Costa Vera Marisa, Silva Renata, Ferreira Luísa Maria, Branco Paula Sério, Carvalho Félix, Bastos Maria Lourdes, Carvalho Rui Albuquerque, Carvalho Márcia, Remião Fernando
REQUI MTE (Rede de Química e Tecnologia), Toxicology Department, Faculty of Pharmacy, University of Porto, Porto, Portugal.
Chem Res Toxicol. 2007 Aug;20(8):1183-91. doi: 10.1021/tx7000916. Epub 2007 Jul 13.
High concentrations of circulating biogenic catecholamines often exist during the course of several cardiovascular disorders. Additionally, coronary dysfunctions are prominent and frequently related to the ischemic and reperfusion phenomenon (I/R) in the heart, which leads to the release of large amounts of catecholamines, namely adrenaline, and to a sustained generation of reactive oxygen species (ROS). Thus, this work aimed to study the toxicity of adrenaline either alone or in the presence of a system capable of generating ROS [xanthine with xanthine oxidase (X/XO)], in freshly isolated, calcium tolerant cardiomyocytes from adult rats. Studies were performed for 3 h, and cardiomyocyte viability, ATP level, lipid peroxidation, protein carbonylation content, and glutathione status were evaluated, in addition to the formation of adrenaline's oxidation products and quinoproteins. Intracellular GSH levels were time-dependently depleted with no GSSG formation when cardiomyocytes were exposed to adrenaline or to adrenaline with X/XO. Meanwhile, a time-dependent increase in the rate of formation of adrenochrome and quinoproteins was observed. Additionally, as a new outcome, 5-(glutathion- S-yl)adrenaline, an adrenaline adduct of glutathione, was identified and quantified. Noteworthy is the fact that the exposure to adrenaline alone promotes a higher rate of formation of quinoproteins and glutathione adduct, while adrenochrome formation is favored where ROS production is stimulated. This study shows that the redox status of the surrounding environment greatly influences adrenaline's oxidation pathway, which may trigger cellular changes responsible for cardiotoxicity.
在几种心血管疾病的病程中，常常存在高浓度的循环生物源性儿茶酚胺。此外，冠状动脉功能障碍很突出，且经常与心脏的缺血和再灌注现象（I/R）相关，这会导致大量儿茶酚胺（即肾上腺素）的释放，并持续产生活性氧（ROS）。因此，本研究旨在探讨单独使用肾上腺素或在存在能够产生活性氧的系统[黄嘌呤与黄嘌呤氧化酶（X/XO）]的情况下，肾上腺素对成年大鼠新鲜分离的、耐钙心肌细胞的毒性。研究进行了3小时，除了评估肾上腺素氧化产物和醌蛋白的形成外，还评估了心肌细胞活力、ATP水平、脂质过氧化、蛋白质羰基化含量和谷胱甘肽状态。当心肌细胞暴露于肾上腺素或肾上腺素与X/XO时，细胞内谷胱甘肽水平随时间依赖性降低，且未形成谷胱甘肽二硫化物（GSSG）。同时，观察到肾上腺色素和醌蛋白形成速率随时间增加。此外，作为一个新的结果，鉴定并定量了5-（谷胱甘肽-S-基）肾上腺素，一种肾上腺素与谷胱甘肽的加合物。值得注意的是，单独暴露于肾上腺素会促进更高的醌蛋白和谷胱甘肽加合物形成速率，而在刺激ROS产生的情况下，肾上腺色素的形成更受青睐。这项研究表明，周围环境的氧化还原状态极大地影响肾上腺素的氧化途径，这可能引发导致心脏毒性的细胞变化。
