Oliveira Paulo J, Esteves Telma, Rolo Anabela P, Palmeira Carlos M, Moreno António J M
Center for Neurosciences and Cellular Biology of Coimbra, Department of Zoology, University of Coimbra, Coimbra, Portugal.
Cardiovasc Toxicol. 2004;4(1):11-20. doi: 10.1385/ct:4:1:11.
It was previously shown that carvedilol, a beta-adrenergic receptor antagonist with antioxidant properties, was able to inhibit the mitochondrial permeability transition (MPT). In the present work, the hypothesis was that the negative impact of carvedilol on the MPT was specifically the result of its antioxidant effect. For the current investigation, we used three different MPT inducers. MPT-associated events were tested to study the protective effect of both carvedilol and cyclosporin-A, the known MPT inhibitor. Carvedilol inhibited mitochondrial swelling with calcium plus phosphate and with calcium plus t-butylhydroperoxide, but not with calcium plus carboxyatractyloside. Carvedilol inhibited the oxidation of thiol groups with calcium plus phosphate (p < 0.01) and with calcium plus t-butylhydroperoxide (p < 0.05), but not with calcium plus carboxyatractyloside--in opposition to the full protection afforded by cyclosporin-A when using calcium and carboxyatractyloside. Our results showed that carvedilol was effective only when the MPT was triggered by a primary oxidative process. This finding implies that the antioxidant properties of carvedilol are crucial for the observed effects and reinforces the advantageous use of carvedilol in cardiac pathologies associated with enhanced cellular oxidative stress.
先前的研究表明，卡维地洛是一种具有抗氧化特性的β-肾上腺素能受体拮抗剂，能够抑制线粒体通透性转换（MPT）。在本研究中，我们提出的假设是，卡维地洛对MPT的负面影响是其抗氧化作用的特定结果。在当前的研究中，我们使用了三种不同的MPT诱导剂。对与MPT相关的事件进行了测试，以研究卡维地洛和已知的MPT抑制剂环孢素A的保护作用。卡维地洛可抑制由钙加磷酸盐以及钙加叔丁基过氧化氢诱导的线粒体肿胀，但不能抑制由钙加羧基苍术苷诱导的线粒体肿胀。卡维地洛可抑制由钙加磷酸盐（p < 0.01）以及钙加叔丁基过氧化氢（p < 0.05）诱导的巯基氧化，但不能抑制由钙加羧基苍术苷诱导的巯基氧化——这与使用钙和羧基苍术苷时环孢素A提供的完全保护相反。我们的结果表明，只有当MPT由原发性氧化过程触发时，卡维地洛才有效。这一发现意味着卡维地洛的抗氧化特性对于所观察到的效应至关重要，并强化了卡维地洛在与细胞氧化应激增强相关的心脏疾病中的有益应用。
