The hydrogen sulphide-releasing derivative of diclofenac protects against ischaemia-reperfusion injury in the isolated rabbit heart
The hydrogen sulphide-releasing derivative of diclofenac protects against ischaemia-reperfusion injury in the isolated rabbit heart
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DOI：
10.1038/sj.bjp.0707540
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发表时间：
2008-01-01
影响因子：
7.3
通讯作者：
Berti, F.
中科院分区：
文献类型：
--
作者：
Rossoni, G.;Sparatore, A.;Berti, F.
背景和目的：硫化氢（H2S）是一种内源性气体介质，在哺乳动物心血管组织的病理生理功能的多层次调节中发挥作用。本文研究了双氯芬酸的一种新的硫化氢释放衍生物S-双氯芬酸的药理活性（2-[（2，6-二氯苯基）氨基]苯乙酸（3 H-1，2-二硫杂环戊烯-3-基-5-基）-苯酯）在受到低流量缺血再灌注损伤的离体兔心脏中的作用。S-双氯芬酸（3、10和30 μ M）尽管抑制心脏组织产生前列环素，但仍实现了冠状动脉灌注压的剂量依赖性正常化，减少了缺血期间的左心室挛缩，并改善了再灌注时的左心室发展压力和+/- dP/dt（max）。再灌注期间，心肌灌流液中肌酸激酶和乳酸脱氢酶活性显著降低。这些作用伴随着还原型谷胱甘肽（GSH）的大量释放，表明H2S部分可能具有上调的半胱氨酸转运。S-双氯芬酸和H2S-供体硫氢化钠（NaHS）的抗缺血活性部分被K-ATP通道拮抗剂格列本脲阻止，表明代谢性缺血预处理中H2S诱导的心脏保护机制类似。灌注与一氧化氮（NO）合酶抑制剂N-G-单甲基-L-精氨酸恶化心肌缺血再灌注损伤，但这是剂量依赖性地防止由S-双氯芬酸和NaHS，这表明释放的硫化氢可能克服NO deficiency.Conclusion和影响：这些数据表明，S-双氯芬酸有显着的抗缺血活性在缺血再灌注兔心脏，尽管抑制前列腺素的产生。GSH形成增加导致K-ATP通道激活可能有助于这种有益作用。S-双氯芬酸的药理学特征及其抗炎活性，减少了胃肠道副作用，为心血管疾病提供了治疗应用。
Background and purpose: Hydrogen sulphide (H2S) is an endogenous gaseous mediator active in the multilevel regulation of pathophysiological functions in mammalian cardiovascular tissues.Experimental approach: This study investigated the pharmacological activity of a new H2S-releasing derivative of diclofenac, S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester) in the isolated rabbit heart submitted to low-flow ischaemia-reperfusion damage.Key results: S-diclofenac (3, 10 and 30 mu M), despite inhibiting prostacyclin generation by cardiac tissues, achieved dose-dependent normalization of coronary perfusion pressure, reducing left ventricular contracture during ischaemia and improving left ventricular developed pressure and +/- dP/dt(max) at reperfusion. Creatine kinase and lactate dehydrogenase activities in heart perfusates were significantly reduced during reperfusion. These effects were accompanied by substantial release of reduced glutathione (GSH), indicating that the H2S moiety may have up-regulated cysteine transport. The anti-ischaemic activities of S-diclofenac and the H2S-donor sodium hydro sulphide (NaHS) were partially prevented by the K-ATP channel antagonist glibenclamide, suggesting a mechanism similar to H2S-induced cardioprotection in metabolic ischaemic preconditioning. Perfusion with the nitric oxide (NO) synthase inhibitor N-G-monomethyl-L-arginine worsened the myocardial ischaemia-reperfusion damage, but this was dose-dependently prevented by S-diclofenac and NaHS, suggesting that the released H2S may have overcome NO deficiency.Conclusion and implications: These data show that S-diclofenac had marked anti-ischaemic activity in ischaemic-reperfused rabbit hearts despite inhibition of prostaglandin generation. Increased GSH formation leading to activation of K-ATP channels may have contributed to this beneficial effect. The pharmacological profile of S-diclofenac and its anti-inflammatory activity, with diminished gastrointestinal side effects, offer therapeutic applications in cardiovascular disease.