Effect of phorbol esters on contractile state and calcium flux in cultured chick heart cells.
Phorbol esters are potent tumor promoters that have been widely used in studies of transmembrane signaling because of their ability to activate protein kinase C. To study the effect of phorbol esters (and indirectly, the role of protein kinase C) on cardiac muscle contractility, we examined the effects of phorbol myristate acetate (PMA) on contractile state, transmembrane 45Ca fluxes, and cytosolic free Ca concentration ([Ca]i) using spontaneously contracting cultured chick ventricular cells. PMA produced a concentration- and time-dependent decrease in the amplitude of cell motion [half maximum inhibitory concentration (IC50) = 130 nM] with maximal effect (54 +/- 5% of control) observed at 1 microM. PMA (1 microM) reduced 45Ca uptake rate by 16 +/- 4% (P less than 0.05) and the size of the rapidly exchangeable Ca pool by 11 +/- 2% (P less than 0.05) but did not alter the 45Ca efflux rate. In fura-2-loaded cells, PMA produced a decrease in [Ca]i from 96 +/- 7 to 72 +/- 5 nM (mean +/- SE; P less than 0.05) with a time course similar to that of alteration in contractile amplitude. PMA had no effect on cellular Na content. Phorbol didecanoate (1 microM), a phorbol diester that does not activate protein kinase C, produced no significant changes in contractile amplitude, 45Ca fluxes, or [Ca]i. These results indicate that PMA influences transsarcolemmal Ca uptake, and thus the excitation-contraction process, and suggest that protein kinase C may modulate myocardial Ca homeostasis and contractile state.
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D003600:Cytosol / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism
D010703:Phorbol Esters; D012964:Sodium; D002118:Calcium