Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA.
Department of Chemistry, University of California, Riverside, CA, 92521, USA.
Redox Biol. 2019 Sep;26:101238. doi: 10.1016/j.redox.2019.101238. Epub 2019 Jun 4.
L-N-Nitro arginine methyl ester (L-NAME) has been widely applied for several decades in both basic and clinical research as an antagonist of nitric oxide synthase (NOS). Herein, we show that L-NAME slowly releases NO from its guanidino nitro group. Daily pretreatment of rats with L-NAME potentiated mesenteric vasodilation induced by nitrodilators such as nitroglycerin, but not by NO. Release of NO also occurred with the NOS-inactive enantiomer D-NAME, but not with L-arginine or another NOS inhibitor L-NMMA, consistent with the presence or absence of a nitro group in their structure and their nitrodilator-potentiating effects. Metabolic conversion of the nitro group to NO-related breakdown products was confirmed using isotopically-labeled L-NAME. Consistent with Fenton chemistry, transition metals and reactive oxygen species accelerated the release of NO from L-NAME. Both NO production from L-NAME and its nitrodilator-potentiating effects were augmented under inflammation. NO release by L-NAME can confound its intended NOS-inhibiting effects, possibly by contributing to a putative intracellular NO store in the vasculature.
L-N-硝基精氨酸甲酯（L-NAME）作为一氧化氮合酶（NOS）的拮抗剂，已在基础和临床研究中广泛应用了几十年。本文作者表明，L-NAME 可缓慢从其胍基硝基基团释放 NO。每天对大鼠进行 L-NAME 预处理，可增强硝化甘油等硝化剂诱导的肠系膜血管舒张，但不能增强 NO 诱导的血管舒张。非活性对映体 D-NAME 也会释放 NO，但 L-精氨酸或另一种 NOS 抑制剂 L-NMMA 则不会，这与它们结构中是否存在硝基以及硝化剂增强作用一致。使用同位素标记的 L-NAME 证实了硝基向与 NO 相关的降解产物的代谢转化。正如芬顿化学原理，过渡金属和活性氧加速了 L-NAME 释放 NO。L-NAME 产生 NO 及其增强硝化剂的作用在炎症下均增强。L-NAME 释放的 NO 可能会干扰其预期的 NOS 抑制作用，这可能是由于其在血管中形成了假定的细胞内 NO 储存库。
