Oxypurinol attenuates mechanical ventilation‐induced diaphragmatic oxidative stress and contractile dysfunction

Abstract

Mechanical ventilation (MV) is used to maintain alveolar ventilation in patients incapable of doing so on their own. Prolonged MV renders the diaphragm inactive and results in diaphragmatic oxidative stress and contractile dysfunction. At present, the pathways responsible for diaphragmatic oxidant production during MV remain unknown. Therefore, we tested the hypothesis that oxypurinol, a xanthine oxidase (XO) inhibitor, would attenuate diaphragmatic oxidative stress and contractile dysfunction during MV. Sprague-Dawley rats were mechanically ventilated for 12 hours with or without oxypurinol. Diaphragms from acutely anesthetized animals served as controls. Following prolonged MV, diaphragmatic XO activity increased 16%, while total glutathione levels decreased 22%. In addition, MV induced a 24% decrease in diaphragmatic maximal specific force. Administration of oxypurinol attenuated the MV-induced increase in: diaphragmatic XO activity; diaphragmatic levels of protein carbonyls; and diaphragmatic contractile dysfunction at stimulation frequencies above 60 Hz. These results suggest that XO contributes to MV-induced oxidative injury in the diaphragm. Furthermore, protection against XO induced oxidative stress with oxypurinol attenuates MV-induced diaphragmatic contractile dysfunction. This work was supported by the NIH RO1 HL072789 (SK Powers) and T32 HD043730 (MA Whidden).