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(Hypertension. 2005;46:366.)
© 2005 American Heart Association, Inc.

Original Articles

Peroxisome Proliferator-Activated Receptor- Activation Reduces Salt-Dependent Hypertension During Chronic Endothelin B Receptor Blockade

Jan Michael Williams; Xueying Zhao; Mong H. Wang; John D. Imig; David M. Pollock

From the Department of Physiology (J.M.W., M.H.W., J.D.I., D.M.P.) and Vascular Biology Center (J.M.W., X.Z., J.D.I., D.M.P.), Medical College of Georgia, Augusta.

Correspondence to David M. Pollock, PhD, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. E-mail dpollock{at}mail.mcg.edu

Endothelin B (ET_B) receptor stimulation inhibits sodium transport in a similar fashion as 20-HETE. Clofibrate, a peroxisome proliferator-activated receptor- (PPAR-) agonist, increases protein expression of cytochrome P450 4A (CYP4A), which is responsible for 20-HETE synthesis in the kidney. Experiments were designed to determine whether clofibrate reduces hypertension associated with chronic ET_B receptor blockade. Male Sprague-Dawley rats received either normal-salt (0.8% NaCl) or high-salt (8% NaCl) diet for 10 days. Female rats were fed a high-salt (8% NaCl) diet for 10 days. During the last 7 days, rats of both sexes were divided into 3 treatment groups: (1) clofibrate in drinking water (80 mg per day), (2) ET_B receptor antagonist A-192621 in food (10 mg/kg per day), or (3) clofibrate and A-192621. During ET_B receptor blockade, clofibrate had no effect on mean arterial pressure (MAP) under normal salt conditions. In contrast, clofibrate significantly inhibited the increase in MAP produced by A-192621 in rats fed a high-salt diet (34±3 versus 19±4 mm Hg; P <0.05). Similar results were observed in female rats administered A-192621 and fed a high-salt diet. ET_B receptor blockade significantly decreased CYP4A protein expression in the renal cortex of rats on high salt. Clofibrate significantly increased renal cortical and medullary CYP4A protein expression in A-192621–treated male rats on high salt. Therefore, chronic PPAR- agonist treatment reduces salt-dependent hypertension produced by ET_B receptor blockade in male and female Sprague-Dawley rats. This suggests a possible relationship between ET_B receptor activation and the maintenance of CYP4A protein expression in the kidney of rats fed a high-salt diet.

Key Words: endothelin • blood pressure • hypertension, sodium-dependent

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