Endothelin antagonists in salt-dependent hypertension associated with renal insufficiency.
Bosentan is a nonspecific antagonist for endothelin (ET) receptors, and BQ123 is a specific inhibitor for ET-A receptors. We compared the effects of bosentan (10 mg/kg intravenously, i.v.) and BQ123 (10 mg/kg/h i.v.) on blood pressure and renal function in deoxycorticosterone acetate (DOCA)-salt rats, Dahl salt-sensitive (Dahl-S) rats, and normotensive Wistar rats. In normotensive Wistar rats, bosentan and BQ123 decreased blood pressure. Only BQ123 decreased glomerular filtration rate (GFR) and filtration fraction. These results indicate that ET-A receptors play a role in glomerular function. In DOCA-salt rats, bosentan and BQ123 caused a decrease in blood pressure to normal range and a decrease in renal vascular resistances. Bosentan decreased filtration fraction. Paradoxically, BQ123 caused a decrease in GFR. In Dahl-S rats, bosentan and BQ123 decreased blood pressure, but blood pressure did not reach normal ranges. Bosentan did not modify renal function, but BQ123 caused a decrease in the GFR and filtration fraction. Our results confirm the importance of specific and nonspecific ET antagonists in decreasing blood pressure in models of salt-dependent hypertension. However nonspecific inhibition of ET action did not improve renal function and specific inhibition of ET-A receptors by BQ123 temporarily worsened renal function.
Doucet
J
J
Unite 367 INSERM, Paris, France.
Gonzalez
W
W
Michel
J B
JB
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D003900:Desoxycorticosterone; D016232:Endothelins / Q000037:antagonists & inhibitors*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D051437:Renal Insufficiency / Q000503:physiopathology*; D012965:Sodium Chloride; D013449:Sulfonamides / Q000494:pharmacology*
D016232:Endothelins; D010456:Peptides, Cyclic; D013449:Sulfonamides; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)