Peroxisome proliferator-activated receptor-alpha 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.
Williams
Jan Michael
JM
Department of Physiology, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500, USA.
Zhao
Xueying
X
Wang
Mong H
MH
Imig
John D
JD
Pollock
David M
DM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002994:Clofibrate / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D065131:Endothelin B Receptor Antagonists; D005260:Female; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology; D008297:Male; D047493:PPAR alpha / Q000819:agonists*; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000494:pharmacology
C120508:A 192621; D065131:Endothelin B Receptor Antagonists; D047493:PPAR alpha; D011759:Pyrrolidines; D017673:Sodium Chloride, Dietary; D012965:Sodium Chloride; D042926:Cytochrome P-450 CYP4A; D002994:Clofibrate