Reiter Christopher D, Wang Xunde, Tanus-Santos Jose E, Hogg Neil, Cannon Richard O, Schechter Alan N, Gladwin Mark T
Critical Care Medicine Department of the Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Nat Med. 2002 Dec;8(12):1383-9. doi: 10.1038/nm1202-799. Epub 2002 Nov 11.
Although the deleterious vasoconstrictive effects of cell-free, hemoglobin-based blood substitutes have been appreciated, the systemic effects of chronic hemolysis on nitric oxide bioavailability have not been considered or quantified. Central to this investigation is the understanding that nitric oxide reacts at least 1,000 times more rapidly with free hemoglobin solutions than with erythrocytes. We hypothesized that decompartmentalization of hemoglobin into plasma would divert nitric oxide from homeostatic vascular function. We demonstrate here that plasma from patients with sickle-cell disease contains cell-free ferrous hemoglobin, which stoichiometrically consumes micromolar quantities of nitric oxide and abrogates forearm blood flow responses to nitric oxide donor infusions. Therapies that inactivate plasma hemoglobin by oxidation or nitric oxide ligation restore nitric oxide bioavailability. Decompartmentalization of hemoglobin and subsequent dioxygenation of nitric oxide may explain the vascular complications shared by acute and chronic hemolytic disorders.
尽管无细胞的、基于血红蛋白的血液替代品具有有害的血管收缩作用已为人所知，但慢性溶血对一氧化氮生物利用度的全身影响尚未得到考虑或量化。这项研究的核心是要明白，一氧化氮与游离血红蛋白溶液的反应速度比与红细胞的反应速度至少快1000倍。我们假设血红蛋白在血浆中的分隔解除会使一氧化氮从稳态血管功能中转移。我们在此证明，镰状细胞病患者的血浆中含有无细胞的亚铁血红蛋白，它按化学计量消耗微摩尔量的一氧化氮，并消除前臂对一氧化氮供体输注的血流反应。通过氧化或一氧化氮连接使血浆血红蛋白失活的疗法可恢复一氧化氮的生物利用度。血红蛋白的分隔解除以及随后一氧化氮的双加氧作用可能解释了急性和慢性溶血性疾病共有的血管并发症。
