title: The effects of arginine and selective inducible nitric oxide synthase inhibitor on pathophysiology of sepsis in a CLP model.
abstract: BACKGROUND
  Sepsis is an arginine-deficient state and is associated with overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS). It has been indicated that low plasma levels of arginine are related to high mortality rates in sepsis. Arginine, however, is also known to be a precursor of NO. Therefore, administration of arginine in septic patients remains controversial. We examined the effects of co-administration of arginine and aminoguanidine, a selective iNOS inhibitor, on sepsis, using rat models.
  
  
  METHODS
  Sepsis was induced in rats by cecal ligation and puncture (CLP). Effects of separate and combined administration of arginine and aminoguanidine were investigated by comparing plasma levels of arginine, expressions of heme oxygenase (HO)-1 and HO-2 in liver and lung, and nitrite + nitrate (NOx) excretion in urine, as well as neuroendocrine responses in urine in the early phase of sepsis. Seven-day survival rates were also examined.
  
  
  RESULTS
  A combination of arginine and aminoguanidine recovered the plasma level of arginine at 6 h post-CLP, decreased expression of HO-1 in liver and lung at 24 h post-CLP, decreased urinary excretion of epinephrine, norepinephrine, dopamine, and 17-hydroxycorticosteroid in the first 24 h post-CLP, and increased 7-d survival.
  
  
  CONCLUSIONS
  It is demonstrated that administration of arginine together with the selective iNOS inhibitor in the early phase of sepsis restores plasma arginine, reduces oxidative stress by probably maintaining NO derived from constitutive NOS, and attenuates neuroendocrine stress responses. This co-administration may be a beneficial treatment approach against sepsis.
authors.affiliation: Division of Emergency Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Xie
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Shinozawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Sasaki
authors.forename: Kiyotsugu
authors.initials: K
authors.lastname: Takuma
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akaishi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamanouchi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Endo
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nomura
authors.forename: Michio
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kudo
authors.forename: Nobuko
authors.initials: N
authors.lastname: Hojo
mesh_terms: D000818:Animals; D001120:Arginine / Q000008:administration & dosage* / Q000097:blood; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006146:Guanidines / Q000008:administration & dosage*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000652:urine; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D009573:Nitrites / Q000652:urine; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D009566:Nitrates; D009573:Nitrites; D001120:Arginine; D019001:Nitric Oxide Synthase; D051547:Heme Oxygenase-1; C004479:pimagedine