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

1 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. 2 Genistein but not daidzein inhibited the positive inotropic effect and the increase in Ca2+ transients induced by ET-1 by crosstalk with NE at low concentrations. 3 Genistein and daidzein antagonized the negative inotropic effect and the decrease in Ca2+ transients induced by ET-1 by crosstalk with NE at high concentrations, but genistein did not affect the antiadrenergic effect of carbachol. 4 Genistein but not daidzein enhanced the positive inotropic effect and the increase in Ca2+ transients induced by NE via β-adrenoceptors, while the enhancing effect of genistein was abolished by the protein tyrosine phosphatase inhibitor vanadate. 5 These findings indicate that genistein (1) induces a positive inotropic effect in association with an increase in Ca2+ 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 β-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. British Journal of Pharmacology (2005) 144, 430–442. doi:10.1038/sj.bjp.0706097