Role of endothelin in hypertension of experimental chronic renal failure.
Surgical ablation of renal mass leads to a reduction in kidney function and commonly to the development of hypertension and chronic renal failure (CRF) in rats. The objective of this study was to determine whether endothelin (ET)-1 is involved in the maintenance of the hypertension that accompanies loss of renal mass. First, we demonstrated the antihypertensive efficacy of PD 155080, a selective, orally active ET(A) receptor antagonist, in a group of rats made hypertensive by continuous intravenous infusion of ET-1 (2.5 pmol x kg(-1) x min[-1]) for 7 days. ET-1 produced a sustained hypertension and PD 155080 (56.4 micromol/kg [25mg/kg] BID PO) normalized blood pressure (BP) during the 5 days of drug administration. In a second experiment, Sprague-Dawley rats underwent a 5/6 reduction in renal mass (RRM); 4 weeks later, PD 155080 administered for 7 days resulted in a sustained reduction in BP. Sham-operated rats also showed a slight hypotensive response to PD 155080 administration. Plasma urea nitrogen, plasma creatinine, urinary protein excretion, and creatinine clearance were not altered by PD 155080 administration in RRM or sham rats. In a third experiment, we investigated the contribution of the renin-angiotensin system to BP control in RRM rats given PD 155080. In these rats, PD 155080 reduced BP during 5 treatment days, and this antihypertensive effect was not altered by coadministration of the angiotensin-converting enzyme inhibitor enalapril in the drinking water (508 micromol/L [250 mg/L]). These results demonstrate that (1) ET-1 plays a role in established RRM hypertension through activation of the ET(A) receptor subtype, (2) lowering blood pressure with PD 155080 in RRM rats does not adversely affect renal function, and 3) the antihypertensive effect of ET(A) receptor antagonism is not opposed by the renin-angiotensin system.
Potter
G S
GS
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824-1317, USA.
Johnson
R J
RJ
Fink
G D
GD
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D004656:Enalapril / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D006977:Hypertension, Renal / Q000209:etiology / Q000503:physiopathology*; D007262:Infusions, Intravenous; D007676:Kidney Failure, Chronic / Q000150:complications / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D012084:Renin-Angiotensin System
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; C093322:PD 155080; D044022:Receptor, Endothelin A; D004656:Enalapril