ARACHIDONIC ACID-INDUCED ENDOTHELIAL-DEPENDENT RELAXATIONS OF CANINE CORONARY-ARTERIES - CONTRIBUTION OF A CYTOCHROME P-450-DEPENDENT PATHWAY

  • 1 March 1987
    • journal article
    • research article
    • Vol. 240  (3) , 856-863
Abstract
Arachidonic acid (AA, 10-8-5 .times. 10-6 M) induced dose-independent relaxations of canine coronary arterial rings precontracted with dinoprost that were significantly greater (P < .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 colbalt 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.

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