Protective Effect of K201 on Isoproterenol-Induced and Ischemic-Reperfusion-Induced Ventricular Arrhythmias in the Rat: Comparison With Diltiazem

Aim: Ventricular arrhythmia (VA) is a risk for sudden death. Polymorphic ventricular tachycardia (VT) degenerating to ventricular fibrillation occurs subsequent to the prolongation of the QT interval following administration of catecholamines under Ca2+ loading. Fatal VA also occurs in ischemia and ischemic–reperfusion. We compared the suppressive effect of K201 (JTV519), a multiple-channel blocker and cardiac ryanodine receptor-calcium release channel (RyR2) stabilizer, with that of diltiazem, a Ca2+ channel blocker, in 2 studies of isoproterenol-induced (n = 30) and ischemic–reperfusion-induced VAs (n = 38) in rats. Methods: Adult male Wistar rats were administered 12 mg/kg/min calcium chloride (CaCl2) for 20 minutes and then 6 μg/kg/min isoproterenol was infused with CaCl2 for a further 20 minutes. In other rats, the left coronary artery was ligated for 5 minutes followed by reperfusion for 20 minutes. K201 or diltiazem (both 1 mg/kg) was administered before infusion of the isoproterenol or induction of ischemia. Results: After administration of isoproterenol under Ca2+ loading, fatal VA frequently occurred in the vehicle (9 of 10 animals, 90%) and diltiazem (8 of 10, 80%) groups, and K201 significantly suppressed the incidences of arrhythmia and mortality (2 of 10, 20%). In the reperfusion study, the incidence and the time until occurrence of reperfusion-induced VA and mortality were significantly suppressed in the K201 (2 of 15 animals, 13%) and diltiaze...
Source: Journal of Cardiovascular Pharmacology and Therapeutics - Category: Cardiology Authors: Tags: Experimental Studies Source Type: research