Abstract
Cardiac ischemia damages the mitochondrial electron transport chain. Irreversible blockade of electron transport at complex I by rotenone decreases ischemic damage to cardiac mitochondria by decreasing the loss of cytochrome c and preserving respiration through cytochrome oxidase. Therapeutic intervention to protect myocardium during ischemia and reperfusion requires the use of a reversible inhibitor that allows resumption of oxidative metabolism during reperfusion. Amobarbital is a reversible inhibitor at the rotenone site of complex I. We asked whether amobarbital administered immediately before ischemia protected respiratory function. Isolated rat hearts were perfused for 15 min followed by 25-min global ischemia at 37°C. Amobarbital-treated hearts received drug for 1 min before ischemia. Subsarcolemmal (SSM) and interfibrillar (IFM) populations of mitochondria were isolated after ischemia, and oxidative phosphorylation was measured. Amobarbital protected oxidative phosphorylation, including through cytochrome oxidase, in both SSM and IFM in a dose-dependent manner, with an optimal dose of 2 to 2.5 mM. Amobarbital also preserved cytochrome c content in both SSM and IFM. Thus, reversible blockade of the electron transport chain during ischemia protects mitochondrial respiration.
Footnotes
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This work was supported by Grant 1POAG15885 from the National Institutes of Health and The Office of Research and Development, Medical Research Service, Department of Veterans Affairs. Q.C. is a recipient of an American Heart Association postdoctoral fellowship (AHA 0425307B).
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doi:10.1124/jpet.105.091702.
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ABBREVIATIONS: SSM, subsarcolemmal mitochondria; IFM, interfibrillar mitochondria; MOPS, 4-morpholinepropanesulfonic acid; TMPD, N,N,N′,N′-tetramethyl p-phenylenediamine.
- Received July 5, 2005.
- Accepted September 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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