Rioux F, Petitclerc E, Audet R, Drapeau G, Fielding R M, Marceau F
Centre de Recherche (Université Laval) de l'Hôtel-Dieu de Quebec, Canada.
J Cardiovasc Pharmacol. 1994 Aug;24(2):229-37.
A genetically engineered recombinant human hemoglobin (rHb1.1) was recently developed for use as a blood substitute (Nature 1992;356:258-60). Like other mammalian hemoglobin (Hb) molecules, it might bind and antagonize the actions of nitric oxide (NO). We used an isolated rabbit aortic ring preparation to examine the ability of rHb1.1 to inhibit acetylcholine (ACh)- and interleukin-1 beta (IL-1 beta)-induced reductions of vasoconstrictor responses to the alpha-adrenoceptor agonist phenylephrine (PE). rHb1.1 (0.04-4.4 microM) rapidly and reversibly inhibited, in a concentration-dependent manner, both ACh- and IL-1 beta-induced decreases in PE contractile responses. These inhibitory effects of rHb1.1 were non-competitive and were equipotent to those of purified, cell-free human Hb (p.hHb). These two forms of soluble Hb were at least 10 times more potent than Hb in erythrocytes (red blood cells: RBC-Hb). Both NG-nitro-L-arginine (10 microM) a NO synthase inhibitor, and LY-83583 (10 microM), a guanylyl cyclase inhibitor, mimicked the effects of rHb1.1. The inhibitory effects of rHb1.1 were not shared by either human serum albumin (HSA 44 microM), which combines with but does not deactivate NO, or cytochrome C (44 microM), a heme-containing protein that does not bind NO; neither were they reversed by L-arginine (L-ARG) (1 mM), the presumed NO precursor. These and other results suggest that the chemical antagonism of NO is likely to be the mechanism by which rHb1.1 and other Hbs inhibit ACh- and IL-1 beta-induced decreases in the response to PE in rabbit aortic rings.
一种基因工程重组人血红蛋白（rHb1.1）最近被开发用作血液替代品（《自然》，1992年；356:258 - 60）。与其他哺乳动物血红蛋白（Hb）分子一样，它可能会结合并拮抗一氧化氮（NO）的作用。我们使用离体兔主动脉环标本，来检测rHb1.1抑制乙酰胆碱（ACh）和白细胞介素 - 1β（IL - 1β）诱导的对α - 肾上腺素能受体激动剂去氧肾上腺素（PE）血管收缩反应降低的能力。rHb1.1（0.04 - 4.4微摩尔）以浓度依赖的方式快速且可逆地抑制ACh和IL - 1β诱导的PE收缩反应降低。rHb1.1的这些抑制作用是非竞争性的，并且与纯化的无细胞人血红蛋白（p.hHb）的抑制作用相当。这两种可溶性Hb形式的效力至少是红细胞中Hb（红细胞血红蛋白：RBC - Hb）的10倍。一氧化氮合酶抑制剂NG - 硝基 - L - 精氨酸（10微摩尔）和鸟苷酸环化酶抑制剂LY - 83583（10微摩尔）都模拟了rHb1.1的作用。人血清白蛋白（44微摩尔）与NO结合但不使其失活，以及细胞色素C（44微摩尔），一种不结合NO的含血红素蛋白质，均未表现出rHb1.1的抑制作用；L - 精氨酸（L - ARG）（1毫摩尔），推测的NO前体，也不能逆转rHb1.1的抑制作用。这些以及其他结果表明，对NO的化学拮抗作用可能是rHb1.1和其他Hb抑制兔主动脉环中ACh和IL - 1β诱导的对PE反应降低的机制。
