Genistein inhibits slow component delayed-rectifier K currents via a tyrosine kinase-independent pathway

In single guinea pig ventricular cells, genistein, a potent inhibitor of pr otein tyrosine kinase (PTK), was found to suppress the delayed-rectifier It (I-K) current. The present study was carried out to examine the underlying mechanism. Ventricular myocytes were voltage-clamped in the conventional w hole-cell mode (36 degrees C). The amplitudes of tail and steady-state (2-s pulse) currents were measured as I-K. Genistein (10-100 mu M) reversibly i nhibited both basal and intrapipette cAMP (1 mM)-enhanced I-K currents in a concentration-dependent manner with a half-maximum inhibitory concentratio n (IC50) at similar to 30 mu M. In contrast, lavendustin A (10 mu M; n = 5) and tyrphostin 51 (100 mu M; n = 5) had no effect on the currents. The inh ibitory action of genistein was also seen after I-K currents were activated by forsIrolin (500 nM) plus intrapipette orthovanadate (500 mu M). The int rapipette cAMP-enhanced I-K was also reduced to a lesser degree by daidzein , an inactive analogue of genistein. Envelope tail and short pulse protocol s revealed that genistein inhibits the slow component of I-K (I-Ks). Thus, the inhibitory action of genistein is not mediated via an inhibition of PTK but may be due to the block of I-Ks channels. (C) 1998 Academic Press.