Abreu R M, Santos D J, Moreno A J
Centro de Neurociências de Coimbra, Universidade de Coimbra, Portugal.
J Pharmacol Exp Ther. 2000 Dec;295(3):1022-30.
The antioxidant effects of carvedilol and its analog BM-910228 (also known as SB 211475) were studied in rat liver mitochondria as well as their action on mitochondrial bioenergetics. Carvedilol and BM-910228 inhibited ADP/Fe(2+)-initiated lipid peroxidation (measured in mitochondrial membranes as thiobarbituric acid reactive substances and oxygen consumption) with IC(50) values of 10.9 and 0. 33 microM, respectively. Under the same conditions, the IC(50) value for Trolox C was 18.8 microM. At the same concentration range showing antioxidant activity both compounds prevent the collapse of transmembranar electric potential induced by ADP/Fe(2+) on respiring mitochondria. Furthermore, both carvedilol and BM-910228 do not display toxic effects on mitochondria up to the concentration showing maximal antioxidant effects ( approximately 40 microM for carvedilol and approximately 1 microM for BM-910228). At higher concentrations of carvedilol (>40 microM), however, the phosphorylation efficiency of mitochondria is depressed as deduced from a decrease in respiratory control and in the ADP/oxygen ratio. The Brand approach was used to assess the effects of carvedilol on oxidative phosphorylation. We found that carvedilol stimulated membrane proton leak and inhibited substrate oxidation, but had no measurable effect on phosphorylation reactions. Because carvedilol exerts its antioxidant properties for nontoxic concentrations, its therapeutic interest is reinforced because it may potentially prevent mitochondrial dysfunctions associated to cell death in several pathophysiological states where excessive production of reactive oxygen species by mitochondria is well documented (e.g., ischemia/reperfusion). Additionally, its hydroxylated analog BM-910228 with notable superior antioxidant activity may significantly contribute to the known therapeutic effects of carvedilol.
研究了卡维地洛及其类似物BM - 910228（也称为SB 211475）在大鼠肝线粒体中的抗氧化作用及其对线粒体生物能量学的影响。卡维地洛和BM - 910228抑制ADP/Fe(2+)引发的脂质过氧化（在线粒体膜中以硫代巴比妥酸反应性物质和氧气消耗来衡量），IC(50)值分别为10.9和0.33微摩尔。在相同条件下，Trolox C的IC(50)值为18.8微摩尔。在显示抗氧化活性的相同浓度范围内，两种化合物都能防止ADP/Fe(2+)对呼吸线粒体诱导的跨膜电位崩溃。此外，直至显示最大抗氧化作用的浓度（卡维地洛约为40微摩尔，BM - 910228约为1微摩尔），卡维地洛和BM - 910228对线粒体均未表现出毒性作用。然而，在卡维地洛浓度较高时（>40微摩尔），从呼吸控制和ADP/氧比值的降低可推断线粒体的磷酸化效率受到抑制。采用Brand方法评估卡维地洛对氧化磷酸化的影响。我们发现卡维地洛刺激膜质子泄漏并抑制底物氧化，但对磷酸化反应没有可测量的影响。由于卡维地洛在无毒浓度下发挥其抗氧化特性，其治疗价值得到增强，因为在一些病理生理状态下，线粒体活性氧过度产生已得到充分证明（例如，缺血/再灌注），它可能潜在地预防与细胞死亡相关的线粒体功能障碍。此外，其具有显著优越抗氧化活性的羟基化类似物BM - 910228可能对卡维地洛已知的治疗效果有显著贡献。
