Antiarrhythmic effects of potassium channel openers in rhythm abnormalities related to delayed repolarization. Circulation 85:1491–1500

Background. Earlier observations have indicated that repolarization-delaying agents may, under certain circumstances, have the propensity to induce polymorphous ventricular tachyarrhythmias (PVTs) (i.e., torsade de pointes). We have studied whether the potassium channel opener pinacidil and two of its pyridylcyanoguanidine analogues (P1075 and P1188) have any antiarrhythmic effects on clofilium-induced PVTs and triggered responses in rabbits in vivo and in vitro. Methods and Result. Anesthetized rabbits were pretreated with propranolol (2,umollkg i.v.) and subse-quently given a concomitant intravenous infusion of clofilium (63 nmol/kg/min for maximally 15 minutes) and the et,-agonist methoxamine (70 nmol/kg/min). In vehicle-pretreated rabbits (n=19), clofilium invariably induced PVTs, which closely resembled torsade de pointes and were preceded by a marked prolongation of the QTU interval (27+2.4,op<0.001). In a separate group of seven rabbits in which monophasic action potentials were recorded from the left ventricular endocardium, the tachyarrhythmia was preceded by deflections consistent with early afterdepolarizations (EADs) ofthe plateau repolarization phase of the monophasic action potentials. Intravenous administration of the pyridylcyanoguanidines in doses reducing mean arterial blood pressure by 25 or 50 mm Hg, respectively, was associated with a dose-dependent attenuation in the occurrence of clofilium-induced PVTs. In the pinacidil-pretreated rabbits (0.41,moV/kg or 1.86,umoU/kg i.v.), th