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 (ICa,L). Gst inhibited ICa,L (IC50 = 47 microM) without affecting its time course or shifting the ICa, L-voltage relationship. At the highest concentration of isoflavone tested (200 microM), ICa,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 microM 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 ICa,L and blocked the inhibition of ICa,L by TK inhibitors. The data suggest a role for the TK-phosphotyrosine phosphatase system in the regulation of cardiac Ca2+ channels.
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type; D002478:Cells, Cultured; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006168:Guinea Pigs; D007529:Isoflavones / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology