Deterioration of the protein kinase C-K(ATP) channel pathway in regulation of coronary flow in hypercholesterolaemic rabbits.
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 microM each), activators of protein kinase C, decreased, whereas staurosporine, (0.1 microM), a protein kinase C inhibitor, increased coronary flow and left ventricular dP/dt, an index of ventricular contractility. Glyburide (5-50 microM), a K(ATP) channel inhibitor, blocked the effect of staurosporine. The phorbol esters were without effect in the presence of pinacidil (5 microM), 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.
Pongo
E
E
Centre of Experimental Surgery and Anaesthesiology, Katholieke Universiteit Minderbroedenstraat 17, B-3000, Leuven, Belgium.
Balla
Z
Z
Mubagwa
K
K
Flameng
W
W
Edes
I
I
Szilvassy
Z
Z
Ferdinandy
P
P
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004791:Enzyme Inhibitors; D015221:Potassium Channels; D015240:Phorbol 12,13-Dibutyrate; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate