Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner ( = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.

中文翻译：

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使用猪冠状动脉闭塞和再灌注模型开发和转化硫代金属硫化物供体

释放硫化物的化合物通过减少线粒体衍生的活性氧的产生来减少再灌注损伤。我们之前描述了临床使用的铜螯合剂四硫代钼酸铵（ATTM）作为啮齿动物的硫化物供体。在这里，我们在临床测试之前评估了对大型哺乳动物的翻译。在健康猪中，静脉注射 ATTM 剂量递增显示出可重复的药代动力学/药效 (PK/PD) 关系，并且不良临床或生化事件最少。在心肌梗塞（冠状动脉左前降支1小时闭塞）再灌注模型中，在再灌注前开始静脉注射ATTM或盐水。 ATTM 以药物暴露依赖性方式保护心脏（24 小时组织学检查）（= 0.58，p < 0.05）。 ATTM 治疗动物的血肌钙蛋白 T 水平显着降低 (p < 0.05)，而心肌谷胱甘肽过氧化物酶活性（一种抗氧化硒蛋白）则升高 (p < 0.05)。总体而言，我们的研究代表了硫化物治疗药物开发的重大进展，并强调了 ATTM 作为再灌注损伤的新型辅助疗法的潜力。从机制上讲，我们的研究表明调节硒蛋白活性可能代表硫化物释放药物的另一种作用模式。