title: Pharmacologically augmented S-nitrosylated hemoglobin improves recovery from murine subarachnoid hemorrhage.
abstract: OBJECTIVE
  S-nitrosylated hemoglobin (S-nitrosohemoglobin) has been implicated in the delivery of O(2) to tissues through the regulation of microvascular blood flow. This study tested the hypothesis that enhancement of S-nitrosylated hemoglobin by ethyl nitrite inhalation improves outcome after experimental subarachnoid hemorrhage (SAH).
  
  
  METHODS
  A preliminary dosing study identified 20 ppm ethyl nitrite as a concentration that produced a 4-fold increase in S-nitrosylated hemoglobin concentration with no increase in methemoglobin. Mice were subjected to endovascular perforation of the right anterior cerebral artery and were treated with 20 ppm ethyl nitrite in air, or air alone for 72 hours, after which neurologic function, cerebral vessel diameter, brain water content, cortical tissue Po(2), and parenchymal red blood cell flow velocity were measured.
  
  
  RESULTS
  At 72 hours after hemorrhage, air- and ethyl nitrite-exposed mice had similarly sized blood clots. Ethyl nitrite improved neurologic score and rotarod performance; abated SAH-induced constrictions in the ipsilateral anterior, middle cerebral, and internal carotid arteries; and prevented an increase in ipsilateral brain water content. Ethyl nitrite inhalation increased red blood cell flow velocity and cortical tissue Po(2) in the ipsilateral cortex with no effect on systemic blood pressure.
  
  
  CONCLUSIONS
  Targeted S-nitrosylation of hemoglobin improved outcome parameters, including vessel diameter, tissue blood flow, cortical tissue Po(2), and neurologic function in a murine SAH model. Augmenting endogenous Po(2)-dependent delivery of NO bioactivity to selectively dilate the compromised cerebral vasculature has significant clinical potential in the treatment of SAH.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
authors.forename: James D
authors.initials: JD
authors.lastname: Reynolds
authors.forename: Richard L
authors.initials: RL
authors.lastname: Auten
authors.forename: Ivan T
authors.initials: IT
authors.lastname: Demchenko
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage* / Q000627:therapeutic use; D000280:Administration, Inhalation; D000818:Animals; D004357:Drug Synergism; D006454:Hemoglobins / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009573:Nitrites / Q000008:administration & dosage*; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000277:Adjuvants, Pharmaceutic; D006454:Hemoglobins; D009573:Nitrites; C103574:S-nitrosohemoglobin; C032712:ethyl nitrite