Chelerythrine and genistein inhibit the endothelin-1-induced increase in myofilament Ca(2+) sensitivity in rabbit...

We performed experiments to elucidate the cellular mechanism for the biphasic inotropic response to endothelin-1 of single rabbit ventricular myocytes loaded with a fluorescent dye, acetoxymethylester of indo-1. Endothelin-1 at 10 nM elicited a biphasic inotropic effect: a transient decrease in cell shortening and Ca(2+) transients followed by an increase in cell shortening without significant elevation of peak Ca(2+) transients. The selective endothelin ET(A) receptor antagonist FR139317 (2(R)-[2(R)-[2(S)-[(1-hexahydro-1H-azepinyl)]carbonyl]amino-4-methylpentanoyl]amino-3-[3-(1-methyl-1H-indolyl)propionyl]amino-3-(2-pyridyl)propionic acid) at 1 microM abolished the biphasic effect of endothelin-1 on cell shortening and Ca(2+) transients. The selective protein kinase C inhibitor chelerythrine at 1 microM and the tyrosine kinase inhibitor genistein at 5 microM inhibited the endothelin-1-induced increase in cell shortening without significantly affecting Ca(2+) transients and the transient decrease in cell shortening and Ca(2+) transients. The present results indicate that both protein kinase C and tyrosine kinase may contribute to the increase in myofilament Ca(2+) sensitivity induced by endothelin-1, whereas the decrease in Ca(2+) transients induced by endothelin-1 may be mediated by a signalling pathway different from that involved in the increase in cardiac contractility in rabbit ventricular myocytes.