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

Add time:08/31/2019    Source:sciencedirect.com

Effects of chelerythrine and bisindolylmaleimide I on action potential duration and on voltage-activated K+ and Ca2+ currents in rat ventricular myocytes were studied using perforated patch-clamp technique. The action potentials were markedly prolonged after application of 20 μM chelerythrine or 100 nM bisindolylmaleimide I. Chelerythrine and bisindolylmaleimide I reduced the amplitude of sustained current (IK,sus) significantly. Transient K+ current (Ito) was inhibited only by chelerythrine. Ca2+ current was reduced only with highest chelerythrine concentration (50 μM). 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 IK,sus substantially. However, Ito and IK,sus were not affected by calphostin C. Direct protein kinase C activators resulted in decrease of outward K+ currents. Chelerythrine blocked Ito in a use-dependent manner and the block did not recover during a 4-min washout. IK,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.

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