Description:
The mechanisms for the loss of muscle contractile function in hyperthermia are poorly understood. Previously we demonstrated that oxidant production is elevated in skeletal muscle during hyperthermia, in part through pathways of arachidonic acid (AA) metabolism. Here, we hypothesized that scavenging of oxidants or blocking AA metabolism preserves function in hyperthermia. Rat diaphragm bundles were exposed to 30 min of 40, 41, 42 or 43ºC. Function was unaffected below 42 ºC but at 43ºC a significant loss of peak force (52.8±7.5% of baseline) and an increase in contracture were observed. Treatment with Tiron or Trolox during and after 43ºC exposure or treatment with DTT after exposure had no effect on loss of function. Lipoxygenase (LOX) and cyclooxygenase (COX) inhibitors (baicalein or ETYA; and indomethacin or ibuprofen, respectively) greatly decreased function and increased contracture at 42°C in a dose dependent manner, and even further at 43°C. The inhibitors decreased function to a greater extent when combined at 42°C (−67.9 Δ%max Force ±2.5). Treatment with the PLA2 inhibitor BEL (20μM) also decreased function at 43°C (−84.3 Δ%max Force ±3.8). Overall, results demonstrate that oxidant stress does not appear to contribute significantly to the loss of function in intact muscle, but AA metabolism through LOX and COX pathways are essential in protecting skeletal muscle during hyperthermia. NHLBI 53333