The present study was attempted to assess the prophylactic and the
therapeutic effect of human recombinant activated
protein C (APC; drotrecogin-alpha, activated) in experimental
heat stroke. Anesthetized rats were divided into two groups and given vehicle
solution 1 h before the start or immediately after the termination of heat stress (isotonic
sodium chloride solution, 2 mL kg(-1) of
body weight, i.v.) or APC (1-10 mg in 2 mL of isotonic
sodium chloride solution per kilogram of
body weight, i.v.). They were exposed to ambient temperature of 40 degrees C for 100 min to induce
heat stroke. When the vehicle-pretreated rats underwent heat stress, their survival time values were found to be 57 to 71 min. Pretreatment or treatment with APC significantly increased survival time (122-221 min). All vehicle-pretreated
heat stroke animals displayed systemic
inflammation (evidenced by increased
TNF-alpha, IL-1alpha, and IL-6) and activated coagulation (evidenced by increased levels of activated partial thromboplastin time, prothrombin time, and
D-dimer and decreased levels of both platelet count and
protein C). Biochemical assay also revealed that both renal and hepatic dysfunction (e.g., increased plasma levels of blood
urea nitrogen,
creatinine,
adenine aminotransferase, aspartate aminotransferase, and
alkaline phosphatase) were noted during
heat stroke. A significant decrease in both cerebral blood flow and partial pressure of
oxygen in hypothalamus were also observed in vehicle-pretreated
heat stroke animals. These
heat stroke reactions were all significantly reduced by pretreatment or treatment with human recombinant APC. The results indicate that human recombinant APC can be used as a prophylactic and a therapeutic agent for experimental
heat stroke by ameliorating systemic
inflammation, hypercoagulable state, and multiple organ dysfunction.