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.