Ignarro L J
Department of Pharmacology, University of California, School of Medicine, Los Angeles 90024.
Hypertension. 1990 Nov;16(5):477-83. doi: 10.1161/01.hyp.16.5.477.
Nitric oxide first captured the interest of biologists when this inorganic molecule was found to activate cytosolic guanylate cyclase and stimulate cyclic guanosine monophosphate (GMP) formation in mammalian cells. Further studies led to the finding that nitric oxide causes vascular smooth muscle relaxation and inhibition of platelet aggregation by mechanisms involving cyclic GMP and that several clinically used nitrovasodilators owe their biological actions to nitric oxide. Nitric oxide possesses physicochemical and pharmacological properties that make it an ideal candidate for a short-term regulator or modulator of vascular smooth muscle tone and platelet function. Nitric oxide is synthesized by various mammalian tissues including vascular endothelium, macrophages, neutrophils, hepatic Kupffer cells, adrenal tissue, cerebellum, and other tissues. Nitric oxide is synthesized from endogenous L-arginine by a nitric oxide synthase system that possesses different cofactor requirements in different cell types. The nitric oxide formed diffuses out of its cells of origin and into nearby target cells, where it binds to the heme group of cytosolic guanylate cyclase and thereby causes enzyme activation. This interaction represents a novel and widespread signal transduction mechanism that links extracellular stimuli to the biosynthesis of cyclic GMP in nearby target cells. The small molecular size and lipophilic nature of nitric oxide enable communication with nearby cells containing cytosolic guanylate cyclase. The extent of transcellular communication is limited by the short half-life of nitric oxide, thereby ensuring a localized response. Labile nitric oxide-generating molecules such as S-nitrosothiols may be involved as precursors or effectors. Further research will provide a deeper understanding of the biology of nitric oxide and the nature of associated pathophysiological states.
当发现这种无机分子能激活胞质鸟苷酸环化酶并刺激哺乳动物细胞中环状鸟苷单磷酸（GMP）的形成时，一氧化氮首次引起了生物学家的关注。进一步的研究发现，一氧化氮通过涉及环状GMP的机制导致血管平滑肌松弛和抑制血小板聚集，并且几种临床使用的硝基血管扩张剂的生物学作用归因于一氧化氮。一氧化氮具有物理化学和药理学特性，使其成为血管平滑肌张力和血小板功能的短期调节剂或调制器的理想候选者。一氧化氮由包括血管内皮、巨噬细胞、中性粒细胞、肝库普弗细胞、肾上腺组织、小脑和其他组织在内的各种哺乳动物组织合成。一氧化氮由内源性L-精氨酸通过一氧化氮合酶系统合成，该系统在不同细胞类型中具有不同的辅因子需求。形成的一氧化氮从其起源细胞扩散到附近的靶细胞中，在那里它与胞质鸟苷酸环化酶的血红素基团结合，从而导致酶激活。这种相互作用代表了一种新的、广泛存在的信号转导机制，将细胞外刺激与附近靶细胞中环状GMP的生物合成联系起来。一氧化氮的小分子尺寸和亲脂性使其能够与含有胞质鸟苷酸环化酶的附近细胞进行通讯。跨细胞通讯的程度受到一氧化氮短半衰期的限制，从而确保局部反应。不稳定的一氧化氮生成分子如S-亚硝基硫醇可能作为前体或效应物参与其中。进一步的研究将更深入地了解一氧化氮的生物学特性以及相关病理生理状态的本质。
