Irbesartan lowers superoxide levels and increases nitric oxide bioavailability in blood vessels from spontaneously hypertensive stroke-prone rats

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Abstract
To determine the effects of the angiotensin II receptor antagonist irbesartan, the calcium-channel blocker amlodipine, and hydrochlorothiazide/hydralazine on superoxide, NAD(P)H oxidase and nitric oxide bioavailability in spontaneously hypertensive stroke-prone rats (SHRSP). Drugs or vehicle were administered for 8 weeks to SHRSP and blood pressure was measured weekly by tail-cuff plethysmography. After 8 weeks, superoxide levels in carotid arteries and aortas were measured by lucigenin chemiluminescence and p22phox expression quantified by immunohistochemistry. In vitro the effects of exposure to drugs and vehicle for 30 min and 4 h on superoxide levels and nitric oxide bioavailability were examined. The latter was expressed as the increase in contractile responses of carotid arteries to phenylephrine in the presence of the nitric oxide synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME). In vivo irbesartan, amlodipine and hydrochlorothiazide/hydralazine produced similar falls in blood pressure, from 162 ± 4 to 125 ± 5, 132 ± 4 and 131 ± 6 mmHg, respectively, but irbesartan caused a greater reduction in superoxide and p22phox; superoxide levels in carotid arteries being 3.1 ± 0.3, 1.1 ± 0.2, 1.9 ± 0.3 and 2.0 ± 0.3 nmoles/mg per min, respectively. In vitro 4 h exposure to irbesartan decreased superoxide levels in the aorta from 2.08 ± 0.68 to 1.48 ± 0.62 nmoles/mg per min and increased nitric oxide bioavailability in carotid arteries. Neither 30 min incubation with irbesartan nor 4 h with amlodipine or hydrochlorothiazide/hydralazine altered superoxide levels. These studies support the hypothesis that AT1 receptor blockade has beneficial effects on superoxide production and nitric oxide bioavailability above that of other classes of antihypertensive agents. Reduced expression of components of the NAD(P)H oxidase may contribute to these effects.