Peroxisome proliferator-activated receptor-α activation reduces salt-dependent hypertension during chronic endothelin B receptor blockade
Peroxisome proliferator-activated receptor-α activation reduces salt-dependent hypertension during chronic endothelin B receptor blockade
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DOI：
10.1161/01.hyp.0000172755.25382.fc
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发表时间：
2005-08-01
期刊：
影响因子：
8.3
通讯作者：
Pollock, DM
中科院分区：
文献类型：
--
作者：
Williams, JM;Zhao, XY;Pollock, DM
内皮素B （ETB）受体刺激抑制钠转运的方式与20-HETE相似。Clofibrate是一种过氧化物酶体增殖物激活受体- α (ppar - α)激动剂，可增加细胞色素P450 4A （CYP4A）的蛋白表达，CYP4A负责肾脏中20-HETE的合成。实验旨在确定氯贝特是否能降低慢性乙脑受体阻断相关的高血压。雄性Sprague - Dawley大鼠分别饲喂正常盐（0.8% NaCl）和高盐（8% NaCl）饮食10天。雌性大鼠饲喂高盐（8% NaCl）饲料10 d。最后7 d，雌雄大鼠分为3个治疗组：(1)氯贝特饮用水（80 mg/ d），(2)乙脑受体拮抗剂A-192621食物（10 mg/kg / d），(3)氯贝特和A-192621。在乙脑受体阻断期间，氯贝特对正常盐条件下的平均动脉压（MAP）没有影响。相比之下，氯贝特显著抑制高盐饮食大鼠a -192621产生的MAP增加（34 +/- 3 vs 19 +/- 4 mm Hg; P < 0.05）。在给予a -192621并饲喂高盐饮食的雌性大鼠中观察到类似的结果。ETB受体阻断显著降低高盐大鼠肾皮质CYP4A蛋白表达。氯贝特显著增加高盐A-192621处理的雄性大鼠肾皮质和髓质CYP4A蛋白表达。因此，慢性ppar - α激动剂治疗可减少雄性和雌性Sprague - Dawley大鼠由ETB受体阻断产生的盐依赖性高血压。这表明高盐饮食大鼠肾脏中ETB受体激活与CYP4A蛋白表达维持之间可能存在关系。
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.