Antiarrhythmic and electrophysiological effects of ICS 205-930, an antagonist of 5-hydroxytryptamine at peripheral receptors.
We assessed 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 in anaesthetised 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 intravenous dose. In vitro, ICS 205-930 reduced the maximum rate of rise of phase 0 of normal sheep Purkinje fibre action potentials in concentrations from 0.5 to 5.0 mg L-1. Action potentials depressed by superfusion with a physiological salt solution modified to mimic the conditions occurring during mild ischaemia 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 fibres inexcitable. These results indicate that ICS 205-930 possesses marked antiarrhythmic activity against ischaemia-induced arrhythmias in anaesthetised rats and that a direct electrophysiological effect of the drug may, at least in part, underlie its protective action.
Williams
F M
FM
Rothaul
A L
AL
Kane
K A
KA
Parratt
J R
JR
D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006339:Heart Rate / Q000187:drug effects*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D010477:Perfusion; D011690:Purkinje Fibers / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D012756:Sheep; D000077526:Tropisetron; D014693:Ventricular Fibrillation / Q000503:physiopathology
D007211:Indoles; D012702:Serotonin Antagonists; D000077526:Tropisetron