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CARDIOVASCULAR

Losartan Reduces the Increased Participation of Cyclooxygenase-2-Derived Products in Vascular Responses of Hypertensive Rats

Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (Y.A., R.H., A.M.B., A.G.-R., A.B., M.J.A., M.S.); and Departamento de Ciencias de la Salud III, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (J.V.P.-G., R.H., M.J.A.)

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, PGF₂, 8-isoprostane, and total antioxidant status (TAS) by commercial kits; superoxide anion () 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 µM reduced phenylephrine responses more in SHR than in WKY rats. COX-2 protein and mRNA expressions, PGF₂, PGI₂, 8-isoprostane, and 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 PGF₂, PGI₂, 8-isoprostane, and production and MDA levels in SHR. Ang II (0.1 µM) induced COX-2 expression in VSMC from SHR that was reduced by 30 µM apocynin and 100 µM 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.

Address correspondence to: Dr. Mercedes Salaices, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid; 28029 Madrid, Spain. E-mail: mercedes.salaices{at}uam.es

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