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

Recently, it was reported that blood vessel immunoreactive endothelin-l (ir ET-1) content is increased in hypertensive uremic rats treated with recombi nant human erythropoietin (rhEPO). The present study was designed to evalua te whether ET-I receptor blockade can prevent the progression of hypertensi on 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 u remia, anemia, and hypertension. After a 4-wk stabilization period, the ani mals 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 we re simultaneously treated with the ETA/ETB receptor antagonist bosentan (10 0 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 wa s recorded before and at 2 and 4 wk after the onset of treatment. Serum cre atinine 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 ag gravated 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, bosent an 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 i n renal failure rats treated with rhEPO. These results suggest that the end othelin system may be involved in the pathogenesis of rhEPO-induced hyperte nsion in uremic rats with a differential role for ETA and ETB receptors.