Effects of genistein on cardiac contractile force and atrial natriuretic peptide secretion in the isolated perfused rat heart.

We examined the effects of a selective protein tyrosine kinase inhibitor, the isoflavonoid genistein, on haemodynamics and atrial natriuretic peptide (ANP) secretion in perfused rat heart preparations. The addition of genistein into the perfusion fluid at concentrations of 11, 22 and 37 microM for 30 min in the spontaneously beating rat hearts caused dose-dependent, sustained increases in contractile force, perfusion pressure and immunoreactive ANP secretion, while heart rate remained constant. The positive inotropic and vasoconstrictor effects of genistein were significantly (P < 0.001) greater in the paced than in spontaneously beating rat hearts. Infusion of the calcium-channel antagonist diltiazem (3 microM) inhibited the genistein-induced positive inotropic effect by 52% (P < 0.001), and KN-62 (1.5 microM), an inhibitor of Ca2+/calmodulin-dependent protein kinase II, by 34% (P < 0.001). The genistein-induced increase in immunoreactive ANP secretion was completely blocked by diltiazem (P < 0.001) while KN-62 delayed (P < 0.02) the increase of immunoreactive ANP concentration in the perfusate. These results show that genistein, at concentrations known to inhibit the activities of protein tyrosine kinases, dose-dependently increased contractile force, coronary vascular tone and ANP secretion from isolated perfused rat hearts. These cardiac effects of genistein may be mediated by elevation of intracellular Ca2+ concentration, as shown by the inhibition of inotropic and secretory effects by both L-type calcium channel antagonist and Ca2+/calmodulin-dependent protein kinase inhibitor.