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ORIGINAL RESEARCH ARTICLE

Acetaminophen in the Hypoxic and Reoxygenated Guinea Pig Myocardium

Tyler H. Rork^*, Knox Van Dyke, Norell M. Spiler^* and Gary F. Merrill^*,1

^* Division of Life Sciences, Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854; and Department of Biochemistry and Molecular Pharmacology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia 26506

To whom requests for reprints should be addressed at ¹ Division of Life Sciences, Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Rd., Piscataway, NJ 08854. E-mail: merrill{at}biology.rutgers.edu

We investigated the effects of 0.35-mM acetaminophen and its vehicle on isolated, perfused guinea pig hearts made hypoxic and subsequently reoxygenated. Hearts were allowed 30 min postinstrumentation to reach baseline, steady-state values, and then were exposed to 6 min of hypoxia (5% O₂, 5% CO₂, balance N₂) followed by 36 min of reoxygenation (95% O₂, 5% CO₂). We recorded hemodynamic, metabolic, and mechanical data in addition to assessing ultrastructure and the capacity of coronary venous effluent to reduce reactive oxygen species. We found that acetaminophen-treated hearts retained a greater fraction of mechanical function during hypoxia and reoxygenation. For example, the average percentage change from baseline of left ventricular developed pressure in acetaminophen- and vehicle-treated hearts at 6 min reoxygenation was 9 ± 2% and –8 ± 5% (P < 0.05), respectively. In addition, electron micrographs revealed greater preservation of myofibrillar ultrastructure in acetaminophen-treated hearts. Biochemical analyses revealed the potential of coronary effluent from acetaminophen-treated hearts to significantly neutralize peroxynitrite-dependent chemiluminescence in all recorded time periods. During early reoxygenation, the percentage inhibition of peroxynitrite-mediated chemiluminescence was 56 ± 10% in vehicle-treated hearts and 99 ± 1% in acetaminophen-treated hearts (P < 0.05). We conclude that acetaminophen has previously unreported cardioprotective properties in the nonischemic, hypoxic, and reoxygenated myocardium mediated through the reduction of reactive oxygen species.

Key Words: Langendorff • ventricular function • peroxynitrite • chemiluminescence • cardioprotection

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