In skeletal muscle, myocytes subjected to ischemia-reperfusion (I/R) injury die by a necrotic pattern. A causative factor in necrotic cell death is the mitochondrial permeability transition (MPT). The MPT is induced by Ca2+and reactive oxygen species (ROS). Intracytosolic calcium concentrations ([Ca2+]i) rise significantly during I/R. The MPT is promoted by elevations in [Ca2+]i because this leads to elevations in mitochondrial matrix free [Ca2+] and the generation of ROS. Two mechanisms by which [Ca2+]i rise during I/R are release from the sarcoplasmic reticulum RYR1 receptor and influx through reversed Na+/Ca2+ exchange. Simultaneously antagonizing these proteins with dantrolene and amiloride may limit the [Ca2+]i rise. This may improve muscle cell viability by diminishing the promoting effects of elevated mitochondrial matrix free [Ca2+] and ROS on the MPT. We used an I/R model consisting of Male Wistar rats weighing approximately 300 grams that had their gracilis muscles isolated on a dominant vascular pedicle. We clamped the pedicle to induce ischemia and unclamping induced reperfusion. We quantified muscle cell viability in our animals through NBT staining after 5.5 hours of ischemia and 24 hours of reperfusion. With no treatment the average muscle cell viability was 7.4% (n=6, std.dev. 1.6%). The treatment groups had six animals per group and consisted of animals given intraperitoneal injections of vehicle (4cc/kg) with or without dantrolene (3-6mg/kg) and/or amiloride (1.3mg/kg) prior to ischemia, during ischemia, and during reperfusion. The results are as follows: vehicle only (avg. viability15.5%, std.dev. 7.9%, p=0.0339), dantrolene with vehicle (avg. viability 17.2%, std.dev. 6.9%, p=0.0067), amiloride with vehicle (avg. viability 16.5%, std.dev. 4.6%, p=0.015), and dantrolene plus amiloride with vehicle (avg. viability 23.1%, std.dev. 12.2%, p=0.0109). The differences in average viability between the vehicle only group and the other treatment groups were not statistically significant. Therefore, we conclude that the improvements in muscle cell viability in the treatment groups are due in large part if not entirely to the vehicle. The improvements are, however, impressive and warrant further investigation. One of the major influx pathways of calcium is reversed Na+/Ca2+ exchange that is thought to be driven by a high intracytosolic [Na+]. Perhaps the administration of deionized water caused hyponatremia in our animals. If this occurred then it could have lead to a decrease in the intracytosolic [Na+] rise and thus decreased calcium influx through the Na+/Ca2+ exchanger effectively reducing the [Ca2+]i rise and its deleterious effects.