EXPERIMENTAL AND/OR GENETICALLY CONTROLLED ALTERATIONS OF THE RENAL MICROSOMAL CYTOCHROME-P450 EPOXYGENASE INDUCE HYPERTENSION IN RATS FED A HIGH-SALT DIET
EXPERIMENTAL AND/OR GENETICALLY CONTROLLED ALTERATIONS OF THE RENAL MICROSOMAL CYTOCHROME-P450 EPOXYGENASE INDUCE HYPERTENSION IN RATS FED A HIGH-SALT DIET
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DOI：
10.1172/jci117608
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发表时间：
1994-12-01
影响因子：
15.9
通讯作者：
CAPDEVILA, JH
中科院分区：
文献类型：
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作者：
MAKITA, K;TAKAHASHI, K;CAPDEVILA, JH
过量的膳食盐在大鼠肾脏中诱导细胞色素P450花生四烯酸表氧化酶同种型（Capdevila，J.H.，S. Wei，J. Yang，A. Karara，H. R.雅各布森法尔克，F. P. Guengerich和R. N.杜波依斯1992. J.Biol.Chem.267：21720-21726）。用环氧酶抑制剂克霉唑治疗高盐饮食的大鼠，平均动脉血压显著升高（盐和盐和克霉唑治疗的大鼠分别为122+/-2和145+/-4 mmHg）。盐和克霉唑依赖性高血压伴随着尿中环氧酶代谢产物排泄的减少和肾微粒体环氧酶反应的选择性抑制。克霉唑的促高血压作用在停止盐或克霉唑治疗时很容易逆转。盐诱导型肾表氧化酶可预防高血压的迹象得到了遗传性盐敏感性高血压Dahl大鼠模型研究的支持。Dahl抗性动物通过诱导其肾微粒体表氧化酶活性对过量膳食盐作出反应（对照组和盐处理组大鼠每分钟每毫克微粒体蛋白分别形成0.102+/-0.01和0.240+/-0.04 nmol产物）。尽管在过量的饮食盐摄入（200+/-20 mmHg）时会出现严重的高血压，但Dahl盐敏感大鼠的肾表氧化酶活性没有增加。这些研究表明，获得性或遗传性的肾表氧化酶活性和/或调节异常可能与啮齿类动物的盐敏感性高血压有关。对人肾表氧化酶及其与盐性高血压关系的研究可能是有用的。
Excess dietary salt induces a cytochrome P450 arachidonic acid epoxygenase isoform in rat kidneys (Capdevila, J. H., S. Wei, J. Yang, A. Karara, H. R. Jacobson, J. R. Falck, F. P. Guengerich, and R. N. Dubois. 1992. J. Biol. Chem. 267:21720-21726). Treatment of rats on a high salt diet with the epoxygenase inhibitor, clotrimazole, produces significant increases in mean arterial blood pressure (122+/-2 and 145+/-4 mmHg for salt and salt- and clotrimazole-treated rats, respectively). The salt- and clotrimazole-dependent hypertension is accompanied by reductions in the urinary excretion of epoxygenase metabolites and by a selective inhibition of the renal microsomal epoxygenase reaction. The prohypertensive effects of clotrimazole are readily reversed when either the salt or clotrimazole treatment is discontinued. The indication that a salt-inducible renal epoxygenase protects against hypertension, are supported by studies with the Dahl rat model of genetic salt-sensitive hypertension. Dahl resistant animals responded to excess dietary salt by inducing the activity of their kidney microsomal epoxygenase(s) (0.102+/-0.01 and 0.240+/-0.04 nmol of products formed/min per mg of microsomal protein for control and salt-treated rats, respectively). Despite severe hypertension during excess dietary salt intake (200+/-20 mmHg), Dahl salt-sensitive rats demonstrated no increase in renal epoxygenase activity.These studies indicate that acquired or inherited abnormalities in renal epoxygenase activities and/or regulation can be related to salt-sensitive hypertension in rodents. Studies on the human renal epoxygenase and its relationship to salt hypertension may prove useful.