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Articles in PresS, published online ahead of print December 5, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00847.2002
Submitted on September 25, 2002
Accepted on December 1, 2002
1 Department of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: terzic.andre{at}mayo.edu.
Modulation of mitochondrial respiratory chain, dehydrogenase and nucleotide metabolizing enzyme activities is fundamental to cellular protection. Here, we demonstrate that the potassium channel opener diazoxide, within its cardioprotective concentration range, modulated the activity of flavin adenine dinucleotide dependent succinate dehydrogenase with an IC50 of 32 µM, and reduced the rate of succinate-supported generation of reactive oxygen species (ROS) in heart mitochondria. 5-hydroxydecanoic fatty acid (5-HD) circumvented diazoxide-inhibited succinate dehydrogenase-driven electron flow, indicating a metabolism-dependent supply of redox equivalents to the respiratory chain. In perfused rat hearts, diazoxide diminished the generation of malondialdehyde, a marker of oxidative stress, which, however, increased upon diazoxide washout. This effect of diazoxide mimicked ischemic preconditioning, and was associated with reduced oxidative damage upon ischemia-reperfusion. Diazoxide reduced cellular and mitochondrial ATPases, along with nucleotide degradation, contributing to preservation of myocardial ATP levels during ischemia. Thus, by targeting nucleotide-requiring enzymes, particularly mitochondrial succinate dehydrogenase and cellular ATPases, diazoxide reduces ROS generation and nucleotide degradation resulting in preservation of myocardial energetics under stress.
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