Antiarrhythmic action of the new calcium antagonist [1,2,5-trimethyl-4-phenyl-4-beta-(N-cyanoethyl-N-4'-methoxybenzyl) -ethylamino]piperidine dihydrochloride.
Arrhythmias induced by coronary artery ligation in cats, by CaCl2 and epinephrine in rats, and by ouabain in guinea-pigs were used as experimental models for studying the effects of a new calcium antagonist AR-1 ([1,2,5-trimethyl-4-phenyl-4-beta-(N-cyanoethyl-N-4'-methoxybenzyl) -ethylamino]piperidine, calcium channel blocker and calmodulin antagonist) on ventricular arrhythmias. Coronary ligation caused 90% lethality (ventricular fibrillation) with 12.5 min in untreated control cats, which was prevented by administration of AR-1 (4 mg/kg body weight (b.w.) before or after arrhythmia induction. Pretreatment with AR-1 afforded protection in a dose-related fashion. A dose of 1.5 mg/KG b.w. increased survival to 45%, and all cats dosed with 3 to 5 mg/Kg b.w. survived. CaCl2 (180 mg/Kg b.w., i.v.) induced ventricular fibrillation and 100% lethality. These effects were completely prevented by an anti-arrhythmic dose of AR-1 (3 mg/kg b.w.). Epinephrine-induced ventricular arrhythmias were also prevented by the same dose of AR-1. AR-1 (5 mg/kg b.w.) did not prevent ouabain (0.5 mg/kg b.w.)-induced arrhythmias that caused death within 17 +/- 3.7 min, but displayed protective effects during 67 +/- 7.7 min. The results from these animal studies, in conjunction with previously studies demonstrating coronarodilatory and anti-platelet efficacy of this compound, collectively suggest that AR-1 has a potential to become a useful antianginal and antiarrhythmic therapeutic agent.
Alexanian
A R
AR
Department of Neurohormonal Biochemistry, Institute of Biochemistry, Yerevan (Republic of Armenia).
Arutyunian
N S
NS
Galoyan
A A
AA
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002122:Calcium Chloride; D002317:Cardiovascular Agents; D003331:Coronary Vessels / Q000502:physiology; D004562:Electrocardiography / Q000187:drug effects; D004837:Epinephrine; D008297:Male; D010042:Ouabain; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000503:physiopathology
C104524:AR-1 (antiarrhythmia agent); D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002317:Cardiovascular Agents; D010880:Piperidines; D010042:Ouabain; D002122:Calcium Chloride; D004837:Epinephrine