Tumor-promoting phorbol esters inhibit cardiac functions and induce redistribution of protein kinase C in perfused beating rat heart.
Activation of protein kinase C has been implicated in the regulation of a variety of cellular reactions. Although we, and others, have found protein kinase C and its substrate proteins to be present in both membrane and cytosolic fractions in the heart, the physiologic role of this kinase in the regulation of cardiac functions remains unknown. In the present study, we found that in isolated perfused rat heart, administration of phorbol esters 4 beta-phorbol 12,13-dibutyrate(PDBu) and 12-0-tetradecanoylphorbol 13-acetate(TPA), which are specific activators of protein kinase C, produced marked dose-dependent negative changes in inotropy and chronotropy. A dose-dependent decrease in coronary flow was also observed. The diacylglycerol analogues, 1,2-oleoylacetyl-glycerol and 1,2-dioctanoylglycerol, produced similar effects as the active phorbol esters on these isolated perfused hearts. An inactive analogue of phorbol ester, 4 alpha-phorbol, failed to produce any effect. Protein kinase C activity in both membrane and cytosolic fractions prepared from rat heart could be activated by TPA and PDBu at the same concentration range as used in the experiments with perfused hearts. Following perfusion of the hearts with PDBu, a rapid translocation of protein kinase C from cytosolic to membrane fractions was also observed. Our findings provide the first direct evidence that protein kinase C may play a potentially important role in the regulation of cardiac functions.
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D003600:Cytosol / Q000201:enzymology; D004075:Diglycerides / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D010477:Perfusion; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000201:enzymology
D002273:Carcinogens; D004075:Diglycerides; D010703:Phorbol Esters; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C