Role of superoxide ion formation in hypothermia/rewarming induced contractile dysfunction in cardiomyocytes

Abstract

Rewarming following accidental hypothermia is associated with circulatory collapse due primarily to impaired cardiac contractile (systolic) function. Previously, we found that reduced myofilament Ca2+ sensitivity underlies hypothermia/rewarming (H/R)-induced cardiac contractile dysfunction. This reduced Ca2+ sensitivity is associated with troponin I (cTnI) phosphorylation. We hypothesize that H/R induces reactive oxygen species (ROS) formation in cardiomyocytes, which leads to cTnI phosphorylation and reduced myofilament Ca2+ sensitivity. To test this hypothesis, we exposed isolated rat cardiomyocytes to a 2-h period of severe hypothermia (15 °C) followed by rewarming (35 °C) with and without antioxidant (TEMPOL) treatment. Simultaneous measurements of cytosolic Ca2+ ([Ca2+]cyto) and contractile (sarcomere shortening) responses indicated that H/R-induced contractile dysfunction and reduced Ca2+ sensitivity was prevented in cardiomyocytes treated with TEMPOL. In addition, TEMPOL treatment blunted H/R-induced cTnI phosphorylation. These results support our overall hypothesis and suggest that H/R disrupts excitation-contraction coupling of the myocardium through a cascade of event triggered by excessive ROS formation during hypothermia. Antioxidant treatment may improve successful rescue of accidental hypothermia victims.