Dexamethasone worsens nitric oxide inhibition-induced hypertension and renal dysfunction

Abstract

Chronic nitric oxide (NO) inhibition with N ω-nitro- L-arginine methyl ester (L-NAME) has previously been reported to produce systemic hypertension, renal vasoconstriction, and renal damage. In this study we investigated whether a compensatory restoration of NO synthesis occurs in chronic L-NAME hypertension and whether chronic treatment with dexamethasone (Dex) (which inhibits inducible NO synthase [iNOS]) can influence the course of the hypertension. We found that in the conscious chronically L-NAME-treated (≈10 mg/kg/24 h) hypertensive rats, acute systemic NOS inhibition elicited a further increase in blood pressure (BP), indicating partial restoration of NO production. Chronic Dex in a dose previously reported to inhibit iNOS (5 μg/24 h), amplified the hypertension (within 2 days), renal vasoconstriction, and reduction in glomerular filtration rate because of L-NAME. In contrast, chronic Dex alone had no effects on renal hemodynamics or BP during the first week, although by the end of week 2 a small increase in BP (≈10 mm Hg) was evident. These results show that BP continues to increase with chronic L-NAME despite partial restoration of NO production. An iNOS, which might be stimulated and escaped inhibition by L-NAME, may be responsible for the compensatory restoration of NO synthesis, serving to attenuate the development of hypertension and renal dysfunction.