title: Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm.
abstract: OBJECTIVE
  Vasospasm-induced delayed cerebral ischemia remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that activating innate neurovascular protective mechanisms by preconditioning (PC) may represent a novel therapeutic approach against SAH-induced vasospasm and neurological deficits and, secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS).
  
  
  METHODS
  Wild-type mice were subjected to hypoxic PC or normoxia followed 24 hours later by SAH. Neurological function was analyzed daily; vasospasm was assessed on post-surgery Day 2. Nitric oxide availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, wild-type and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits.
  
  
  RESULTS
  PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in nitric oxide availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in wild-type mice treated with the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester and in eNOS-null mice.
  
  
  CONCLUSIONS
  Endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced by PC. eNOS-derived nitric oxide is a critical mediator of PC-induced neurovascular protection. These data provide strong "proof-of-principle" evidence that PC represents a promising new strategy to reduce vasospasm and delayed cerebral ischemia after SAH.
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Ananth K
authors.initials: AK
authors.lastname: Vellimana
authors.forename: Eric
authors.initials: E
authors.lastname: Milner
authors.forename: Tej D
authors.initials: TD
authors.lastname: Azad
authors.forename: Michael D
authors.initials: MD
authors.lastname: Harries
authors.forename: Meng-Liang
authors.initials: ML
authors.lastname: Zhou
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gidday
authors.forename: Byung Hee
authors.initials: BH
authors.lastname: Han
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Zipfel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control*; D020301:Vasospasm, Intracranial / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III