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.