Effects of carvedilol and its analog BM-910228 on mitochondrial function and oxidative stress

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 actio n on mitochondrial bioenergetics. Carvedilol and BM-910228 inhibited ADP/Fe 2+-initiated lipid peroxidation (measured in mitochondrial membranes as thi obarbituric acid reactive substances and oxygen consumption) with IC50 valu es of 10.9 and 0.33 muM, respectively. Under the same conditions, the IC50 value for Trolox C was 18.8 muM. At the same concentration range showing an tioxidant activity both compounds prevent the collapse of transmembranar el ectric potential induced by ADP/Fe2+ on respiring mitochondria. Furthermore , both carvedilol and BM-910228 do not display toxic effects on mitochondri a up to the concentration showing maximal antioxidant effects (approximate to 40 muM for carvedilol and approximate to1 muM for BM-910228). At higher concentrations of carvedilol (>40 muM), however, the phosphorylation effici ency 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 carv edilol stimulated membrane proton leak and inhibited substrate oxidation, b ut had no measurable effect on phosphorylation reactions. Because carvedilo l exerts its antioxidant properties for nontoxic concentrations, its therap eutic interest is reinforced because it may potentially prevent mitochondri al dysfunctions associated to cell death in several pathophysiological stat es where excessive production of reactive oxygen species by mitochondria is well documented (e.g., ischemia/reperfusion). Additionally, its hydroxylat ed analog BM-910228 with notable superior antioxidant activity may signific antly contribute to the known therapeutic effects of carvedilol.