L-type Ca2+ current in guinea pig ventricular myocytes treated with modulators of tyrosine phosphorylation

Guinea pig ventricular myocytes in whole cell configuration were treated with tyrosine kinase (TK) inhibitors [genistein (Gst), tyrphostin A23 (T23), and tyrphostin A25 (T25)] and with inactive analogs [daidzein, genistin, and tyrphostin A1 (T1)] to measure effects on L-type Ca2+ current (I-Ca,I-L) Gst inhibited I-Ca,I-L (IC50 = 47 mu M) without affecting its time course or shifting the I-Ca,I-L-voltage relationship. At the highest concentration of isoflavone tested (200 mu M), I-Ca,I-L was inhibited by 66 +/- 7% (Gst), 22 +/- 2% (daidzein), and 1 +/- 3% (genistin). Inhibition of ICa,L by the active tyrphostins was significantly larger than inhibition by T1; at 200 mu M the inhibitions were 72 +/- 6% (T23), 71 +/- 6% (T25), and 27 +/- 6% (T1). The phosphotyrosine phosphatase inhibitor orthovanadate (1 mM) had a small stimulatory effect (6 +/- 2%) on basal I-Ca,I-L and blocked the inhibition of I-Ca,I-L by TK inhibitors. The data suggest a role for the TK-phosphotyrosine phosphatase system in the regulation of cardiac Ca2+ channels.