Activated protein C can be used as a prophylactic as well as a therapeutic agent for heat stroke in rodents.
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.
Lin
Xiao-Jing
XJ
Rehabilitation Department of Spinal Cord Injury, General Hospital Jinan Military, Shandong, China.
Li
Yi-Lei
YL
Mei
Gui-Ping
GP
Zou
Fei
F
He
Dan-Dan
DD
Liu
Xue-Qin
XQ
Li
Ya-Jie
YJ
Zhao
Ting-Bao
TB
Lin
Mao-Tsun
MT
D000469:Alkaline Phosphatase / Q000378:metabolism; D000619:Aminohydrolases / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D005334:Fever / Q000517:prevention & control; D018883:Heat Stroke / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D007022:Hypotension / Q000517:prevention & control; D007249:Inflammation / Q000517:prevention & control*; D053582:Interleukin-1alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D011486:Protein C / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000890:Anti-Infective Agents; D053582:Interleukin-1alpha; D015850:Interleukin-6; D011486:Protein C; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase; D000619:Aminohydrolases; C018774:adenine deaminase; C421124:drotrecogin alfa activated