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 Ca(2+) 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 Ca(2+ )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 (CaCl(2)) for 20 minutes and then 6 μg/kg/min isoproterenol was infused with CaCl(2) 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 Ca(2+) 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 diltiazem (1 of 9 animals, 11%) groups compared to the vehicle group (8 of 14 animals, 57%).
Significance: Induction of VA in an experimental model was achieved with a low dose of isoproterenol under Ca(2+) loading. K201 markedly suppressed both the isoproterenol-induced and the reperfusion-induced VAs, whereas diltiazem did not suppress the isoproterenol-induced VA. The results suggest that both VAs are related to early after depolarization (EAD) and indicate that K201 has the potential to suppress EAD by stabilizing RyR2 to mediate Ca(2+) release from the sarcoplasmic reticulum and acting as a multiple-channel blocker.