Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension:: Mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and glomerulosclerosis
Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension:: Mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and glomerulosclerosis
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DOI：
10.1681/asn.v115835
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发表时间：
2000-05-01
影响因子：
13.6
通讯作者：
Lüscher, TF
中科院分区：
文献类型：
--
作者：
Barton, M;Vos, I;Lüscher, TF
本研究调查了肾一氧化氮合酶（NOS）、内皮素的作用以及盐敏感性高血压中肾血管功能障碍的可能机制。盐敏感 (DS) 和盐抗性 (DR) Dahl 大鼠单独接受高盐饮食 (4% NaCl) 或联合 ETA 受体拮抗剂 LU135252（每天 60 mg/kg）治疗 8 周。盐负荷显着增加了 DR 大鼠肾皮质和髓质的 NOS 活性（pmol 瓜氨酸/mg 蛋白质每分钟），分别增加了 270% 和 246%，而 DS 大鼠则没有。 DS 大鼠的高血压与肾动脉肥大、血管和肾内皮素-1 (ET-1) 蛋白含量增加以及肾小球硬化有关。在高血压 DS 大鼠的肾动脉中，但在主动脉中，内皮依赖性乙酰胆碱舒张作用没有改变；然而，由于前列腺素介导的内皮依赖性收缩增强和基础一氧化氮释放减弱而导致内皮功能障碍。用LU135252治疗部分降低了高血压，但完全阻止了组织ET-1的激活而不影响ET-3水平。这与肾 NOS 活性的轻微增加、内皮功能障碍和肾动脉肥大的正常化以及肾小球硬化的显着减弱有关。因此，DS 大鼠无法响应盐负荷而增加 NOS 活性。这种异常可能导致组织 ET-1 系统激活、肾血管收缩异常和肾损伤。慢性 ETA 受体阻断可使盐引起的肾动脉变化正常化，并减少肾小球损伤，这表明 ET 拮抗剂在盐敏感型高血压中具有治疗潜力。
This study investigated the role of renal nitric oxide synthase (NOS), endothelin, and possible mechanisms of renovascular dysfunction in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated for 8 wk with high salt diet (4% NaCl) alone or in combination with the ETA receptor antagonist LU135252 (60 mg/kg per d). Salt loading markedly increased NOS activity (pmol citrulline/mg protein per min) in renal cortex and medulla in DR but not in DS rats by 270 and 246%, respectively. Hypertension in DS rats was associated with renal artery hypertrophy, increased vascular and renal endothelin-1 (ET-1) protein content, and glomerulosclerosis. in the renal artery but not in the aorta of hypertensive DS rats, endothelium-dependent relaxation to acetylcholine was unchanged; however, endothelial dysfunction due to enhanced prostanoid-mediated, endothelium-dependent contractions and attenuation of basal nitric oxide release was present. Treatment with LU135252 reduced hypertension in part, but completely prevented activation of tissue ET-I without affecting ET-3 levels. This was associated with a slight increase of renal NOS activity, normalization of endothelial dysfunction and renal artery hypertrophy, and marked attenuation of glomerulosclerosis. Thus, DS rats fail to increase NOS activity in response to salt loading. This abnormality may predispose to activation of the tissue ET-1 system, abnormal renal vasoconstriction, and renal injury. Chronic ETA receptor blockade normalized salt-induced changes in the renal artery and reduced glomerular injury, suggesting therapeutic potential for ET antagonists in salt-sensitive forms of hypertension.