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.
Voutilainen-Myllylä
Sari
S
Department of Physical Sciences, Division of Biophysics, University of Oulu, P.O. Box 3000, FIN-90014 Oulu yliopisto, Finland.
Tavi
Pasi
P
Weckström
Matti
M
D000200:Action Potentials / Q000187:drug effects*; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010617:Phenanthridines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000378:metabolism
D000470:Alkaloids; D053119:Benzophenanthridines; D015220:Calcium Channels; D007211:Indoles; D008301:Maleimides; D010617:Phenanthridines; D015221:Potassium Channels; D012965:Sodium Chloride; C016299:chelerythrine; D011493:Protein Kinase C; C070515:bisindolylmaleimide I