Cytochrome P450 metabolites of arachidonic acid may be important mediatorsin angiotensin II-induced vasoconstriction in the rat mesentery in vivo

We have investigated the role of cytochrome P450 (CYP-450) metabolites of a rachidonic acid in the modulation of vascular reactivity to angiotensin II in vivo using an in situ blood-perfused mesenteric preparation in anaesthet ized spontaneously hypertensive rats (SHR). Miconazole, a non-selective inh ibitor of CYP-450 that inhibits both hydroxylation and epoxidation, substan tially 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 onl y a modest suppression of vasoconstrictor responses to angiotensin II. N-Me thylsulphonyl-12, 12-dibromododec-11-enamide (DDMS), a new selective inhibi tor of CYP-450 omega-hydroxylase activity, decreased mean intra-arterial bl ood pressure and significantly attenuated mesenteric angiotensin Ii-induced vasoconstrictor responses in SHR. Isolated mesenteric vessels were able to metabolize C-14-labelled arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) in vitro, and this was substantially inhibited by DDMS. The result s from the present studies combined with the existing evidence that angiote nsin II stimulates the release of 20-HETE, a CYP-450 metabolite of arachido nic acid, suggest that CYP-450-derived HETEs may be important mediators in angiotensin It-induced vasoconstriction. However, the development of more s ensitive assays for the detection in vivo of 20-HETE in mesenteric vessels would be required to confirm these findings.