Reversible Blockade of Electron Transport during Ischemia Protects Mitochondria and Decreases Myocardial Injury following Reperfusion
Abstract
Cardiac mitochondria sustain damage during ischemia and reperfusion, contributing to cell death. The reversible blockade of electron transport during ischemia with amobarbital, an inhibitor at the rotenone site of complex I, protects mitochondria against ischemic damage. Amobarbital treatment immediately before ischemia was used to test the hypothesis that damage to mitochondrial respiration occurs mainly during ischemia and that protection of mitochondria during ischemia leads to decreased cardiac injury with reperfusion. Langendorff-perfused Fischer-344 rat hearts were treated with amobarbital (2.5 mM) or vehicle for 1 min immediately before 25 min of global ischemia. Both groups were reperfused for 30 min without additional treatment. Subsarcolemmal (SSM) and interfibrillar (IFM) populations of mitochondria were isolated after reperfusion. Ischemia and reperfusion decreased state 3 and increased state 4 respiration rate in both SSM and IFM. Amobarbital treatment protected oxidative phosphorylation measured following reperfusion and improved the coupling of respiration. Cytochrome c content measured in SSM and IFM following reperfusion decreased in untreated, but not in amobarbital-treated, hearts. H(2)O(2) release from SSM and IFM isolated from amobarbital-treated hearts during reperfusion was markedly decreased. Amobarbital treatment before ischemia improved recovery of contractile function (percentage of preischemic developed pressure: untreated 51 +/- 4%, n = 12; amobarbital 70 +/- 4%, n = 11, p < 0.01) and substantially reduced infarct size (untreated 32 +/- 2%, n = 7; amobarbital 13 +/- 2%, n = 7, p < 0.01). Thus, mitochondrial damage occurs mainly during ischemia rather than during reperfusion. Reperfusion in the setting of preserved mitochondrial respiratory function attenuates the mitochondrial release of reactive oxygen species, enhances contractile recovery, and decreases myocardial infarct size.
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Although nonmitochondrial sources of ROS exist during ischemia, the majority of ROS are likely derived from the mitochondrial respiratory complexes.
“Although nonmitochondrial sources of ROS exist during ischemia [e.g., NAD(P)H oxidase (141, 188, 328) and xanthine oxidase (25) in vasculature], the majority of ROS are likely derived from the mitochondrial respiratory complexes, as shown by the damage to respiratory complexes (212, 213, 245) and the effect of mitochondrial inhibitors (5, 28, 71, 81–86).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [81]
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References 39 · Cited by 215
- Authors
- Chen, Q., Moghaddas, S., Hoppel, C. L., & Lesnefsky, E. J.
- Affiliations
- Louis Stokes Cleveland VA Medical Center (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2006-12
- Volume
- 319
- Issue
- 3
- Pages
- 1405-1412
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W1965091767
- Cited by
- 215
- References
- 39
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 12 · 2020: 13 · 2019: 6 · 2018: 8 · 2017: 19 · 2016: 11 · 2015: 8 · 2014: 15 · 2013: 12 · 2012: 16
- FWCI
- 8.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01AG015885)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- amobarbital, mitochondrial complex I inhibition, myocardial ischemia-reperfusion injury, heart mitochondria, mitochondrial respiration, oxidative phosphorylation, cytochrome c release, hydrogen peroxide release, reactive oxygen species, myocardial infarct size, contractile recovery
- MeSH terms
- Amobarbital, Animals, Citrate (si)-Synthase, Cytochromes, Electron Transport, Hydrogen Peroxide, Male, Mitochondria, Heart, Myocardial Contraction, Myocardial Infarction, Myocardium, Oxidative Phosphorylation, Oxygen Consumption, Rats, Inbred F344, Sarcolemma, Myocardial Reperfusion Injury, Cytochromes c, Rats, In Vitro Techniques
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