Inhibition of L-type calcium current by genistein, a tyrosine kinase inhibitor, in pregnant rat myometrial cells

Possible regulation of L-type Ca2+ channels by tyrosine kinase was examined in freshly isolated uterine smooth muscle cells obtained from late pregnant (18-19 day) rat, using whole-cell voltage clamp. Bath application of genistein, an inhibitor of tyrosine kinase, decreased L-type Ca2+ current (I-Ca(L)) dose-dependently. The maximal inhibition of I-Ca(L) was 46% and the concentration for half-maximal inhibition (IC(50)) was 50 mu M (at a holding potential of - 60 mV). The effect of genistein was reversible. Daidzein, an inactive analog of genistein, had no inhibitory effect on I-Ca(L) at concentrations as high as 300 mu M. The steady-state inactivation curve for I-Ca(L) was shifted to the left by genistein (15 mV at 100 mu M), whereas the activation curve was not affected, suggesting that genistein exerts a voltage-dependent block. These results suggest that the L-type Ca2+ channels in myometrial cells may be modulated by endogenous tyrosine kinase, i.e., they are in a tonically stimulated state due to tyrosine kinase activity. This modulatory mechanism may play a role on the regulation of Ca2+ influx and uterine contraction during normal labor and preterm labor.