Increased extracellular K+ concentration reduces the efficacy of N-methyl-D-aspartate receptor antagonists to block spreading depression-like depolarizations and spreading ischemia.
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.
Petzold
Gabor C
GC
Department of Neurology, Charité-University Medicine Berlin, Berlin, Germany.
Windmüller
Olaf
O
Haack
Stephan
S
Major
Sebastian
S
Buchheim
Katharina
K
Megow
Dirk
D
Gabriel
Siegrun
S
Lehmann
Thomas-Nicolas
TN
Drenckhahn
Christoph
C
Peters
Oliver
O
Meierkord
Hartmut
H
Heinemann
Uwe
U
Dirnagl
Ulrich
U
Dreier
Jens P
JP
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
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