Differential action of a protein tyrosine kinase inhibitor, genistein, on the positive inotropic effect of endothelin‐1 and norepinephrine in canine ventricular myocardium

Abstract

Experiments were carried out in isolated canine ventricular trabeculae and acetoxymethylester of indo-1-loaded single myocytes to elucidate the role of protein tyrosine kinase (PTK) in the inotropic effect of endothelin-1 (ET-1) induced by crosstalk with norepinephrine (NE). The PTK inhibitor genistein was used as a pharmacological tool. Genistein but not daidzein inhibited the positive inotropic effect and the increase in Ca(2+) transients induced by ET-1 by crosstalk with NE at low concentrations. Genistein and daidzein antagonized the negative inotropic effect and the decrease in Ca(2+) transients induced by ET-1 by crosstalk with NE at high concentrations, but genistein did not affect the antiadrenergic effect of carbachol. Genistein but not daidzein enhanced the positive inotropic effect and the increase in Ca(2+) transients induced by NE via beta-adrenoceptors, while the enhancing effect of genistein was abolished by the protein tyrosine phosphatase inhibitor vanadate. These findings indicate that genistein (1) induces a positive inotropic effect in association with an increase in Ca(2+) transients, (2) inhibits the positive inotropic effect of ET-1 induced by crosstalk with NE, and (3) enhances the positive inotropic effect of NE induced via beta-adrenoceptors by inhibition of PTK. In addition, genistein inhibits the negative inotropic effect of ET-1 induced by crosstalk with NE through a PTK-unrelated mechanism. PTK may play a crucial role in the receptor-mediated regulation of cardiac contractile function in canine ventricular myocardium.