The nitric oxide pathway plays a critical role in vascular homeostasis. Increased levels of systemic nitric oxide (NO) are observed in preclinical models of sepsis and endotoxemia. This has led to the postulation that vasodilation by inducible nitric oxide synthase (iNOS) generated NO may be a mechanism of hypotension in sepsis. However, contrary to the expected pharmacological action of a nitric oxide synthase (NOS) inhibitor, clinical studies with L-NAME produced adverse cardiac and pulmonary events, and higher mortality in sepsis patients. Thus, the potential adverse effects of NO in human sepsis and shock have not been fully established. In recent years, the emerging new understanding of the NO pathway has shown that an endogenously produced inhibitor of NOS, asymmetric dimethylarginine (ADMA), a host response to infection, may play an important role in the pathophysiology of sepsis as well as organ damage during ischemia–reperfusion. ADMA induces microvascular dysfunction, proinflammatory and prothrombotic state in endothelium, release of inflammatory cytokines, oxidative stress and mitochondrial dysfunction. High levels of ADMA exist in sepsis patients, which may produce adverse effects like those observed with L-NAME. Several studies have demonstrated the association of plasma ADMA levels with mortality in sepsis patients. Preclinical studies in sepsis and ischemia–reperfusion animal models have shown that lowering of ADMA reduced organ damage and improved survival. The clinical finding with L-NAME and the preclinical research on ADMA “bed to bench” suggest that ADMA lowering could be a potential therapeutic approach to attenuate progressive organ damage and mortality in sepsis. Testing of this approach is now feasible by using the pharmacological molecules that specifically lower ADMA.

中文翻译：

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脓毒症中 NO 通路和降低 ADMA 作为潜在治疗方法的新观点

一氧化氮途径在血管稳态中起关键作用。在脓毒症和内毒素血症的临床前模型中观察到全身一氧化氮 (NO) 水平升高。这导致了这样一种假设，即诱导型一氧化氮合酶 (iNOS) 产生的 NO 引起的血管舒张可能是败血症中低血压的一种机制。然而，与一氧化氮合酶 (NOS) 抑制剂的预期药理作用相反，L-NAME 的临床研究在脓毒症患者中产生了不良的心脏和肺部事件以及更高的死亡率。因此，NO 在人类败血症和休克中的潜在不利影响尚未完全确定。近年来，对 NO 途径的新认识表明，内源性 NOS 抑制剂不对称二甲基精氨酸 (ADMA) 是宿主对感染的反应，可能在脓毒症的病理生理学以及缺血再灌注过程中的器官损伤中起重要作用。ADMA 诱导内皮的微血管功能障碍、促炎和促血栓状态、炎性细胞因子的释放、氧化应激和线粒体功能障碍。脓毒症患者中存在高水平的 ADMA，这可能会产生与 L-NAME 观察到的不良反应。几项研究表明，血浆 ADMA 水平与脓毒症患者的死亡率有关。脓毒症和缺血再灌注动物模型的临床前研究表明，降低 ADMA 可减少器官损伤并提高存活率。L-NAME 的临床发现和 ADMA“床对板凳”的临床前研究表明，降低 ADMA 可能是减轻脓毒症进行性器官损伤和死亡率的潜在治疗方法。现在可以通过使用专门降低 ADMA 的药理学分子来测试这种方法。