Chronic nitric oxide inhibition aggravates hypertension in erythropoietin-treated renal failure rats

Alterations in nitric oxide (NO) and endothelin-1 (ET-1) production have re cently been reported in erythropoietin (r-HuEPO)-induced hypertension in re nal failure rats. The present study was designed to evaluate the effect of NO synthase inhibition with the L-arginine analog N-G-nitro-L-arginine meth yl ester (L-NAME) on blood pressure (BP) and ET-1 production in control and in uremic rats treated or not treated with r-HuEPO. Renal failure was indu ced by a two-stage 5/6 nephrectomy. Control and uremic rats were studied se parately and subdivided into four groups: vehicle, r-HuEPO, L-NAME + vehicl e and L-NAME + r-HuEPO. L-NAME (100 mg/kg/day), r-HuEPO (100 U/kg, subcutan eously, three times per week), the vehicle or both were administered during 4 weeks in control rats and during 2 weeks in uremic rats. Systolic BP was recorded before and after the onset of treatment at weeks 2 and 4 in contr ol rats and at weeks 1 and 2 in uremic rats. Hematocrit, serum creatinine, plasma, blood vessel (thoracic aorta and mesenteric artery bed) and renal c ortex immunoreactive (ir) ET-1 concentrations were measured at the end of t he protocol. L-NAME enhanced BP in control and uremic rats and the increase was significantly higher in uremic rats under r-HuEPO therapy (222 +/-7 mm Hg vs 198 +/- 6 mmHg, p<0.05). L-NAME induced an increase in thoracic aorta ir-ET-1 concentrations in control and uremic rats. In contrast, ir-ET-1 co ncentrations were unchanged in the mesenteric arterial bed and the renal co rtex of control and uremic animals. R-HuEPO increased thoracic aorta ir-ET- 1 contents in L-NAME treated control and uremic rats. These results underli ne the important role of NO release in opposing the action of vasopressors on blood vessel tone which appears more important in uremic rats treated wi th r-HuEPO. L-NAME treatment increased large vessel, but not small resistan ce artery ir-ET-1 concentrations, suggesting differential regulation of ET- 1 production in different vascular beds under chronic NO synthase inhibitio n.