The effect of phorbol esters and diacylglycerol analogues on the basal phosphoinositide turnover in isolated guinea pig hearts.
Langendorff perfusion of guinea pig hearts with phorbol 12-myristate, 13-acetate or 1,2-dioctanoylglycerol caused a progressive impairment of contraction and relaxation of the left ventricle. Exposure of the hearts to 4 microM phorbol 12-myristate, 13-acetate or 200 microM 1,2-dioctanoylglycerol for 3 minutes resulted in a redistribution of protein kinase C activity and increased phosphorylation of a 28 kDa cytosolic protein. Examination of the incorporation of [32P]Pi into phosphatidylinositols and inositoltrisphosphates, under identical conditions, revealed that the degree of 32P-labeling of phosphatidylinositol, phosphatidylinositol 4-monophosphate and phosphatidylinositol 4.5-bisphosphate was significantly increased. However, the degree of phosphate labeling of inositol trisphosphates was decreased. The effects of phorbol 12-myristate, 13-acetate and 1,2-dioctanoylglycerol on the intermediates of the phosphatidylinositol cycle were observed in the presence of prazosin, propranolol and atropine. Examination of the activity of phosphoinositide-specific phospholipase C in the perfused guinea pig hearts revealed that treatment with phorbol 12-myristate, 13-acetate was associated with a decrease in the membrane-associated enzymatic activity, assayed at low concentrations of calcium. Control hearts, perfused with a phorbol ester (4 alpha-phorbol 12,13-didecanoate) which does not activate protein kinase C, did not show any changes in cardiac contraction and relaxation or in the intermediates of the phosphatidylinositol cycle. The findings suggest that the basal production of inositol phosphates may be down-regulated by agents which activate protein kinase C in guinea pig hearts.
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Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, OH 45267-0575.
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D000818:Animals; D004075:Diglycerides / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010477:Perfusion; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism
D004075:Diglycerides; D010716:Phosphatidylinositols; C044295:1,2-dioctanoylglycerol; D011493:Protein Kinase C; D010738:Type C Phospholipases; D013755:Tetradecanoylphorbol Acetate