title: The role of selective nitric oxide synthase inhibitor on nitric oxide and PGE2 levels in refractory hemorrhagic-shocked rats.
abstract: BACKGROUND
  The up-regulation of nitric oxide (NO) and cyclooxgenase-2 (COX-2) has been implicated in the pathophysiology of hemorrhagic shock. We examined the effects of aminoguanidine (AG), which is a known inducible nitric oxide synthase (iNOS) inhibitor, and NS-398, a known COX-2 inhibitor, in our rat model of refractory hemorrhagic shock (RHS).
  
  
  METHODS
  We measured tissue iNOS and COX-2 protein expression, brain and plasma nitrate/nitrite and prostaglandin E2 (PGE2) levels, plasma creatinine and glutamic oxalacetic transaminase (GOT) levels, quantified the histological damages in kidney, liver, lung, and brain, survival rate, and mean arterial blood pressure (MABP) in RHS rats.
  
  
  RESULTS
  Semiquantitative analysis of tissues showed iNOS protein was not detected in AG + RHS rats but was detected in normal saline and NS-398 RHS rats. Tissue COX-2 protein was not detected in AG and NS-398 RHS rats but was detected in normal saline + RHS rats. The levels of brain and plasma nitrate/nitrite and PGE2 and plasma creatinine and GOT were significantly lower in the AG + RHS rat group when compared with the normal saline RHS rat group. Histological examinations also showed a reduction in organ damage for AG + RHS rats when compared with treated RHS rats. AG + RHS rats showed significantly increased survival and MABP level when compared with treated RHS rats.
  
  
  CONCLUSIONS
  Our present findings suggest that NO produced by iNOS might result in organ damages. This in turn might lead to COX-2 up-regulation, and it increases the production of reactive oxygen species and toxic prostanoids. NO-mediated organ damage might be one way in which toxic products of COX-2 might further contribute to NO's deleterious effect in the later stages of RHS. It is therefore suggested that treatment of AG via inhibition of NO might contribute to improved physiological parameters and survival rates following RHS.
authors.affiliation: Department of Pharmacology, National University of Singapore.
authors.forename: Shirhan
authors.initials: S
authors.lastname: Md
authors.forename: Shabbir M
authors.initials: SM
authors.lastname: Moochhala
authors.forename: Kerwin Low
authors.initials: KL
authors.lastname: Siew Yang
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.forename: Farhana
authors.initials: F
authors.lastname: Anuar
authors.forename: Pamela
authors.initials: P
authors.lastname: Mok
authors.forename: Kian Chye
authors.initials: KC
authors.lastname: Ng
mesh_terms: D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001794:Blood Pressure; D001921:Brain / Q000473:pathology; D003404:Creatinine / Q000097:blood; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D015151:Immunoblotting; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D009562:Nissl Bodies; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D013449:Sulfonamides / Q000494:pharmacology; D015996:Survival Rate
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D006146:Guanidines; D009566:Nitrates; D009573:Nitrites; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009569:Nitric Oxide; D003404:Creatinine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D001219:Aspartate Aminotransferases; D015232:Dinoprostone; C004479:pimagedine