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 protein tyrosine kinase (PTK), was found to suppress the delayed-rectifier K (IK) current. The present study was carried out to examine the underlying mechanism. Ventricular myocytes were voltage-clamped in the conventional whole-cell mode (36°C). The amplitudes of tail and steady-state (2-s pulse) currents were measured as IK. Genistein (10–100μ ) reversibly inhibited both basal and intrapipette cAMP (1 m )-enhanced IKcurrents in a concentration-dependent manner with a half-maximum inhibitory concentration (IC50) at 30μ . In contrast, lavendustin A (10μ ;n=5) and tyrphostin 51 (100μ ;n=5) had no effect on the currents. The inhibitory action of genistein was also seen after IKcurrents were activated by forskolin (500 n ) plus intrapipette orthovanadate (500μ ). The intrapipette cAMP-enhanced IKwas also reduced to a lesser degree by daidzein, an inactive analogue of genistein. Envelope tail and short pulse protocols revealed that genistein inhibits the slow component of IK(IKs). Thus, the inhibitory action of genistein is not mediated via an inhibition of PTK but may be due to the block of IKschannels.