title: Increased extracellular K+ concentration reduces the efficacy of N-methyl-D-aspartate receptor antagonists to block spreading depression-like depolarizations and spreading ischemia.
abstract: OBJECTIVE
  Spreading depression (SD)-like depolarizations may augment neuronal damage in neurovascular disorders such as stroke and traumatic brain injury. Spreading ischemia (SI), a particularly malignant variant of SD-like depolarization, is characterized by inverse coupling between the spreading depolarization wave and cerebral blood flow. SI has been implicated in particular in the pathophysiology of subarachnoid hemorrhage. Under physiological conditions, SD is blocked by N-methyl-D-aspartate receptor (NMDAR) antagonists. However, because both SD-like depolarizations and SI occur in presence of an increased extracellular K+ concentration ([K+]o), we tested whether this increase in baseline [K+]o would reduce the efficacy of NMDAR antagonists.
  
  
  METHODS
  Cranial window preparations, laser Doppler flowmetry, and K+-sensitive/reference microelectrodes were used to record SD, SD-like depolarizations, and SI in rats in vivo; microelectrodes and intrinsic optical signal measurements were used to record SD and SD-like depolarizations in human and rat brain slices.
  
  
  RESULTS
  In vivo, the noncompetitive NMDAR antagonist dizocilpine (MK-801) blocked SD propagation under physiological conditions, but did not block SD-like depolarizations or SI under high baseline [K+]o. Similar results were found in human and rat neocortical slices with both MK-801 and the competitive NMDAR antagonist D-2-amino-5-phosphonovaleric acid.
  
  
  CONCLUSIONS
  Our data suggest that elevated baseline [K+]o reduces the efficacy of NMDAR antagonists on SD-like depolarizations and SI. In conditions of moderate energy depletion, as in the ischemic penumbra, or after subarachnoid hemorrhage, NMDAR inhibition may not be sufficient to block these depolarizations.
authors.affiliation: Department of Neurology, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Gabor C
authors.initials: GC
authors.lastname: Petzold
authors.forename: Olaf
authors.initials: O
authors.lastname: Windmüller
authors.forename: Stephan
authors.initials: S
authors.lastname: Haack
authors.forename: Sebastian
authors.initials: S
authors.lastname: Major
authors.forename: Katharina
authors.initials: K
authors.lastname: Buchheim
authors.forename: Dirk
authors.initials: D
authors.lastname: Megow
authors.forename: Siegrun
authors.initials: S
authors.lastname: Gabriel
authors.forename: Thomas-Nicolas
authors.initials: TN
authors.lastname: Lehmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Drenckhahn
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.forename: Hartmut
authors.initials: H
authors.lastname: Meierkord
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: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy; D013181:Cortical Spreading Depression / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004566:Electrodes; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007477:Ions; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017078:Laser-Doppler Flowmetry; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D011188:Potassium / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007477:Ions; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D011188:Potassium