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

Abstract
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.
AuthorsJan Michael Williams, Xueying Zhao, Mong H Wang, John D Imig, David M Pollock
JournalHypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 46 Issue 2 Pg. 366-71 (Aug 2005) ISSN: 1524-4563 [Electronic] United States
PMID15967866 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • A 192621
  • Endothelin B Receptor Antagonists
  • PPAR alpha
  • Pyrrolidines
  • Sodium Chloride, Dietary
  • Sodium Chloride
  • Cytochrome P-450 CYP4A
  • Clofibrate
Topics
  • Animals
  • Blood Pressure (drug effects)
  • Clofibrate (pharmacology)
  • Cytochrome P-450 CYP4A (antagonists & inhibitors)
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Endothelin B Receptor Antagonists
  • Female
  • Hypertension (chemically induced, metabolism, physiopathology)
  • Kidney Cortex (drug effects, enzymology)
  • Male
  • PPAR alpha (agonists)
  • Pyrrolidines (administration & dosage, pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Chloride
  • Sodium Chloride, Dietary (administration & dosage, pharmacology)

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