Antiarrhythmic and Electrophysiological Effects of ICS 205-930, an Antagonist of 5-Hydroxytryptamine at Peripheral Receptors

Abstract

The antiarrhythmic activity of ICS 205-930 [(3.alpha.-tropanyl)-1H-indole-3-carboxylic acid ester], a selective antagonist at neuronal 5-hydroxytryptamine M-receptors, against the arrhythmias that occur following occlusion of the left main coronary artery was investigated in anesthetized rats and subsequent release (reperfusion). The incidence of reperfusion-induced ventricular fibrillation and ventricular tachycardia was significantly reduced by pretreatment with ICS 205-930 (0.3 and 1.0 mg kg-1 i.v. and 10 and 30 mg kg-1 p.o.). The arrhythmias that occurred during 30 min of coronary artery occlusion were also less severe in animals given ICS 205-930 (1.0 and 5.0 mg kg-1 i.v.). Arterial blood pressure was not altered by the drug and heart rate was only slightly reduced by the highest i.v. dose. In vitro, ICS 205-930 reduced the maximum rate of rise of phase 0 of normal sheep Purkinje fiber action potentials in concentrations from 0.5-5.0 mg l-1. Action potentials depressed by superfusion with a physiological salt solution modified to mimic the conditions occurring during mild ischemia were similarly affected by ICS 205-930. The highest drug concentration studied under these conditions was 1.5 mg l-1 since, in combination with the modified physiological salt solution, this rendered some of the Purkinje fibers inexcitable. ICS 205-930 possessed marked antiarrhythmic activity against ischemia-induced arrhythmias in anesthetized rats and a direct electrophysiological effect of the drug may at least in part, underlie its protective action.