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1 Department of Internal Medicine, Pulmonary and Critical Care Medicine, Dorothy M. Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA
2 Department of Anesthesiology, The Ohio State University, Columbus, OH, USA
* To whom correspondence should be addressed. E-mail: clanton.1{at}osu.edu.
Superoxide (O2.-) is released from skeletal muscle at rest and is particularly elevated during conditions of heat stress (42°C). Previous studies have shown that in isolated rat diaphragm O2.- release is not dependent on mitochondrial electron transport, NAD(P)H oxidase activity or the integrity of membrane anion channels. This study hypothesized that O2.- release, as measured by cytochrome c reduction, is linked to metabolism of arachidonic acid. Phospholipase A2 inhibition with manoalide significantly decreased O2.- release. In downstream pathways, neither the blockage of cyclooxygenase with indomethacin nor the inhibition of cytochrome P450-dependent monooxygenase with SKF 525A decreased O2.- release. However, lipoxygenase (LOX) inhibition with general LOX blockers 5,8,11,14-eicosatetraynoic acid and cinnamyl-3,4-dihydroxy-a
-cyanocinnamate, greatly attenuated the signal. Furthermore, the specific 5-LOX inhibitor diethylcarbamazine also significantly decreased O2.- release. Immunohistochemistry localized 5- and 12-LOX to the cytosol and sarcolemma of muscle cells. Confocal studies, using the O2.--sensitive fluorescent indicator, hydroethidine, demonstrated that LOX inhibition had no significant influence on intracellular O2.- formation. When compared to the cytochrome c results, this indicates that intra- and extracellular O2.- must arise from different sources. These data show for the first time that arachidonic acid metabolism through LOX activity, is a major source of extracellular O2.- release in skeletal muscle.
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