Losartan reduces the increased participation of cyclooxygenase-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 (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)I2, PGF(2alpha), 8-isoprostane, and total antioxidant status (TAS) by commercial kits; superoxide anion (O2*-) 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 microM reduced phenylephrine responses more in SHR than in WKY rats. COX-2 protein and mRNA expressions, PGF(2alpha), 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 on phenylephrine responses in SHR. Losartan also increased TAS and reduced PGF(2alpha), PGI2, 8-isoprostane, and O2*- production and MDA levels in SHR. Ang II (0.1 microM) induced COX-2 expression in VSMC from SHR that was reduced by 30 microM apocynin and 100 microM allopurinol, 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.