Differential effects of endothelin-1 antagonists on erythropoietin-induced hypertension in renal failure

Recently, it was reported that blood vessel immunoreactive endothelin-l (irET-1) content is increased in hypertensive uremic rats treated with recombinant human erythropoietin (rhEPO). The present study was designed to evaluate whether ET-I receptor blockade can prevent the progression of hypertension in renal failure rats receiving rhEPO and, if so, whether selective ETA and nonselective ETA/ETB receptor antagonists are equally effective. Renal failure was induced by a two-stage 5/6 nephrectomy; the animals developed uremia, anemia, and hypertension. After a 4-wk stabilization period, the animals received either rhEPO (100 U/kg, subcutaneously, three times per week) or the vehicle for 4, wk. In protocol A, half of the rats in each group were simultaneously treated with the ETA/ETB receptor antagonist bosentan (100 mg/kg per d). In protocol B, half of the rats in each group received the selective ETA receptor antagonist LU135252 (50 mg/kg per d). Systolic BP was recorded before and at 2 and 4 wk after the onset of treatment. Serum creatinine levels and hematocrit were measured before treatment and at the end of the study. Creatinine clearance rates and plasma irET-1 concentrations were determined at the end of the study, rhEPO corrected the anemia, but aggravated the hypertension. There was a slight and similar increase in serum creatinine throughout the treatment period in all groups of rats. Both ET-1 receptor antagonists bosentan and LU135252 were effective in attenuating the progression of hypertension in uremic rats receiving the vehicle (P < 0.05). Treatment with LU135252 corrected the increase in BP in rhEPO-treated rats (160 +/- 7 mmHg versus 187 +/- 9 mmHg, P < 0.05). In contrast, bosentan did not attenuate the progression of hypertension in rhEPO-treated rats (172 +/- 10 mmHg versus 168 +/- 9 mmHg, NS). In summary, selective ETA but not ETA/ETB receptor blockade can prevent the aggravation of hypertension in renal failure rats treated with rhEPO. These results suggest that the endothelin system may be involved in the pathogenesis of rhEPO-induced hypertension in uremic rats with a differential role for ETA and ETB receptors.