Published Online
on May 5, 2005

A more recent version of this article appeared on June 1, 2005

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Submitted on February 10, 2005
Accepted on March 3, 2005

Increased Extracellular K⁺ Concentration Reduces the Efficacy of N-methyl-D-aspartate Receptor Antagonists to Block Spreading Depression-Like Depolarizations and Spreading Ischemia

Gabor C. Petzold MD; Olaf Windmüller MS; Stephan Haack MS; Sebastian Major MD; Katharina Buchheim MD; Dirk Megow PhD; Siegrun Gabriel PhD; Thomas-Nicolas Lehmann MD; Christoph Drenckhahn MD; Oliver Peters MD; Hartmut Meierkord MD; Uwe Heinemann MD; Ulrich Dirnagl MD; and Jens P. Dreier MD^*

From the Department of Neurology (G.C.P., S.M., K.B., C.D., H.M., U.D., J.P.D.) and the Department of Experimental Neurology (G.C.P., O.W., S.H., S.M., D.M., C.D., U.D.), Charité-University Medicine Berlin, Berlin, Germany; the Johannes Müller Institute of Physiology (S.G., U.H.), Charité-University Medicine Berlin, Berlin, Germany; the Department of Neurosurgery (T.-N.L.), Charité-University Medicine Berlin, Berlin, Germany; and the Department of Psychiatry (O.P.), Charité-University Medicine Berlin, Berlin, Germany.

^* To whom correspondence should be addressed. E-mail: jens.dreier{at}charite.de.

Background and Purpose--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.

Key words: brain injuries • N-methyl-D-aspartate • spreading cortical depression • stroke • subarachnoid hemorrhage • trauma

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