Arachidonic acid-induced endothelial-dependent relaxations of canine coronary arteries: contribution of a cytochrome P-450-dependent pathway.
Arachidonic acid (AA, 10(-8)-5 X 10(-6) M) induced dose-dependent relaxations of canine coronary arterial rings precontracted with dinoprost that were significantly greater (P less than .001) if the endothelium was intact. Cyclooxygenase inhibition with indomethacin displaced the dose-response curve to AA to the right but did not prevent the relaxant effects of the fatty acid. SKF-525A, an inhibitor of cytochrome P-450-dependent enzymes, also attenuated the response to AA although the combination of SKF-525A and indomethacin prevented any relaxant effect. Induction of cytochrome P-450-dependent enzymes in the coronary artery with 3-methylcholanthrene and beta-naphthoflavone given in vivo (40 mg/kg/day for 3 days) or depletion of these enzymes with cobalt chloride (24 mg/kg/day for 2 days) resulted in an enhancement or diminution, respectively, of AA-induced endothelial-dependent relaxations. These results implicate a cytochrome P-450-dependent mixed function oxidase in the endothelial-dependent relaxations to AA in the canine coronary artery. Precontraction of coronary arteries with U46619 in contrast to dinoprost failed to display endothelial-dependent relaxations to AA, whereas the responses to bradykinin and acetylcholine were also partially attenuated. Pharmacologic manipulations of AA metabolism via cyclooxygenase and cytochrome P-450-dependent monooxygenases indicate that the endothelial-dependent relaxations induced by bradykinin are partially dependent upon metabolites of AA, whereas the relaxations produced by acetylcholine are independent of AA metabolites, suggesting that a number of potential relaxing factors may be released from the endothelium.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology*; D001571:Benzoflavones / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015237:Dinoprost; D004285:Dogs; D004727:Endothelium / Q000502:physiology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D011335:Proadifen / Q000494:pharmacology; D011460:Prostaglandins F / Q000494:pharmacology; D019324:beta-Naphthoflavone
D001095:Arachidonic Acids; D001571:Benzoflavones; D011460:Prostaglandins F; D016718:Arachidonic Acid; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D015237:Dinoprost; D007213:Indomethacin