Deterioration of the protein kinase C-KATP channel pathway in regulation of coronary flow in hypercholesterolaemic rabbits

Abstract We studied the effect of experimental hypercholesterolaemia/atherosclerosis on changes in coronary flow and cardiac function, induced by protein kinase C and ATP-sensitive K + (K ATP ) channel modulators in isolated Langendorff-perfused rabbit hearts. Both phorbol 12-myristate-13-acetate (PMA) and phorbol 12,13-dibutyrate (PDB, 0.1 μM each), activators of protein kinase C, decreased, whereas staurosporine, (0.1 μM), a protein kinase C inhibitor, increased coronary flow and left ventricular d P /d t , an index of ventricular contractility. Glyburide (5–50 μM), a K ATP channel inhibitor, blocked the effect of staurosporine. The phorbol esters were without effect in the presence of pinacidil (5 μM), a K ATP channel activator. Neither the protein kinase C modulators nor glyburide produced any effect on coronary flow and left ventricular contractility, when the hearts were prepared from animals either maintained on a cholesterol (1.5%)-enriched diet or treated with lovastatin (5 mg/kg/day per os). Treatment with farnesol (1 mg/kg twice a day for 7 days intravenously) restored the reactivity of hearts from either hypercholesterolaemic or lovastatin-treated animals to protein kinase C modulators. We conclude that non-cholesterol mevalonate products are necessary for the functional integrity of the protein kinase C–K ATP channel pathway in the rabbit heart.