Antiarrhythmic effects of potassium channel openers in rhythm abnormalities related to delayed repolarization.
Authors: Carlsson L , Abrahamsson C , Drews L , Duker G 
Published: June 2012

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 RESULTS
Anesthetized rabbits were pretreated with propranolol (2 mumol/kg i.v.) and subsequently given a concomitant intravenous infusion of clofilium (63 nmol/kg/min for maximally 15 minutes) and the alpha 1-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%, p less than 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) of the 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 mumol/kg or 1.86 mumol/kg i.v.), the occurrence of PVTs was reduced from seven of seven rabbits to five of six and to three of seven rabbits (p = 0.035 versus vehicle-pretreated controls), respectively. In rabbits pretreated with the low dose of P1075 (0.01 mumol/kg i.v.), PVT occurrence was reduced from six of six rabbits to two of six rabbits (p = 0.030), whereas in six rabbits given the high dose of P1075 (0.13 mumol/kg), no PVTs appeared (p = 0.001). When the sulfonylurea glibenclamide (10 mumol/kg i.v.) was administered to rabbits before P1075 (0.13 mumol/kg) was infused, clofilium induced PVTs in five of six rabbits (not significantly different from the incidence in the vehicle-pretreated rabbits). Pretreatment with P1188 (4.36 mumol/kg or 11.88 mumol/kg i.v.) caused a reduction in the occurrence of PVT from six of six rabbits to five of six and to none of six rabbits (p = 0.001), respectively. In the six animals pretreated with the high dose of P1188 in which no clofilium-induced arrhythmias were elicited, glibenclamide (20 mumol/kg i.v.) was injected after the entire dose of clofilium had been administered. In these rabbits, premature ventricular systoles and PVTs appeared within a few minutes in five and four of the animals, respectively. In contrast to the pyridylcyanoguanidines, diltiazem pretreatment (0.9 mumol/kg i.v., decreasing arterial pressure by 50 mm Hg) did not attenuate PVT occurrence (five of six rabbits). Acute administration of P1075 (0.13 mumol/kg) during recurrent attacks of PVTs abruptly regularized the rhythm in 12 of 13 animals and diminished EADs observed in monophasic action potentials recorded from the left ventricular endocardium. In in vitro experiments, action potentials were simultaneously recorded from rabbit Purkinje fibers and ventricular muscle cells. Clofilium markedly prolonged action potential duration in Purkinje fibers but not in ventricular muscle cells, and eventually, bradycardia-dependent EADs and triggered activity were elicited. P1075 completely abolished EADs and triggered activity in all (six of six) experiments. Glibenclamide antagonized the suppressive effect of P1075; hence, EADs and triggered responses reappeared and resembled those present before P1075.

CONCLUSIONS
These results suggest that ATP-sensitive potassium channel activat

BACKGROUND
Earlier observations have indicated that repolarization-delaying agents may, under certain circumstances, have the propensity to induce polymorp