Liu Taiming, Zhang Meijuan, Li Qian, Schroeder Hobe, Power Gordon G, Blood Arlin B
Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Redox Biol. 2025 Mar;80:103513. doi: 10.1016/j.redox.2025.103513. Epub 2025 Jan 24.
Repeated use of nitroglycerin results in a loss of its vasodilatory efficacy which limits its clinical use for the treatment of angina pectoris. This tolerance phenomenon is a defining characteristic of all compounds classified as nitrodilators, which includes NTG as well as S-nitrosothiols and dinitrosyl iron complexes. These compounds vasodilate via activation of soluble guanylate cyclase, although they do not release requisite amounts of free nitric oxide (NO) and some do not even cross the plasma membrane. Here we demonstrate that nitrodilators cause vasodilation via mobilization of NO moiety from a nitrodilator-activated NO store (NANOS) pre-formed in the vascular smooth muscle cell, similar to the mechanism by which UV light is also known to cause vasodilation and tolerance. Intraperitoneal nitrite prevented NTG tolerance in coronary arteries of rats that received NTG transdermal patches for 4 days, and potentiated NTG- and GSNO- mediated mesenteric vasodilation in intact rats. Consistent with the incorporation of nitrite into the depletable NANOS, incubation of arteries with N-nitrite resulted in the accumulation of high molecular weight N-NO-containing compounds in arteries, and subsequent exposure to NTG, GSNO, or UV light resulted in efflux of N-NO species. In addition, HO and metal/metalloproteins synergistically facilitated NO release from nitrite, while the oxidative stress associated with inflammation and nitrite synergistically potentiated the nitrodilator-mediated vasodilation. In conclusion, NTG mediates vasodilation via activation of a depletable intracellular store of NO that can be replenished by nitrite, thereby preventing tolerance.
反复使用硝酸甘油会导致其血管舒张功效丧失，这限制了其在治疗心绞痛方面的临床应用。这种耐受性现象是所有被归类为硝基扩张剂的化合物的一个决定性特征，其中包括硝酸甘油以及S-亚硝基硫醇和二亚硝基铁配合物。这些化合物通过激活可溶性鸟苷酸环化酶来实现血管舒张，尽管它们不会释放出所需量的游离一氧化氮（NO），而且有些甚至无法穿过质膜。在这里，我们证明硝基扩张剂通过从血管平滑肌细胞中预先形成的硝基扩张剂激活的NO储存库（NANOS）中动员NO部分来引起血管舒张，这类似于紫外线引起血管舒张和耐受性的机制。腹腔注射亚硝酸盐可预防接受硝酸甘油透皮贴剂4天的大鼠冠状动脉中的硝酸甘油耐受性，并增强完整大鼠中硝酸甘油和GSNO介导的肠系膜血管舒张。与亚硝酸盐掺入可消耗的NANOS一致，用N-亚硝酸盐孵育动脉会导致动脉中高分子量含N-NO化合物的积累，随后暴露于硝酸甘油、GSNO或紫外线会导致N-NO物质外流。此外，HO和金属/金属蛋白协同促进亚硝酸盐释放NO，而与炎症相关的氧化应激和亚硝酸盐协同增强硝基扩张剂介导的血管舒张。总之，硝酸甘油通过激活可消耗的细胞内NO储存库来介导血管舒张，该储存库可被亚硝酸盐补充，从而防止耐受性。
