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心血管治疗靶点在 NO-sGC-cGMP 信号通路:批判性概述。

Cardiovascular therapeutics targets on the NO-sGC-cGMP signaling pathway: a critical overview.

机构信息

Laboratory of Endothelial Function, Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Avenida Bandeirantes, 3900, 14048- São Paulo 900, Ribeirão Preto/São Paulo, Brazil.

出版信息

Curr Drug Targets. 2012 Aug;13(9):1207-14. doi: 10.2174/138945012802002348.

Abstract

In a brief overview, in NO-sGC-cGMP signaling in a blood vessel, l-arginine is converted in the endothelium monolayer by the endothelial nitric oxide synthase (eNOS) to NO which diffuses into both the vessel lumen and the vessel wall, thereby activating soluble guanylate cyclase (sGC). Heme-dependent sGC stimulators and hem-independent sGC activators increase the cellular cGMP concentration via the direct activation of sGC, which results in both vasorelaxation and inhibition of platelet aggregation. Studies of the 90's definitively established the role of endothelium in all cardiovascular diseases, which were associated with endothelial dysfunction by impaired release of endothelium-derived relaxing factors with consequent risk of spasm and thrombosis. The rationale of this review is based on the fact that the discovery of NO changed the concepts of cardiovascular disease mechanisms. However, considering the jargon "from the bench to clinical practice" we concluded that a potential therapeutic revolution did not follow the pathophysiological revolution. The review is focused on general aspects without regard for advanced research aspects, and designed in two main groups: the NO/cGMP positive stimulators and blockers as "future and encouraging" new therapeutic drugs. The potential vasodilators include 1) NOS uncoupling; 2) NOS enhancers (AVE compounds); 3) NO donors (nitrovasodilators); 4) NO-independent activators (BAY compounds), and; 5) PDE5 inhibitors. The potential vasoconstrictors include 1) NOS-blockers (L-NAME, L-NMMA); 2) sGC-blockers (methylene blue), and; 3) PDEs. Few texts, selected by excellence and relevance, were crucial and considerably facilitated the elaboration of this text, in addition to our own experimental and clinical experience working on vasoplegic endothelium dysfunction.

摘要

简要概述,在血管中的 NO-sGC-cGMP 信号转导中,l-精氨酸在血管内皮细胞单层中被内皮型一氧化氮合酶(eNOS)转化为 NO,NO 扩散到血管腔和血管壁中,从而激活可溶性鸟苷酸环化酶(sGC)。血红素依赖性 sGC 刺激剂和血红素非依赖性 sGC 激活剂通过直接激活 sGC 增加细胞内 cGMP 浓度,从而导致血管舒张和血小板聚集抑制。90 年代的研究明确确立了内皮在所有心血管疾病中的作用,这些疾病与内皮功能障碍有关,内皮功能障碍导致内皮衍生舒张因子释放受损,从而增加痉挛和血栓形成的风险。本综述的基本原理基于这样一个事实,即 NO 的发现改变了心血管疾病机制的概念。然而,考虑到“从实验室到临床实践”的行话,我们得出结论,潜在的治疗革命并没有跟随病理生理学革命。综述侧重于一般方面,而不考虑高级研究方面,并分为两个主要组:NO/cGMP 正刺激剂和阻滞剂作为“未来和令人鼓舞”的新治疗药物。潜在的血管扩张剂包括 1)NOS 解偶联;2)NOS 增强剂(AVE 化合物);3)NO 供体(硝基血管扩张剂);4)NO 非依赖性激活剂(BAY 化合物);5)PDE5 抑制剂。潜在的血管收缩剂包括 1)NOS 阻滞剂(L-NAME、L-NMMA);2)sGC 阻滞剂(亚甲蓝);3)PDEs。少数精选的优秀和相关文本对本文的撰写至关重要,并极大地提供了便利,此外,我们还根据自己在血管扩张性内皮功能障碍方面的实验和临床经验进行了阐述。

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