Oxidative stress causes renal dopamine D1 receptor dysfunction and salt-sensitive hypertension in Sprague-Dawley rats
Oxidative stress causes renal dopamine D1 receptor dysfunction and salt-sensitive hypertension in Sprague-Dawley rats
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DOI：
10.1161/hypertensionaha.107.102111
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发表时间：
2008-02-01
期刊：
影响因子：
8.3
通讯作者：
Lokhandwala, Mustafa F.
中科院分区：
文献类型：
--
作者：
Banday, Anees A.;Lau, Yuen-Sum;Lokhandwala, Mustafa F.
在钠摄入增加期间，肾脏多巴胺在维持钠稳态和血压（BP）方面起着重要作用。本研究旨在确定肾脏多巴胺D1受体（D1 R）功能障碍是否有助于氧化应激期间盐敏感性的增加。将雄性Sprague-Dawley大鼠分为不同的组，接受自来水（载体）; 1% NaCl（高盐[HS]）; L-丁硫基亚砜亚胺（BSO），一种氧化剂;和HS加BSO，有或没有Tempol，一种抗氧化剂，持续12天。与溶媒组相比，HS组尿多巴胺含量增加，基础肾Na/K-ATP酶活性降低，但对血压无影响。BSO处理的大鼠表现出氧化应激和血压轻度升高。在这些大鼠中，D1 R表达和G蛋白偶联减少，D1 R激动剂SKF 38393不能抑制Na/K-ATP酶活性和促进钠排泄。同时给予BSO和HS引起氧化应激，D1 R功能障碍，并在BP显着增加。虽然肾脏多巴胺的产生增加，但它未能降低这些动物的基础Na/K-ATP酶活性。用Tempol治疗BSO加HS大鼠降低了氧化应激，恢复了内源性和外源性D1 R激动剂介导的Na/K-ATP酶抑制和正常化BP。总之，在HS摄入过程中，通过Na/K-ATP酶抑制增加多巴胺的产生防止了BP的增加。在氧化应激期间，D1 R功能缺陷，并且存在轻度高血压。然而，在存在氧化应激的情况下，HS摄入会导致血压显着升高，这是由于肾脏D1 R功能缺陷导致多巴胺无法抑制Na/K-ATP酶并促进钠排泄。
Renal dopamine plays an important role in maintaining sodium homeostasis and blood pressure (BP) during increased sodium intake. The present study was carried out to determine whether renal dopamine D1 receptor (D1R) dysfunction contributes to increase in salt sensitivity during oxidative stress. Male Sprague-Dawley rats, divided into various groups, received tap water (vehicle); 1% NaCl (high salt [HS]); L-buthionine sulfoximine (BSO), an oxidant; and HS plus BSO with or without Tempol, an antioxidant, for 12 days. Compared with vehicle, HS intake increased urinary dopamine production and decreased basal renal Na/K-ATPase activity but did not affect BP. BSO-treated rats exhibited oxidative stress and a mild increase in BP. In these rats, D1R expression and G protein coupling were reduced, and SKF38393, a D1R agonist, failed to inhibit Na/K-ATPase activity and promote sodium excretion. Concomitant administration of BSO and HS caused oxidative stress, D1R dysfunction, and a marked increase in BP. Although renal dopamine production was increased, it failed to reduce the basal Na/K-ATPase activity in these animals. Treatment of BSO plus HS rats with Tempol decreased oxidative stress and restored endogenous, as well as exogenous, D1R agonist-mediated Na/K-ATPase inhibition and normalized BP. In conclusion, during HS intake, the increased dopamine production via Na/K-ATPase inhibition prevents an increase in BP. During oxidative stress, D1R function is defective, and there is mild hypertension. However, in the presence of oxidative stress, HS intake causes marked elevation in BP, which results from a defective renal D1R function leading to the failure of dopamine to inhibit Na/K-ATPase and promote sodium excretion.