Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China.
Department of Clinical Pharmacy, Institute of Clinical Pharmacy, the 2nd Affiliated Hospital, Harbin Medical University, Harbin, China.
Br J Pharmacol. 2018 Apr;175(8):1305-1317. doi: 10.1111/bph.13817. Epub 2017 May 10.
Our recent studies show that the reduced activity of epithelial sodium channels (ENaC) in endothelial cells accounts for the adaptation of vasculature to salt in Sprague-Dawley rats. The present study examines a hypothesis that enhanced ENaC activity mediates the loss of vasorelaxation in Dahl salt-sensitive (SS) rats.
We used the cell-attached patch-clamp technique to record ENaC activity in split-open mesenteric arteries. Western blot and immunofluorescence staining were used to evaluate the levels of aldosterone, ENaC, eNOS and NO. Blood pressure was measured with the tail-cuff method and the artery relaxation was measured with the wire myograph assay.
High-salt (HS) diet significantly increased plasma aldosterone and ENaC activity in the endothelial cells of Dahl SS rats. The endothelium-dependent artery relaxation was blunted by HS challenge in these rats. Amiloride, a potent blocker of ENaC, increased both phosphorylated eNOS and NO and therefore prevented the HS-induced loss of vasorelaxation. As, in SS rats, endogenous aldosterone was already elevated by HS challenge, exogenous aldosterone did not further elevate ENaC activity in the rats fed with HS. Eplerenone, a mineralocorticoid receptor antagonist, attenuated the effects of HS on both ENaC activity and artery relaxation.
These data suggest that HS diet blunts artery relaxation and causes hypertension via a pathway associated with aldosterone-dependent activation of ENaC in endothelial cells. This pathway provides one of the mechanisms by which HS causes hypertension in Dahl SS rats.
This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
我们最近的研究表明，内皮细胞中上皮钠通道（ENaC）活性的降低是 Sprague-Dawley 大鼠血管适应盐的原因。本研究提出了一个假设，即增强 ENaC 活性介导了 Dahl 盐敏感（SS）大鼠血管舒张功能的丧失。
我们使用分离的肠系膜动脉细胞贴附式膜片钳技术记录 ENaC 活性。Western blot 和免疫荧光染色用于评估醛固酮、ENaC、eNOS 和 NO 的水平。血压通过尾套法测量，动脉舒张通过线描肌描记法测量。
高盐（HS）饮食显著增加了 Dahl SS 大鼠内皮细胞中的血浆醛固酮和 ENaC 活性。HS 挑战使这些大鼠的内皮依赖性动脉舒张功能受损。ENaC 的强效阻滞剂氨氯地平增加了磷酸化 eNOS 和 NO 的水平，从而防止了 HS 引起的血管舒张功能丧失。由于 SS 大鼠的内源性醛固酮在 HS 挑战时已经升高，HS 饮食并没有进一步增加 HS 喂养大鼠的 ENaC 活性。盐皮质激素受体拮抗剂依普利酮减弱了 HS 对 ENaC 活性和动脉舒张的影响。
这些数据表明，HS 饮食通过与内皮细胞中醛固酮依赖性 ENaC 激活相关的途径使动脉舒张功能减弱并导致高血压。该途径为 HS 引起 Dahl SS 大鼠高血压的机制之一。
本文是心血管疾病小分子聚焦专题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
