Nucleoside monophosphorothioates as the new hydrogen sulfide precursors with unique properties
Nucleoside monophosphorothioates as the new hydrogen sulfide precursors with unique properties
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DOI：
10.1016/j.phrs.2014.01.003
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发表时间：
2014-03-01
影响因子：
9.3
通讯作者：
Wojtak, Andrzej
中科院分区：
文献类型：
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作者：
Beltowski, Jerzy;Guranowski, Andrzej;Wojtak, Andrzej
硫化氢(H_2S)是哺乳动物组织中以L-半胱氨酸为底物的酶促合成的气体递质。硫化氢供体被认为是治疗心血管、神经和炎症性疾病的潜在药物。最近的研究表明，人工合成的核苷酸类似物，腺苷和鸟苷5‘-硫代硫酸酯(AMPS和GMPS)可以被纯化的组氨酸三联体核苷酸结合蛋白(HINT)分别转化为H_2S和AMP或GMP。我们考察了AMPS和GMPS能否作为完整生物系统中的H_2S供体。用特异极谱传感器测定大鼠离体肾小球产生H_2S。当肾小球与AMPS或GMPS和离子型嘌呤能P2X(7)受体/通道激动剂BzATP孵育时，可检测到H_2S的产生。GMPS比等摩尔AMPS产生更多的H_2S。硫代核苷与BzATP一起松弛血管紧张素II预缩窄的肾小球。肾动脉内注入AMPS或GMPS联合BzATP可增加肾小球滤过分数和肾小球滤过率，但对肾血管阻力和肾血流量无影响。AMPS而不是GMPS被分离的肾小球转化为腺苷，然而腺苷不参与AMPS诱导的H_2S的合成，因为腺苷和特定的腺苷受体激动剂对H_2S的产生没有任何影响。AMPS能增加AMP刺激的蛋白激酶(AMPK)的磷酸化水平，但GMPS不能，但AMPK抑制剂化合物C对AMPS诱导的H_2S生成无影响。综上所述，核苷硫化物在体外可转化为H_2S，从而松弛体外肾小球，提高体内肾小球滤过率。AMPS和GMPS可作为实验研究中的H_2S供体，也可作为H_2S释放药物。(C)2014爱思唯尔有限公司。保留所有权利。
Hydrogen sulfide (H2S) is the gasotransmitter enzymatically synthesized in mammalian tissues from L-cysteine. H2S donors are considered as the potential drugs for the treatment of cardiovascular, neurological and inflammatory diseases. Recently, it has been demonstrated that synthetic nucleotide analogs, adenosine- and guanosine 5'-monophosphorothioates (AMPS and GMPS) can be converted to H2S and AMP or GMP, respectively, by purified histidine triad nucleotide-binding (Hint) proteins. We examined if AMPS and GMPS can be used as the H2S donors in intact biological systems. H2S production by isolated rat kidney glomeruli was measured by the specific polarographic sensor. H2S production was detected when glomeruli were incubated with AMPS or GMPS and ionotropic purinergic P2X(7) receptor/channel agonist, BzATP. More H2S was generated from GMPS than from equimolar amount of AMPS. Nucleoside phosphorothioates together with BzATP relaxed angiotensin II-preconstricted glomeruli. In addition, infusion of AMPS or GMPS together with BzATP into the renal artery increased filtration fraction and glomerular filtration rate but had no effect on renal vascular resistance or renal blood flow. AMPS but not GMPS was converted to adenosine by isolated glomeruli, however, adenosine was not involved in AMPS-induced H2S synthesis because neither adenosine nor specific adenosine receptor agonists had any effect on H2S production. AMPS, but not GMPS, increased phosphorylation level of AMP-stimulated protein kinase (AMPK), but AMPK inhibitor, compound C, had no effect on AMPS-induced H2S production. In conclusion, nucleoside phosphorothioates are converted to H2S which relaxes isolated kidney glomeruli in vitro and increases glomerular filtration rate in vivo. AMPS and GMPS can be used as the H2S donors in experimental studies and possibly also as the H2S-releasing drugs. (C) 2014 Elsevier Ltd. All rights reserved.