Received for publication October 10, 2006.
Revised January 17, 2007.
Accepted for publication January 19, 2007.

Losartan reduces the increased participation of COX-2 derived products in vascular responses of hypertensive rats

Abstract

This study analyzes the role of angiotensin II (Ang II), via AT₁ receptors, in the involvement of cyclooxygenase-2 (COX-2)-derived prostanoids in phenylephrine responses in normotensive (WKY) and spontaneously hypertensive (SHR) rats. Aorta from rats untreated or treated for 12 weeks with losartan (15 mg/kg·day) or hydralazine plus hydrochlorothiazide (44 and 9.4 mg/kg·day, respectively) and vascular smooth muscle cells (VSMC) from SHR were used. Vascular reactivity was analyzed by isometric recording, COX-2 expression by Western blot and RT-PCR, PGI₂, PGF₂, 8-isoprostane and total antioxidant status (TAS) by commercial kits, superoxide anion (O₂^.-) using lucigenin chemiluminiscence and plasmatic malondialdehyde (MDA) by thiobarbituric acid assay. The COX-2 inhibitor NS 398 (1 µM) reduced phenylephrine responses more in SHR than in WKY. COX-2 protein and mRNA expressions, PGF₂, PGI₂, 8-isoprostane and O₂^.- production and MDA levels were higher in SHR but TAS was similar in both strains. Losartan, but not hydralazine-hydrochlorothiazide treatment, reduced COX-2 expression and the effect of NS 398 in SHR. Losartan also increased TAS and reduced PGF₂, PGI₂, 8-isoprostane and O₂^.- production and MDA levels in SHR. Ang II (0.1 µM) induced COX-2 expression in VSMC from SHR, that was reduced by apocynin (30 µM) and allopurinol (100 µM), NADPH oxidase and xanthine oxidase inhibitors, respectively. In conclusion, AT₁ receptor activation by Ang II could be involved in the increased participation of COX-2-derived contractile prostanoids in vasoconstriction to phenylephrine with hypertension, probably through COX-2 expression regulation. The increased oxidative stress seems to be one of the mechanisms involved.

Key words: Hypertension, angiotensin II, aorta, contractile prostanoids, cyclooxygenase-2, oxidative stress

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