Probucol and the cholesterol synthesis inhibitors simvastatin and triparanol regulate Iks channel function differently

Abstract

Channels responsible for slowly activating delayed-rectifier potassium current (I(Ks)) are composed of KCNQ1 and KCNE1 subunits, and these channels play a role in the repolarization of cardiac action potentials. Recently, we showed that the antihyperlipidemic drug probucol, which induces QT prolongation, decreases the I(Ks) after 24-h treatment. In the present study, we investigated the effects of three cholesterol-lowering agents (probucol, an enhancer of cholesterol efflux; simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; and triparanol, a 3β-hydroxysterol-▵24-reductase inhibitor) on cholesterol synthesis, the KCNQ1 current (I KCNQ1), and the I(Ks) to clarify the differences in the modes of action of these agents on the I(Ks). Probucol did not inhibit cholesterol synthesis and had no effect on I KCNQ1, while I(Ks) decreased after 24-h treatment. Simvastatin inhibited cholesterol synthesis and decreased I KCNQ1 and I(Ks). Additionally, the activation kinetics of I(Ks) became faster, compared with that of control I(Ks). Triparanol inhibited cholesterol synthesis but did not reduce I KCNQ1 and I(Ks). However, the activation kinetics of I(Ks) became faster. Our data indicated that the mechanism by which probucol inhibits I(Ks) was not mediated by the inhibition of cholesterol synthesis but depended on an interaction with the KCNQ1/KCNE1 complex. Meanwhile, the reduction in cholesterol induced by simvastatin and triparanol is one of the mechanisms that affects the kinetics of I(ks).