title: Cytochrome P450 metabolites of arachidonic acid may be important mediators in angiotensin II-induced vasoconstriction in the rat mesentery in vivo.
abstract: We have investigated the role of cytochrome P450 (CYP-450) metabolites of arachidonic acid in the modulation of vascular reactivity to angiotensin II in vivo using an in situ blood-perfused mesenteric preparation in anaesthetized spontaneously hypertensive rats (SHR). Miconazole, a non-selective inhibitor of CYP-450 that inhibits both hydroxylation and epoxidation, substantially suppressed mesenteric vasoconstrictor responses to angiotensin II in SHR, but had no effect on responses to noradrenaline or sympathetic nerve stimulation. In normotensive Wistar-Kyoto (WKY) rats, miconazole caused only a modest suppression of vasoconstrictor responses to angiotensin II. N-Methylsulphonyl-12, 12-dibromododec-11-enamide (DDMS), a new selective inhibitor of CYP-450 omega-hydroxylase activity, decreased mean intra-arterial blood pressure and significantly attenuated mesenteric angiotensin II-induced vasoconstrictor responses in SHR. Isolated mesenteric vessels were able to metabolize (14)C-labelled arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) in vitro, and this was substantially inhibited by DDMS. The results from the present studies combined with the existing evidence that angiotensin II stimulates the release of 20-HETE, a CYP-450 metabolite of arachidonic acid, suggest that CYP-450-derived HETEs may be important mediators in angiotensin II-induced vasoconstriction. However, the development of more sensitive assays for the detection in vivo of 20-HETE in mesenteric vessels would be required to confirm these findings.
authors.affiliation: Department of Medicine and West Australian Heart Research Institute, The University of Western Australia, Medical Research Foundation Building, Perth 6000, Western Australia, Australia.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Chu
authors.forename: K D
authors.initials: KD
authors.lastname: Croft
authors.forename: D A
authors.initials: DA
authors.lastname: Kingsbury
authors.forename: J R
authors.initials: JR
authors.lastname: Falck
authors.forename: K M
authors.initials: KM
authors.lastname: Reddy
authors.forename: L J
authors.initials: LJ
authors.lastname: Beilin
mesh_terms: D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D019540:Area Under Curve; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008825:Miconazole / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013450:Sulfones / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000577:Amides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D013450:Sulfones; D000804:Angiotensin II; D016718:Arachidonic Acid; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; C117975:DDMS; D009638:Norepinephrine