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

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Abstract
Endothelin B (ET B ) receptor stimulation inhibits sodium transport in a similar fashion as 20-HETE. Clofibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) 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 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-α 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.