Chelerythrine and bisindolylmaleimide I prolong cardiac action potentials by protein kinase C-independent mechanism.

Effects of chelerythrine and bisindolylmaleimide I on action potential duration and on voltage-activated K(+) and Ca(2+) currents in rat ventricular myocytes were studied using perforated patch-clamp technique. The action potentials were markedly prolonged after application of 20 microM chelerythrine or 100 nM bisindolylmaleimide I. Chelerythrine and bisindolylmaleimide I reduced the amplitude of sustained current (I(K,sus)) significantly. Transient K(+) current (I(to)) was inhibited only by chelerythrine. Ca(2+) current was reduced only with highest chelerythrine concentration (50 microM). Application of chelerythrine and bisindolylmaleimide I inhibited outward K(+) currents significantly also in ruptured patch-clamp configuration. Bisindolylmaleimide V, an inactive analogue of bisindolylmaleimide I, decreased I(K,sus) substantially. However, I(to) and I(K,sus) were not affected by calphostin C. Direct protein kinase C activators resulted in decrease of outward K(+) currents. Chelerythrine blocked I(to) in a use-dependent manner and the block did not recover during a 4-min washout. I(K,sus) was not blocked by this mechanism by either inhibitor. We conclude that chelerythrine and bisindolylmaleimide I inhibit outward K(+) currents independently of protein kinase C inhibition.