Feelisch M, te Poel M, Zamora R, Deussen A, Moncada S
Department of Pharmacology, Schwarz Pharma AG, Monheim, Germany.
Nature. 1994 Mar 3;368(6466):62-5. doi: 10.1038/368062a0.
Thirteen years after its discovery, there is still controversy over the chemical identity of endothelium-derived relaxing factor (EDRF). Although pharmacological and chemical evidence indicates that EDRF is nitric oxide, other candidates, including S-nitrosocysteine, dinitrosyl-iron-cysteine complex, nitroxyl and hydroxylamine, have been proposed to account for the vasorelaxant properties of EDRF. Such diverse compounds should differ in their stability and in reactivity with oxyhaemoglobin and with redox-active nucleophiles such as thiols. Here we use a bioassay to compare the pharmacodynamic profiles of these and other compounds with those of nitric oxide and EDRF. We find that some S-nitrosothiols, dinitrosyl-iron-cysteine complex, sodium nitroxyl and hydroxylamine can be eliminated as candidates as they are more stable than EDRF and less susceptible to inhibition by oxyhaemoglobin. Co-infusion of cysteine revealed major differences between the remaining candidates because it reduced the effect of authentic nitric oxide and EDRF on the bioassay tissues but enhanced the survival of S-nitrosocysteine and S-nitrosocysteamine. Our results further support the evidence that EDRF, the pharmacological entity described by Furchgott and Zawadzki, is nitric oxide.
内皮源性舒张因子（EDRF）被发现13年后，其化学本质仍存在争议。尽管药理学和化学证据表明EDRF是一氧化氮，但也有人提出其他候选物质，包括S-亚硝基半胱氨酸、二亚硝基铁-半胱氨酸复合物、硝酰基和羟胺，来解释EDRF的血管舒张特性。这些不同的化合物在稳定性以及与氧合血红蛋白和诸如硫醇等氧化还原活性亲核试剂的反应性方面应该存在差异。在此，我们使用一种生物测定法来比较这些化合物以及其他化合物与一氧化氮和EDRF的药效学特征。我们发现一些S-亚硝基硫醇、二亚硝基铁-半胱氨酸复合物、硝酰基钠和羟胺可以被排除在候选范围之外，因为它们比EDRF更稳定，且更不易受到氧合血红蛋白的抑制。半胱氨酸的共同输注揭示了其余候选物质之间的主要差异，因为它降低了纯一氧化氮和EDRF对生物测定组织的作用，但提高了S-亚硝基半胱氨酸和S-亚硝基半胱胺的存留率。我们的结果进一步支持了这样的证据，即由弗奇戈特和扎瓦茨基描述的药理学实体EDRF就是一氧化氮。
