Inhibition of heart mitochondrial lipid peroxidation by non-toxic concentrations of carvedilol and its analog BM-910228

Carvedilol, a non-selective beta -adrenoreceptor blocker, has been shown to possess a high degree of cardioprotection in experimental models of myocar dial damage. Reactive oxygen species have been proposed to be implicated in such situations, and antioxidants have been demonstrated to provide partia l protection to the reported damage. The purpose of our study was to invest igate the antioxidant effect of carvedilol and its metabolite BM-910228 by measuring the extent of lipid peroxidation in a model of severe oxidative d amage induced by ADP/FeSO4 in isolated rat heart mitochondria. Carvedilol a nd BM-910228 inhibited the thiobarbituric acid-reactive substance formation and oxygen consumption associated with lipid peroxidation with IC50 values of 6 and 0.22 muM, respectively. Under the same conditions, the IC50 value s of alpha -tocopheryl succinate and Trolox were 125 and 31 muM, respective ly. As expected, the presence of carvedilol and BM-910228 preserved the str uctural and functional integrity of mitochondria under oxidative stress con ditions for the same concentration range shown to inhibit lipid peroxidatio n, since they prevented the collapse of the mitochondrial membrane potentia l (Delta psi) induced by ADP/FeSO4 in respiring mitochondria. It should be stressed that neither carvedilol nor BM-910228 induced any toxic effect on mitochondrial function in the concentration range of the compounds that inh ibits the peroxidation of mitochondrial membranes. In conclusion, the antio xidant properties of carvedilol may contribute to the cardioprotective effe cts of the compound, namely through the preservation of mitochondrial funct ions whose importance in myocardial dysfunction is clearly documented. Addi tionally, its hydroxylated analog BM-910220, with its notably superior anti oxidant activity, may significantly contribute to the therapeutic effects o f carvedilol. (C) 2001 Elsevier Science Inc. All rights reserved.