title: Carvedilol inhibits mitochondrial complex I and induces resistance to H2O2 -mediated oxidative insult in H9C2 myocardial cells.
abstract: Carvedilol, a beta-adrenoreceptor antagonist with strong antioxidant activity, produces a high degree of cardioprotection in a variety of experimental models of ischemic cardiac injury. Although growing evidences suggest specific effects on mitochondrial metabolism, how carvedilol would exert its overall activity has not been completely disclosed. In the present work we have investigated the impact of carvedilol-treatment on mitochondrial bioenergetic functions and ROS metabolism in H9C2 cells. This analysis has revealed a dose-dependent decrease in respiratory fluxes by NAD-dependent substrates associated with a consistent decline of mitochondrial complex I activity. These changes were associated with an increase in mitochondrial H(2)O(2) production, total glutathione and protein thiols content. To evaluate the antioxidant activity of carvedilol, the effect of the exposure of control and carvedilol-pretreated H9C2 cells to H(2)O(2) were investigated. The H(2)O(2)-mediated oxidative insult resulted in a significant decrease of mitochondrial respiration, glutathione and protein thiol content and in an increased level of GSSG. These changes were prevented by carvedilol-pretreatment. A similar protective effect on mitochondrial respiration could be obtained by pre-treatment of the cells with a sub-saturating amount of rotenone, a complex I inhibitor. We therefore suggest that carvedilol exerts its protective antioxidant action both by a direct antioxidant effect and by a preconditioning-like mechanism, via inhibition of mitochondrial complex I.
authors.affiliation: Department of Medical Biochemistry, Biology and Physics, University of Bari, 70124 Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Sgobbo
authors.forename: Consiglia
authors.initials: C
authors.lastname: Pacelli
authors.forename: Ignazio
authors.initials: I
authors.lastname: Grattagliano
authors.forename: Gaetano
authors.initials: G
authors.lastname: Villani
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cocco
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D004622:Embryo, Mammalian; D005609:Free Radicals / Q000032:analysis / Q000378:metabolism; D005978:Glutathione / Q000032:analysis; D019803:Glutathione Disulfide / Q000032:analysis; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000032:analysis; D013997:Time Factors
chemical_list: D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D002227:Carbazoles; D005609:Free Radicals; D011412:Propanolamines; D013438:Sulfhydryl Compounds; D000077261:Carvedilol; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I; D005978:Glutathione; D019803:Glutathione Disulfide