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 ω-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 14C-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.
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February 09 2000
Cytochrome P450 metabolites of arachidonic acid may be important mediators in angiotensin II-induced vasoconstriction in the rat mesentery in vivo
Z. M. CHU;
Z. M. CHU
*Department of Medicine and West Australian Heart Research Institute, The University of Western Australia, Medical Research Foundation Building, Rear 50 Murray Street, Perth 6000, Western Australia, Australia
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K. D. CROFT;
*Department of Medicine and West Australian Heart Research Institute, The University of Western Australia, Medical Research Foundation Building, Rear 50 Murray Street, Perth 6000, Western Australia, Australia
Correspondence: Associate Professor Kevin D. Croft (e-mail [email protected]).
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D. A. KINGSBURY;
D. A. KINGSBURY
*Department of Medicine and West Australian Heart Research Institute, The University of Western Australia, Medical Research Foundation Building, Rear 50 Murray Street, Perth 6000, Western Australia, Australia
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J. R. FALCK;
J. R. FALCK
†Biochemistry Department, University of Texas Southwestern Medical Center, Dallas, TX 75235-9038, U.S.A.
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K. M. REDDY;
K. M. REDDY
†Biochemistry Department, University of Texas Southwestern Medical Center, Dallas, TX 75235-9038, U.S.A.
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L. J. BEILIN
L. J. BEILIN
*Department of Medicine and West Australian Heart Research Institute, The University of Western Australia, Medical Research Foundation Building, Rear 50 Murray Street, Perth 6000, Western Australia, Australia
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Publisher: Portland Press Ltd
Received:
June 30 1999
Revision Received:
September 22 1999
Accepted:
December 09 1999
Online ISSN: 1470-8736
Print ISSN: 0143-5221
The Biochemical Society and the Medical Research Society © 2000
2000
Clin Sci (Lond) (2000) 98 (3): 277–282.
Article history
Received:
June 30 1999
Revision Received:
September 22 1999
Accepted:
December 09 1999
Citation
Z. M. CHU, K. D. CROFT, D. A. KINGSBURY, J. R. FALCK, K. M. REDDY, L. J. BEILIN; Cytochrome P450 metabolites of arachidonic acid may be important mediators in angiotensin II-induced vasoconstriction in the rat mesentery in vivo. Clin Sci (Lond) 1 March 2000; 98 (3): 277–282. doi: https://doi.org/10.1042/cs0980277
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