Effects of antiarrhythmic agents on isoproterenol-induced ventricular fibrillation in heavy rats: a possible model of sudden cardiac death.

Heavy male Sprague-Dawley rats die of ventricular fibrillation within 2 to 3 h after isoproterenol administration. Thus, the isoproteronol-treated heavy rat would be a useful model for screening drugs that may prevent sudden cardiac death. Isoproterenol (1 mg/kg s.c.) caused ventricular fibrillation in 79% of 121 vehicle-pretreated heavy rats (greater than 500 g); 82% of the fibrillating rats died, but the remaining 18% spontaneously reverted and survived. A protecting agent should increase the number of survivors by reducing the incidence of ventricular fibrillation and/or by increasing the incidence of spontaneous reversions. Pretreatment (i.p.) with quinidine (40 mg/kg), procainamide (40 mg/kg), phenytoin (40 mg/kg), clofilium (5 mg/kg), verapamil (10 mg/kg), or propranolol (10 mg/kg) reduced the incidence of isoproterenol-induced ventricular fibrillation and death; bretylium (10 mg/kg) and nicotinic acid (100 mg/kg) had no effect. A lower dose of propranolol (2.5 mg/kg) or clofilium (1.5 mg/kg) but not quinidine (10 mg/kg), procainamide (10 mg/kg), or phenytoin (10 mg/kg) also reduced the incidence of ventricular fibrillation. Only clofilium tended to increase the incidence of spontaneous reversions.

Age-dependent changes in electrophysiologic characteristics of fast and slow action potentials in rat papillary muscle.

Isolated papillary muscles from juvenile (about 2 months old, average weight of 250 g) and young adult rats (about 4 months old, average weight 485 g) were studied for age-dependent differences in the characteristics of fast and slow action potentials (APs). The fast and slow APs were recorded in 5.4 mM and 25 mM K+-Tyrode solutions, respectively (stimulation rate of 1 Hz). For the slow APs, the dose-response curves for isoproterenol versus Vmax (the maximum rate of rise of the APs), overshoot, and AP amplitude were linear between 10(-9) M and 10(-6) M (10(-5 M in some cases) in the juvenile and young adult rats. Isoproterenol pretreatment (1 mg/kg s.c., 1 h prior) decreased the slope of the dose-response curve, and saturation was achieved at a lower concentration. The Vmax, overshoot, and amplitude of both the fast and slow APs were somewhat smaller in the young adult rats than in the juvenile rats; there were no differences in the resting potential, AP duration, or threshold voltage. These results suggest that activation of a greater fraction of the beta-adrenergic receptors is coupled directly or indirectly to activation of a greater fraction of the slow channels. The pretreatment data suggest that down-regulation of the beta-adrenergic receptor may occur. The conductance per channel for the fast Na+ channels and slow channels, and (or) the number of both types of functional channels, may decrease with age.

Synthesis and comparison of some cardiovascular properties of the stereoisomers of labetalol.

A useful method for the separation of labetalol into its two racemic diastereomers, as well as a stereoselective synthesis of its four stereoisomers, is described. The absolute stereochemistry of each isomer was determined by analysis of the DC spectra and confirmed by X-ray analysis. The alpha- and beta 1-adrenergic blocking properties, as well as the relative antihypertensive activities, have been measured in rats. The R,R isomer, 2a (SCH 19927), possesses virtually all of the beta 1-blocking activity elicited by labetalol and displays little alpha-blocking activity. In contrast, the S,R isomer, 3a, has most of the alpha-blocking activity. Of the four isomers, only 2a has antihypertensive potency comparable to that of labetalol. These findings, coupled with published data showing that labetalol possesses beta-adrenergic mediated peripheral vasodilating activity deriving essentially from its R,R isomer, lead to the following conclusion: The antihypertensive activity of labetalol can be ascribed to at least three identified complementary mechanisms, beta-adrenergic blockade, beta-adrenergic mediated vasodilatation, and alpha-adrenergic blockade, whereas the antihypertensive activity of 2a derives from the first two mechanisms only.

Pharmacology of Sch 11973, N-(2-phenylisopropyl)-N-p-toluene sulfonyl urea, a potential new antianginal agent.

Antianginal drugs were evaluated on the basis of their ability to protect against subepicardial electrogram changes induced by local ventricular ischemia in anesthetized dogs. Sch 11973 [N-(2-phenylisopropyl)-N-p-toluene sulfonyl urea], a potential new antianginal agent, was also effective against local ventricular ischemia with its maximum effect appearing at 1mg/kg, i.v. or i.d. and with a duration of at least 2 hours. Nitroglycerin, at a dose of 0.04 mg/kg given bucally, exerted less protection, lasting on the average less than 15 minutes. Protection by propranolol at 1 mg/kg, i.v., was not better than nitroglycerin, but lasted up to one hour, while dipyridamole was ineffective when given in a dose range of 0.1-10 mg/kg, i.v. Sch 11973 differed from standard antianginal agents which may act via beta-adrenergic blocking activity or alteration of cardiac or circulatory dynamics since no acute pharmacological changes were observed after Sch 11973 was administered.