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J Thorac Cardiovasc Surg 2001;121:0298-0306
© 2001 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Diazoxide protects mitochondria from anoxic injury: Implications for myopreservation

From the Division of Cardiovascular Diseases and the Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, Minn.

Supported in part by grants from the National Institutes of Health (HL-64822, HL-07111), American Heart Association, Miami Heart Research Institute, the Bruce and Ruth Rappaport Program in Vascular Biology and Gene Delivery, and a CR20 Clinical Research Award from the Mayo Foundation. A.T. is an Established Investigator of the American Heart Association.

Received for publication May 23, 2000. Revisions requested June 20, 2000; revisions received July 7, 2000. Accepted for publication Sept 8, 2000. Address for reprints: Andre Terzic, MD, PhD, Guggenheim-7F, Mayo Clinic and Foundation, Rochester, MN 55905 (E-mail: terzic.andre{at}mayo.edu).

Background: Heart muscle primarily relies on adenosine triphosphate produced by oxidative phosphorylation and is highly vulnerable to anoxic insult. Although a number of strategies aimed at improving myopreservation are available, no effective means of preserving mitochondrial energetics under conditions of anoxic injury have been developed. Openers of mitochondrial adenosine triphosphate–sensitive potassium channels have emerged as powerful cardioprotective agents presumably capable of maintaining mitochondrial function under metabolic stress. Here, we evaluated the ability of a prototype mitochondrial adenosine triphosphate–sensitive potassium channel opener, diazoxide, to preserve oxidative phosphorylation in mitochondria subjected to anoxia and reoxygenation.
Methods: Mitochondria were isolated from rat hearts and subjected to 20 minutes of anoxia, followed by reoxygenation. Mitochondrial respiration and oxidative phosphorylation, as well as mitochondrial integrity, were assessed by means of ion-selective minielectrodes, high-performance liquid chromatography, fluorometry, and electron microscopy.
Results: Anoxia-reoxygenation decreased the rate of adenosine diphosphate–stimulated oxygen consumption, inhibited adenosine triphosphate production, and disrupted mitochondrial integrity. On average, anoxic stress reduced adenosine diphosphate–stimulated respiration from 291 ± 14 to 141 ± 15 ng-atoms O₂ · min^–1 · mg^–1 protein and decreased the rate of adenosine triphosphate production from 752 ± 14 to 414 ± 34 nmol adenosine triphosphate · min^–1 · mg^–1 protein. After anoxia, the majority (88%) of mitochondria was damaged or swollen and released adenylate kinase, a marker of mitochondrial integrity. Diazoxide (100 µmol/L), present throughout anoxia, preserved adenosine diphosphate–stimulated respiration at 255 ± 7 ng-atoms O₂ · min^–1 · mg^–1 protein and adenosine triphosphate production at 640 ± 39 nmol adenosine triphosphate · min^–1 · mg^–1 protein. Diazoxide also protected mitochondrial structure from anoxia-mediated damage, so that after anoxic stress, 67% of mitochondria remained intact and adenylate kinase was confined to the mitochondria.
Conclusions: The present study demonstrates that diazoxide diminishes anoxia-induced functional and structural deterioration of cardiac mitochondria. By protecting mitochondria and preserving myocardial energetics, diazoxide may be useful under conditions of reduced oxygen availability, including global surgical ischemia or storage of donor heart.

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