Miller M R, Megson I L, Roseberry M J, Mazzei F A, Butler A R, Webb D J
Clinical Pharmacology Unit, University of Edinburgh, Western General Hospital, EH4 2LH, Scotland, Edinburgh, UK.
Eur J Pharmacol. 2000 Sep 1;403(1-2):111-9. doi: 10.1016/s0014-2999(00)00572-0.
Organic nitrates, such as glyceryl trinitrate, are nitric oxide (NO) donor drugs that engender tolerance with long-term use. Here, we tested the hypothesis that our novel S-nitrosothiols, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6, tetra-O-acetyl-beta-D-glucopyranose (RIG200) and S-nitroso-N-valeryl-D-penicillamine (D-SNVP), do not induce vascular tolerance ex vivo. Femoral arteries from adult male Wistar rats were preconstricted with phenylephrine and perfused with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Perfusion pressure was measured during 20-h treatment with supramaximal concentrations of NO donor (10 microM). Perfusion with glyceryltrinitrate caused a vasodilatation, which recovered over 2-20 h. In contrast, the S-nitrosothiols caused vasodilatations that were maintained throughout the 20-h perfusion period. Responses to S-nitrosothiols were partially reversed by the NO scavenger ferrohaemoglobin and fully reversed by the soluble guanylate cyclase inhibitor [1H-[1,2,4] oxadiazole [4,3-a]quinoxaline-1-one (ODQ). Glyceryltrinitrate-tolerant vessels were fully responsive to bolus injections of S-nitrosothiols. Resistance to tolerance is an attractive property of our novel compounds, particularly in view of their sustained activity in arteries with damaged endothelium.
有机硝酸盐，如硝酸甘油，是一氧化氮（NO）供体药物，长期使用会产生耐受性。在此，我们测试了一种假设，即我们新型的S-亚硝基硫醇，N-（S-亚硝基-N-乙酰青霉胺）-2-氨基-2-脱氧-1,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖（RIG200）和S-亚硝基-N-戊酰-D-青霉胺（D-SNVP），在体外不会诱导血管耐受性。成年雄性Wistar大鼠的股动脉先用去氧肾上腺素预收缩，然后用一氧化氮合酶抑制剂N（ω）-硝基-L-精氨酸甲酯（L-NAME）灌注。在用超最大浓度的NO供体（10μM）进行20小时治疗期间测量灌注压力。用硝酸甘油灌注引起血管舒张，在2至20小时内恢复。相比之下，S-亚硝基硫醇引起的血管舒张在整个20小时灌注期内保持。对S-亚硝基硫醇的反应被NO清除剂高铁血红蛋白部分逆转，并被可溶性鸟苷酸环化酶抑制剂[1H-[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮（ODQ）]完全逆转。硝酸甘油耐受的血管对S-亚硝基硫醇的推注完全有反应。耐受性抗性是我们新型化合物的一个有吸引力的特性，特别是考虑到它们在受损内皮的动脉中的持续活性。
