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

This study analyzes the role of angiotensin II (Ang II), via AT 1 receptors, in the involvement of cyclooxygenase (COX)-2-derived prostanoids in phenylephrine responses in normotensive rats (Wistar Kyoto; WKY) and spontaneously hypertensive rats (SHR). 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 reverse transcription-polymerase chain reaction; prostaglandin (PG)I-2, PGF(2)alpha, 8-isoprostane, and total antioxidant status (TAS) by commercial kits; superoxide anion (O-2((.) over bar)) by lucigenin chemiluminescence; and plasmatic malondialdehyde (MDA) by thiobarbituric acid assay. The COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398) at 1 mu M reduced phenylephrine responses more in SHR than in WKY rats. COX-2 protein and mRNA expressions, PGF2 alpha, PGI(2), 8-isoprostane, and O-2((.) over bar) 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 on phenylephrine responses in SHR. Losartan also increased TAS and reduced PGF(2 alpha), PGI(2), 8-isoprostane, and O-2((.) over bar) production and MDA levels in SHR. Ang II (0.1 mu M) induced COX-2 expression in VSMC from SHR that was reduced by 30 mu M apocynin and 100 mu M allopurinol, NADPH oxidase, and xanthine oxidase inhibitors, respectively. In conclusion, AT(1) 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.