Chelerythrine and genistein inhibit the endothelin-1-induced increase in myofilament Ca(2+) sensitivity in rabbit ventricular myocytes.
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.
Wang
H
H
Department of Pharmacology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
Endoh
M
M
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D000470:Alkaloids; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D053119:Benzophenanthridines; D002118:Calcium / Q000378:metabolism*; D048429:Cell Size / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D010617:Phenanthridines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011817:Rabbits; D044022:Receptor, Endothelin A; D013050:Spectrometry, Fluorescence
D000470:Alkaloids; D001381:Azepines; D053119:Benzophenanthridines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007211:Indoles; D010617:Phenanthridines; D044022:Receptor, Endothelin A; C079574:FR 139317; D019833:Genistein; C016299:chelerythrine; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; C048960:indo-1; D002118:Calcium