title: Nitric oxide modulates spreading depolarization threshold in the human and rodent cortex.
abstract: OBJECTIVE
  Recent clinical data have suggested that prolonged cortical spreading depolarizations (CSDs) contribute to the pathogenesis of delayed ischemic neurologic deficits after subarachnoid hemorrhage. Elevated extracellular potassium concentrations and lowered nitric oxide (NO) levels have been detected in experimental and clinical subarachnoid hemorrhage. We investigated whether a similar extracellular composition renders the brain more susceptible to CSDs.
  
  
  METHODS
  Electrophysiologic and blood flow changes were studied in vivo in rats. Intrinsic optical signals, alterations of NO level, and electrophysiologic changes were investigated in rodent and human brain slices.
  
  
  RESULTS
  Elevation of subarachnoid extracellular potassium in rats in vivo triggered CSDs. Using NO-sensitive dyes, we found that CSDs induce NO synthesis in neurons and endothelial cells. When we blocked NO synthesis in vivo, CSDs occurred at a significantly lower threshold and propagated with a wave of ischemia. This increased susceptibility for CSDs by a low NO level was confirmed in rat and human neocortical slices and depended on P/Q-type calcium channels and N-methyl-D-aspartate receptors, but not on guanylate cyclase. Mice deficient in endothelial NO synthase, in contrast to mice deficient in neuronal NO synthase, had an inherently lower threshold.
  
  
  CONCLUSIONS
  Basal NO production determined CSD threshold. The threshold effect depended predominantly on endothelial NO synthase. Reduced NO levels, as in patients with subarachnoid hemorrhage, may render the brain more susceptible to CSDs. Because CSDs have been linked to the pathogenesis of delayed ischemic neurologic deficits, raising its threshold by increasing NO availability may prove therapeutically beneficial in patients with subarachnoid hemorrhage.
authors.affiliation: Department of Experimental Neurology, Charité University Medicine Berlin, Berlin, Germany. gpetzold@mcb.harvard.edu
authors.forename: Gabor C
authors.initials: GC
authors.lastname: Petzold
authors.forename: Stephan
authors.initials: S
authors.lastname: Haack
authors.forename: Oliver
authors.initials: O
authors.lastname: von Bohlen Und Halbach
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.forename: Thomas-Nicolas
authors.initials: TN
authors.lastname: Lehmann
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinemann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.forename: Jens P
authors.initials: JP
authors.lastname: Dreier
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000502:physiology; D002540:Cerebral Cortex / Q000098:blood supply / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology; D013181:Cortical Spreading Depression / Q000502:physiology*; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000502:physiology; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009924:Organ Culture Techniques; D011188:Potassium / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D013345:Subarachnoid Hemorrhage / Q000378:metabolism / Q000503:physiopathology*; D013346:Subarachnoid Space / Q000378:metabolism
chemical_list: D020864:Calcium Channels, N-Type; D005456:Fluorescent Dyes; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011188:Potassium; D016194:Receptors, N-Methyl-D-Aspartate; C496314:NOS3 protein, human; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat