Protein tyrosine kinases and L-type Ca2+ currents in cells that have survived in epicardial border zone of canine infarcted heart.
Previously a reduction was shown in the density of the L-type Ca currents in cells that have survived in the epicardial border zone of the 5-day infarcted canine heart (IZ). A hyporesponsiveness of I(CaL) to beta-adrenergic stimulation in IZs versus cells from the noninfarcted heart (NZs) was also shown. To determine the role of protein tyrosine kinase (PTK) activity in this altered adrenergic response as well as in the reduced basal current function in IZs, the effects of genistein and T23, specific inhibitors of PTK, on basal I(CaL) in the absence and presence of isoproterenol (5 nM ) were studied using whole-cell patch-clamp techniques. Genistein reduction of I(CaL) was similar in NZs and IZs and was not mimicked by daidzein, an inactive analogue of genistein. Submaximal isoproterenol produced a small response in both cell types that was potentiated in the presence of genistein. T23 also reduced I(CaL) in both NZs and IZs; however, submaximal isoproterenol was not potentiated in its presence. In sum, basal I(CaL) is sensitive to genistein and T23, suggesting that persistent PTK activity contributes to I(CaL) in both NZs and IZs. With genistein but not with T23, there is an enhanced sensitivity of I(CaL) to isoproterenol in both NZs and IZs but peak I(CaL) is not fully restored in IZs. Thus, dysregulation of PTK activity cannot account for the reduced basal Ca currents or hyporesponsiveness of I(CaL) to isoproterenol in the cells that have survived in the infarcted heart.
Yagi
Takuya
T
Center of Molecular Therapeutics, Department of Pharmacology, Columbia University, New York, New York 10032, USA.
Boyden
Penelope A
PA
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D019833:Genistein; D011505:Protein-Tyrosine Kinases