title: Neuronal nitric oxide synthase inhibition attenuates cardiopulmonary dysfunctions after combined burn and smoke inhalation injury in sheep.
abstract: OBJECTIVE
  We hypothesized that nitric oxide derived from the neuronal nitric oxide synthase (NOS) is responsible for much of the injury resulting from skin burn and smoke inhalation. Therefore, we aimed to examine the effects of selective neuronal NOS inhibition on cardiopulmonary functions and cellular injury in sheep with acute respiratory distress syndrome secondary to combined burn and smoke inhalation injury.
  
  
  METHODS
  Prospective, randomized, controlled laboratory experiment.
  
  
  METHODS
  Investigational intensive care unit.
  
  
  METHODS
  A total of 22 chronically instrumented adult ewes.
  
  
  METHODS
  Sheep were randomly assigned to either healthy controls (sham), injured controls (40% third-degree flame burn; 48 breaths of cotton smoke), or an injury group treated with the specific neuronal NOS inhibitor 7-nitroindazole (1 mg x kg(-1) x hr(-1)) from 1 hr postinjury to the end of the 48-hr study period. Hypoxic pulmonary vasoconstriction was assessed as decrease in left pulmonary blood flow in response to single-lung hypoxic challenges (100% nitrogen) at baseline, 24 hrs, and 48 hrs.
  
  
  RESULTS
  The combination injury contributed to a approximately 90% loss of hypoxic pulmonary vasoconstriction and was associated with significant pulmonary shunting and death of one animal. The increase in nitrate/nitrite plasma levels in injured controls (12 hrs: 17 +/- 2 vs. 6 +/- 1 microM in sham animals; p < .001) was linked to increases in inducible NOS messenger RNA and 3-nitrotyrosine formation in lung tissue (48 hrs: 22 +/- 1 vs. 0.8 +/- 0.3 nM in sham animals; p < .001). 7-Nitroindazole treatment prevented the injury-associated changes in inducible NOS messenger RNA, nitrate/nitrite, and 3-nitrotyrosine, thereby attenuating the loss of hypoxic pulmonary vasoconstriction and improving gas exchange. In addition, 7-nitroindazole decreased lung tissue concentrations of hemoxygenase-1 and ameliorated myocardial depression, airway obstruction, pulmonary edema, ventilatory pressures, and histopathologic changes seen in injured controls.
  
  
  CONCLUSIONS
  The present study provides evidence that neuronal NOS-derived nitric oxide plays a pivotal role in the pathogenesis of acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.
authors: Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany. Martin.Westphal@gmx.net
authors: Martin
authors: M
authors: Westphal
authors: Perenlei
authors: P
authors: Enkhbaatar
authors: Frank C
authors: FC
authors: Schmalstieg
authors: Gabriela A
authors: GA
authors: Kulp
authors: Lillian D
authors: LD
authors: Traber
authors: Naoki
authors: N
authors: Morita
authors: Robert A
authors: RA
authors: Cox
authors: Hal K
authors: HK
authors: Hawkins
authors: Beena B
authors: BB
authors: Westphal-Varghese
authors: Helen E
authors: HE
authors: Rudloff
authors: Dirk M
authors: DM
authors: Maybauer
authors: Marc O
authors: MO
authors: Maybauer
authors: Ann S
authors: AS
authors: Burke
authors: Kazunori
authors: K
authors: Murakami
authors: Fiona
authors: F
authors: Saunders
authors: Eszter M
authors: EM
authors: Horvath
authors: Csaba
authors: C
authors: Szabo
authors: Daniel L
authors: DL
authors: Traber
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects; D000818:Animals; D002056:Burns / Q000150:complications*; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007191:Indazoles / Q000097:blood / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000503:physiopathology; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000150:complications*
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole