Peroxisome proliferator-activated receptor-α activation reduces salt-dependent hypertension during chronic endothelin B receptor blockade

Endothelin B (ETB) receptor stimulation inhibits sodium transport in a similar fashion as 20-HETE. Clofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) 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 ETB 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) ETB receptor antagonist A-192621 in food (10 mg/kg per day), or ( 3) clofibrate and A-192621. During ETB 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. ETB 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-alpha agonist treatment reduces salt-dependent hypertension produced by ETB receptor blockade in male and female Sprague - Dawley rats. This suggests a possible relationship between ETB receptor activation and the maintenance of CYP4A protein expression in the kidney of rats fed a high-salt diet.