Differential Effects of Endothelin-1 Antagonists on Erythropoietin-Induced Hypertension in Renal Failure

. Recently, it was reported that blood vessel immuno-reactive endothelin-1 (irET-1) content is increased in hypertensive uremic rats treated with recombinant human erythropoietin (rhEPO). The present study was designed to evaluate whether ET-1 receptor blockade can prevent the progression of hypertension in renal failure rats receiving rhEPO and, if so, whether selective ET A and nonselective ET A /ET B 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 ET A /ET B receptor antagonist bosentan (100 mg/kg per d). In protocol B, half of the rats in each group received the selective ET A 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 ET A but not ET A /ET B 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 ET A and ET B receptors.