Vascular effects of arachidonic acid in the rat perfused heart. Role of the endothelium, cyclooxygenase, cytochrome P450, and K(+) channels.
The vascular effects of arachidonic acid (AA) were addressed in the rat perfused heart in terms of metabolic pathways and effector mechanisms. Under basal perfusion pressure, AA elicited dilator responses. However, in hearts treated with nitroarginine to eliminate nitric oxide and to elevate perfusion pressure, the predominant effect of AA was vasoconstriction which was converted to a vasodilator effect by inhibition of cyclooxygenase or antagonism of TP receptors. The vasodilator effect of AA in nitroarginine- and indomethacin-treated hearts was greatly attenuated by clotrimazole, an inhibitor of cytochrome P450, and by inhibition of K(+) channels with tetraethylammonium; in the absence of indomethacin, clotrimazole enhanced the vasoconstrictor effect of AA. When endothelin was used to constrict the coronary vasculature, AA also produced cyclooxygenase-dependent vasoconstriction. In hearts constricted with the endoperoxide analogue, U46619, only endothelium-dependent vasodilator effects of AA were observed that were reduced by indomethacin or clotrimazole. These results indicate that the coronary vasoconstrictor effect of AA which is expressed with elevated tone, results from its conversion by cyclooxygenase to a product(s) that activates TP receptors. The vasodilator effect exhibits two endothelium-dependent components, one mediated by cyclooxygenase products and the other by a cytochrome P450-derived product that activates K(+) channels.
Qiu
Y
Y
Department of Cell Biology, University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine, Stratford, NJ 08084, USA.
Quilley
J
J
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001481:Basal Metabolism / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology / Q000502:physiology; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology; D019335:Nitroarginine / Q000494:pharmacology; D010477:Perfusion; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D065607:Cytochrome P-450 Enzyme Inhibitors; D016232:Endothelins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D016718:Arachidonic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003577:Cytochrome P-450 Enzyme System; D011451:Prostaglandin-Endoperoxide Synthases