ETA receptor blockade prevents hypertension associated with exogenous endothelin-1 but not renal mass reduction in the rat.
The purpose of this study was to determine the effect of chronic ETA receptor blockade, using the orally active antagonist A-127722 in rats with reduced renal mass. The initial series of experiments was designed to characterize the effects of the ETA-selective antagonist A-127722 on arterial pressure and renal function when administered via drinking water over a 4-wk period. Male Sprague-Dawley rats were acclimated to metabolism cages, and baseline 24-h urine collections were obtained. A-127722 was placed in the drinking water at concentrations that delivered doses of 1 to 10 mg/kg per d. The compound had no effect on any of the variables measured, including arterial pressure, food and water intake, urine volume, and sodium and potassium excretion. In a separate group of rats, ETA receptor blockade was verified after 3 d of drinking water containing A-127722. Rats were anesthetized, a jugular vein catheter was inserted for infusions, and a femoral artery catheter was used for monitoring arterial pressure. The pressor response to intravenous injection of Big endothelin-1 (1 nmol/kg, intravenously) was inhibited by > 50% in rats given A-127722 at 10 mg/kg per d, which confirms the efficacy of A-127722 in blocking ETA-mediated responses when placed in drinking water. In an additional series of experiments, rats were anesthetized, the right kidney was removed, and two of three major branches of the left renal artery were ligated. After recovery, rats were returned to their cages and given A-127722 in the drinking water to deliver 1 or 10 mg/kg per d. Control rats underwent the same surgical procedures but were given tap water to drink. After 4 wk, rats that were treated with A-127722 developed similar increases in arterial pressure and urinary protein excretion as rats that received tap water. Therefore, although the ETA receptor antagonist A-127722 can inhibit ETA-mediated hypertension, it has no effect on hypertension produced by a reduction in renal mass. It is concluded that ETA receptor activation does not play a significant role in the functional derangements associated with renal mass reduction in the rat.
Pollock
D M
DM
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois, USA.
Polakowski
J S
JS
D000284:Administration, Oral; D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000008:administration & dosage*; D006977:Hypertension, Renal / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D011498:Protein Precursors / Q000008:administration & dosage*; D011507:Proteinuria / Q000209:etiology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D000077868:Atrasentan