Assessing Muscle Protection with Pharmacological Post-Conditioning Agents in an Acute Ischemia Reperfusion Model

Background Cardiorespiratory complications remain as a primary source of morbidity in elective aortic surgeries and heart transplantations. This is in part due to induced tissue ischemia, resulting in an increased risk in reperfusion injuries. In particular, diaphragmatic dysfunction and/or atrial fibrillation produced by ischemia reperfusion (I/R) injuries contributes to clinical complications after cardiothoracic surgeries. Therefore, post‐conditioning of the diaphragm and cardiac muscles with pharmacological agents may play a critical role in conferring protection and restoring tissue function in such patients. Methods Portions of muscle were removed from swine diaphragm (n=5) and from a human heart deemed non‐viable for transplant (n=1). The diaphragm or ventricular endocardial surface (trabeculae) were dissected into bundles, attached to force transducers, and submersed into tissue baths. Electrical stimulation was applied to the bundles, and peak forces of muscle contractions were recorded. These tissues were exposed to hypoxia followed by reoxygenation to assess resultant damage throughout a recovery period. Randomly, after the hypoxic periods, bundles were treated with given concentrations of either Omegaven fatty acid emulsions, delta‐opioid (DPDPE), and tauroursodeoxycholic acid (TUDCA). Results Percent changes in peak forces of the swine diaphragm and human trabeculae muscle contractions post‐conditioned with these agents and various concentrations showed no significant changes from controls (p>0.05). Non‐toxic agents with potential therapeutic benefits could be applied to various in situ animal models to provide further insights as to the dosing paradigms for full‐organ effects. Conclusion This experimental approach with isolated muscle bundles within tissues baths has the potential to be both a time‐and cost‐effective means for screening pre‐ and post‐conditioning pharmacological agents. Further work is needed to find the drugs, dosages, and hypoxia levels necessary to determine whether the tissue baths mimic an ideal I/R model in vitro . Support or Funding Information This project was funded in part by IEM and Medtronic, Inc. Support for summer student research was provided by the Clinical and Translational Science Institute Advanced Research Program 2015 at the University of Minnesota.