Differential effects of endothelin-1 antagonists on erythropoietin-induced hypertension in renal failure.
Recently, it was reported that blood vessel immunoreactive 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 LU 135252 (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.
Brochu
E
E
Research Centre and Division of Nephrology, CHUQ, L'Hôtel-Dieu de Québec Hospital and Laval University, Canada.
Lacasse
S
S
Larivière
R
R
Kingma
I
I
Grose
J H
JH
Lebel
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D003404:Creatinine / Q000097:blood; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000097:blood; D004921:Erythropoietin / Q000633:toxicity; D006400:Hematocrit; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011994:Recombinant Proteins; D013449:Sulfonamides / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011994:Recombinant Proteins; D013449:Sulfonamides; D004921:Erythropoietin; C107831:darusentan; D003404:Creatinine; D000077300:Bosentan