Opening of Mitochondrial K ATP Channels Triggers the Preconditioned State by Generating Free Radicals
Abstract
Abstract —The critical time for opening mitochondrial (mito) K ATP channels, putative end effectors of ischemic preconditioning (PC), was examined. In isolated rabbit hearts 29±3% of risk zone infarcted after 30 minutes of regional ischemia. Ischemic PC or 5-minute exposure to 10 μmol/L diazoxide, a mito K ATP channel opener, reduced infarction to 3±1% and 8±1%, respectively. The mito K ATP channel closer 5-hydroxydecanoate (200 μmol/L), bracketing either 5-minute PC ischemia or diazoxide infusion, blocked protection (24±3 and 28±6% infarction, respectively). However, 5-hydroxydecanoate starting 5 minutes before long ischemia did not affect protection. Glibenclamide (5 μmol/L), another K ATP channel closer, blocked the protection by PC only when administered early. These data suggest that K ATP channel opening triggers protection but is not the final step. Five minutes of diazoxide followed by a 30-minute washout still reduced infarct size (8±3%), implying memory as seen with other PC triggers. The protection by diazoxide was not blocked by 5 μmol/L chelerythrine, a protein kinase C antagonist, given either to bracket diazoxide infusion or just before the index ischemia. Bracketing preischemic exposure to diazoxide with 50 μmol/L genistein, a tyrosine kinase antagonist, did not affect infarction, but genistein blocked the protection by diazoxide when administered shortly before the index ischemia. Thus, although it is not protein kinase C-dependent, the protection by diazoxide involves tyrosine kinase. Bracketing diazoxide perfusion with N -(2-mercaptopropionyl) glycine (300 μmol/L) or Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (7 μmol/L), each of which is a free radical scavenger, blocked protection, indicating that diazoxide triggers protection through free radicals. Therefore, mito K ATP channels are not the end effectors of protection, but rather their opening before ischemia generates free radicals that trigger entrance into a preconditioned state and activation of kinases.
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ROS trigger or mediate ischemic and pharmacologic preconditioning of hearts.
“It is now well known that ROS trigger or mediate ischemic and pharmacologic preconditioning of hearts (15, 27, 102, 181, 183, 248, 254, 303).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [248]
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- Authors
- Pain, T., Yang, X.-M., Critz, S. D., Yue, Y., Nakano, A., Liu, G. S., Heusch, G., Cohen, M. V., & Downey, J. M.
- Affiliations
- University of South Alabama (US)
- Venue
- Circulation Research
- Published
- 2000-09-15
- Volume
- 87
- Issue
- 6
- Pages
- 460-466
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2124027170
- Cited by
- 662
- References
- 2
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 5 · 2021: 7 · 2020: 16 · 2019: 6 · 2018: 7 · 2017: 19 · 2016: 13 · 2015: 12 · 2014: 29 · 2013: 26 · 2012: 29
- FWCI
- 33.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL20648, R01HL050688, HL50688, R01HL020648)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- mitochondrial KATP channels, ischemic preconditioning, diazoxide, 5-hydroxydecanoate, glibenclamide, myocardial infarct size, free radicals, tyrosine kinase, protein kinase C, genistein, chelerythrine, N-acetyl-p-benzoquinone imine, MnTBAP, cardioprotection, regional myocardial ischemia
- MeSH terms
- Adenosine Triphosphate, Alkaloids, Animals, Decanoic Acids, Diazoxide, Enzyme Inhibitors, Free Radicals, Glyburide, Hemodynamics, Hydroxy Acids, Mitochondria, Heart, Myocardial Infarction, Phenanthridines, Protein-Tyrosine Kinases, Rabbits, Blotting, Western, Potassium Channels, Free Radical Scavengers, Ischemic Preconditioning, Myocardial, Genistein, Mitogen-Activated Protein Kinases, Potassium Channel Blockers, Protein Kinase Inhibitors, p38 Mitogen-Activated Protein Kinases, Benzophenanthridines
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