Effect of antioxidant therapy on blood pressure and NO synthase expressionin hypertensive rats

Earlier studies have demonstrated evidence for increased reactive oxygen sp ecies, enhanced NO synthase (NOS) expression, and elevated NO production in spontaneously hypertensive rats (SHR). Given the negative-feedback regulat ion of NOS by NO, we hypothesized that enhanced NO inactivation by ROS may contribute to compensatory upregulation of NOS in SHR. The present study wa s designed to test this hypothesis. Eight-week-old male SHR and Wistar-Kyot o rats were treated for 3 weeks with either a placebo or the potent antioxi dant, lazaroid (desmethyltirilazad, 10 mg.kg(-1).d(-1), by gastric gavage). Tail arterial blood pressure, urinary excretion of NO metabolites (ie, nit rate and nitrite), and immunodetectable NOS isotype proteins in the vascula r, renal, cardiac, and cerebral tissues were measured. The placebo-treated SHR group showed a marked elevation of blood pressure and a significant upr egulation of aorta, kidney, and cardiac tissue endothelial and inducible NO S (eNOS and iNOS, respectively) proteins and of brain and renal tissue neur onal NOS. Lazaroid therapy ameliorated hypertension and mitigated the upreg ulation of eNOS and iNOS in vascular, renal, and cardiac tissues but had li mited effect on the expression of renal and brain neuronal NOS. In. contras t, lazaroid therapy had no effect on blood pressure, urinary nitrate and ni trite excretion, or tissue NOS isotype expressions in the Wistar-Kyoto grou p. These findings support the role of oxidative stress in the genesis and/o r maintenance of hypertension and compensatory upregulation of the expressi on of eNOS and iNOS in SHR.