Megson I L, Morton S, Greig I R, Mazzei F A, Field R A, Butler A R, Caron G, Gasco A, Fruttero R, Webb D J
Clinical Pharmacology Unit, University of Edinburgh, Western General Hospital.
Br J Pharmacol. 1999 Feb;126(3):639-48. doi: 10.1038/sj.bjp.0702346.
Previous studies show that linking acetylated glucosamine to S-nitroso-N-acetyl-D,L-penicillamine (SNAP) stabilizes the molecule and causes it to elicit unusually prolonged vasodilator effects in endothelium-denuded, isolated rat femoral arteries. Here we studied the propanoyl (SNPP; 3 carbon side-chain), valeryl (SNVP; 5C) and heptanoyl (SNHP; 7C) N-substituted analogues of SNAP (2C), to further investigate other molecular characteristics that might influence chemical stability and duration of vascular action of S-nitrosothiols. Spectrophotometric analysis revealed that SNVP was the most stable analogue in solution. Decomposition of all four compounds was accelerated by Cu(II) and cysteine, and neocuproine, a specific Cu(I) chelator, slowed decomposition of SNHP. Generation of NO from the compounds was confirmed by electrochemical detection at 37 degrees C. Bolus injections of SNAP (10 microl; 10(-8)-10(-3) M) into the perfusate of precontracted, isolated rat femoral arteries taken from adult male Wistar rats (400-500 g), caused concentration-dependent, transient vasodilatations irrespective of endothelial integrity. Equivalent vasodilatations induced by SNVP and SNHP were transient in endothelium-intact vessels but failed to recover to pre-injection pressures at moderate and high concentrations (10(-6)-10(-3) M) in those denuded of endothelium. This sustained effect (> 1 h) was most prevalent with SNHP and was largely reversed by the NO scavenger, haemoglobin. We suggest that increased lipophilicity of SNAP analogues with longer sidechains facilitates their retention by endothelium-denuded vessels; subsequent slow decomposition within the tissue generates sufficient NO to cause prolonged vasodilatation. This is a potentially useful characteristic for targeting NO delivery to areas of endothelial damage.
先前的研究表明，将乙酰化葡糖胺与S-亚硝基-N-乙酰-D,L-青霉胺（SNAP）相连可使该分子稳定，并使其在去内皮的离体大鼠股动脉中引发异常持久的血管舒张作用。在此，我们研究了SNAP（2个碳侧链）的丙酰基（SNPP；3个碳侧链）、戊酰基（SNVP；5个碳）和庚酰基（SNHP；7个碳）N-取代类似物，以进一步研究可能影响亚硝基硫醇化学稳定性和血管作用持续时间的其他分子特性。分光光度分析表明，SNVP是溶液中最稳定的类似物。所有四种化合物的分解都被Cu(II)和半胱氨酸加速，而特异性Cu(I)螯合剂新铜试剂减缓了SNHP的分解。通过在37℃下的电化学检测证实了这些化合物产生一氧化氮。向取自成年雄性Wistar大鼠（400 - 500 g）的预收缩离体大鼠股动脉灌注液中推注SNAP（10微升；10(-8)-10(-3) M），无论内皮完整性如何，都会引起浓度依赖性的短暂血管舒张。SNVP和SNHP诱导的等效血管舒张在内皮完整的血管中是短暂的，但在去内皮的血管中，在中等和高浓度（10(-6)-10(-3) M）时未能恢复到注射前的压力。这种持续效应（> 1小时）在SNHP中最为普遍，并且在很大程度上被一氧化氮清除剂血红蛋白逆转。我们认为，具有更长侧链的SNAP类似物亲脂性增加，有助于它们被去内皮的血管保留；随后在组织内缓慢分解产生足够的一氧化氮，从而导致持久的血管舒张。这对于将一氧化氮递送至内皮损伤区域而言是一个潜在有用的特性。
