Abstract
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/Fe2+-initiated lipid peroxidation (measured in mitochondrial membranes as thiobarbituric acid reactive substances and oxygen consumption) with IC50 values of 10.9 and 0.33 μM, respectively. Under the same conditions, the IC50value for Trolox C was 18.8 μM. At the same concentration range showing antioxidant activity both compounds prevent the collapse of transmembranar electric potential induced by ADP/Fe2+ on respiring mitochondria. Furthermore, both carvedilol and BM-910228 do not display toxic effects on mitochondria up to the concentration showing maximal antioxidant effects (≈40 μM for carvedilol and ≈1 μM for BM-910228). At higher concentrations of carvedilol (>40 μM), 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.
Footnotes
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Send reprint requests to: Prof. António J. M. Moreno, Center for Neurosciences, Department of Zoology, University of Coimbra, 3049-517 Coimbra, Portugal. E-mail:moreno{at}ci.uc.pt
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↵1 This work was supported by a research grant from Fundação para a Ciência e Tecnologia (FCT) (Project no. PRAXIS/PSAU/SAU/S/16/96).
- Abbreviations:
- ROS
- reactive oxygen species
- DMSO
- dimethyl sulfoxide
- RCR
- respiratory control ratio
- ΔΨ
- transmembrane electric potential
- Δp
- proton motive force
- TPP+
- tetraphenylphosphonium ion
- TBARS
- thiobarbituric acid reactive substances
- MDA
- malonic dialdehyde
- FCCP
- p-trifluoromethoxyphenylhydrazone
- ATPase
- ATP synthase
- Received May 4, 2000.
- Accepted August 11, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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