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,L)). Gst inhibited I(Ca,L) (IC₅₀ = 47 μM) without affecting its time course or shifting the I(Ca,L)-voltage relationship. At the highest concentration of isoflavone tested (200 μM), I(Ca,L) was inhibited by 66 ± 7% (Gst), 22 ± 2% (daidzein), and 1 ± 3% (genistin). Inhibition of I(Ca,L) by the active tyrphostins was significantly larger than inhibition by T1; at 200 μM 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,L) and blocked the inhibition of I(Ca,L) by TK inhibitors. The data suggest a role for the TK-phosphotyrosine phosphatase system in the regulation of cardiac Ca²⁺ Channels.