Cytochrome P-450-dependent monooxygenase activity and endothelial-dependent relaxations induced by arachidonic acid.
The authors have recently identified a cytochrome P-450-dependent monooxygenase in vascular tissue, localized primarily to the endothelium. As this enzyme system can metabolize arachidonic acid (AA) to novel products, some of which produce vasodilation, the pathways involved in the vascular actions of AA (10(-8) to 5 X 10(-6) M) were examined on rings of rabbit pulmonary artery. In pulmonary rings with a low basal tension (1.5 g), AA produces a weak contraction which is prevented by removal of the endothelium or the addition of indomethacin (10(-6) M) but not SKF 525A (10(-5) M), suggesting the formation of an endothelial-dependent vasoconstrictor cyclooxygenase product. In contrast, rings precontracted to 3.5 to 4 g tension with phenylephrine (7 X 10(-7) M) exhibit a dose-related relaxation to AA, which is significantly greater (P less than .001, n = 32) in preparations with an intact endothelium. The endothelium-independent relaxation is suppressed by indomethacin whereas indomethacin fails to attenuate the endothelium-dependent response. In contrast, SKF 525A, an inhibitor of cytochrome P-450-dependent monooxygenase, markedly inhibits (P less than .001) AA-induced relaxations in intact rings in a dose-dependent manner while not affecting the response in rings denuded of endothelium. Intact vessels treated with SKF 525A (10(-6) M) appear to show diversion of the AA to vasodilator cyclooxygenase products, since the subsequent addition of indomethacin produces a further reduction of the AA-induced relaxations, whereas by itself indomethacin has no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Pinto
A
A
Abraham
N G
NG
Mullane
K M
KM
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology*; D001571:Benzoflavones / Q000494:pharmacology; D001808:Blood Vessels / Q000201:enzymology*; D003035:Cobalt / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System; D004357:Drug Synergism; D004727:Endothelium / Q000502:physiology*; D005227:Fatty Acids / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D010105:Oxygenases / Q000032:analysis*; D010656:Phenylephrine / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D019324:beta-Naphthoflavone
D001095:Arachidonic Acids; D001571:Benzoflavones; D005227:Fatty Acids; D011720:Pyrazoles; D010656:Phenylephrine; D016718:Arachidonic Acid; D003035:Cobalt; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D010105:Oxygenases; C018021:cobaltous chloride; D007213:Indomethacin