Arginine metabolic pathways determine its therapeutic benefit in experimental heatstroke: role of Th1/Th2 cytokine balance

Nitric Oxide. 2006 Dec;15(4):408-16. doi: 10.1016/j.niox.2006.04.003. Epub 2006 Apr 26.


We have demonstrated that therapeutic administration of L-arginine (L-arg) (120 mg/kg) at +2 h of whole body hyperthermia (WBH) could rescue the mice from heatstroke-induced death. Studies were undertaken to elucidate the role of L-arg in the immunomodulation of the heat-stressed mice. Administration of L-arginine (L-arg), (120 mg/kg, i.p.), at +2 h of WBH, rescued the mice from heat-induced death and reduced the hypothermia. At +4 and +24 h of WBH, levels of IL-1beta, IFN-gamma, nitrite, TNF-alpha, IL-4, TGF-beta1, inducible form of nitric oxide synthase (iNOS), and corticosterone significantly increased compared to the sham group. The elevated levels of Th(1) cytokines, namely TNF-alpha, IL-1beta, IFN-gamma, nitrite, and iNOS, decreased significantly both at +4 and +24 h of WBH, following L-arg administration. However, L-arg administration did not reduce the increased levels of Th(2) cytokines, namely IL-4 and TGF-beta1, in WBH mice at +4 h of WBH. L-arg administration significantly increased the levels of Th(2) cytokines at +24 h of WBH, compared to the saline-treated WBH mice. L-arg administration significantly increased both the splenic and hepatic arginase activity at +4 and +24 h of WBH compared to the saline-treated WBH mice. L-NAME treatment at +2 h of WBH and anti-TGF-beta antibody treatment at 0 h of WBH significantly increased the mortality compared to the saline-treated WBH mice. Altered liver histopathology was attenuated following the administration of L-arg at +2 h of WBH. These results suggest that therapeutic administration of L-arg at appropriate concentration and time attenuates the acute inflammatory response, leading to the rescue of mice from heatstroke.

MeSH terms

  • Animals
  • Antibodies / therapeutic use
  • Arginine / metabolism*
  • Corticosterone / blood
  • Cytokines / blood*
  • Dexamethasone / therapeutic use
  • Heat Stroke / blood*
  • Heat Stroke / drug therapy
  • Heat Stroke / therapy
  • Liver / enzymology
  • Mice
  • NG-Nitroarginine Methyl Ester / therapeutic use
  • Nitric Oxide Synthase Type II / metabolism
  • Nitrites / blood
  • Th1 Cells / metabolism*
  • Th2 Cells / metabolism*
  • Transforming Growth Factor beta / immunology


  • Antibodies
  • Cytokines
  • Nitrites
  • Transforming Growth Factor beta
  • Dexamethasone
  • Arginine
  • Nitric Oxide Synthase Type II
  • NG-Nitroarginine Methyl Ester
  • Corticosterone