta-receptor blocking agent, has been developed for use in clinical conditions requiring controlled beta-receptor blockade. Its esterase-induced rapid metabolic inactivation and resulting brief pharmacologic effect provides control over the magnitude and duration of beta-receptor blockade. In placebo-controlled clinical trials, the effects of infusion of esmolol on the sympathetically mediated hemodynamic responses to stressful events during the perioperative period were evaluated in patients scheduled for surgical procedures under general anesthesia. In patients undergoing either noncardiac or cardiac surgical procedures, esmolol was effective in attenuating tachycardia that is normally seen during induction of anesthesia, laryngoscopy and endotracheal intubation, or sternotomy and aortic dissection by reducing the hemodynamic stress on the heart with negligible adverse effects. This much-desired cardioprotective effect of esmolol will be of special value to patients with coronary artery disease and patients with an unstable cardiovascular status who are undergoing major surgical procedures with general anesthesia.

Beta-blocking and hemodynamic effects of ASL-8052.

The hemodynamic and cardiac beta-blocking effects of ASL-8052 (esmolol), an ultrashort-acting beta-blocker, were examined in pentobarbital-anesthetized dogs. The compound produced dose-dependent reductions in heart rate, left ventricular dP/dt, right ventricular contractile force, and diastolic arterial blood pressure in dogs with intact autonomic function. ASL-8052 was devoid of any hemodynamic effects in ganglion-blocked animals. Responses to isoproterenol (except for diastolic blood pressure) were blocked by ASL-8052 in qualitatively similar fashion in both groups of animals. The compound reduced the rate-pressure product and decreased diastolic coronary blood flow. The reactive hyperemic response to a 10-s occlusion of the left circumflex coronary artery was not modified by ASL-8052. Heart rate and contractile force dose-response curves to isoproterenol were equally shifted to the right in a dose-dependent, parallel fashion by constant infusion of ASL-8052. During infusion of large doses in reserpinized dogs, the compound decreased heart rate, contractility, and arterial blood pressure, while left ventricular end-diastolic pressure increased. No intrinsic sympathomimetic effect was observed. Tachycardia induced by either stimulation of the right ansa subclavia or intravenous injection of isoproterenol was blocked to an equivalent degree by ASL-8052. These data indicate that ASL-8052 produces hemodynamic effects that are characteristic of and explained by beta-adrenergic receptor blockade. However, direct cardiac depression is observed at extremely high doses.

Cardiovascular pharmacology of ASL-8052, an ultra-short acting beta blocker.

ASL-8052, a novel ultra-short acting beta receptor blocking agent, was infused i.v. and its cardiovascular effects were investigated in conscious, as well as anesthetized rabbits. On i.v. infusion, its effects reached a steady state within 6 min and on termination of infusion, complete recovery occurred within 20 min. In conscious rabbits it inhibited isoproterenol-induced tachycardia and hypotension. There was more pronounced inhibition of the cardioaccelerator effects of isoproterenol than its hypotensive effects. ASL-8052 produced dose dependent bradycardia in conscious rabbits which was more marked in rabbits pretreated with atropine methyl nitrate. When infused in larger doses, a significant decrease in mean arterial pressure was seen in conscious as well as anesthetized rabbits. This hypotensive effect was not blocked by prior beta receptor blockade with propranolol. ASL-8052-induced hypotension was found to be due to a significant decrease in total peripheral resistance. It also produced vasodilation in the mesenteric vascular bed. The role of the liver in the clearance of ASL-8052 was investigated. When infused into the portal vein, the response to ASL-8052 was markedly attenuated, while an equivalent dose infused into the femoral vein produced a significant level of beta receptor blockade. These results suggest that ASL-8052 is an ultra-short acting beta receptor blocking agent with vasodilator effects in rabbits. While the liver may play a significant role in the clearance of ASL-8052 from circulation, the role of extra-hepatic mechanisms in the rapid decay of its pharmacological effects remains to be investigated.