title: A role of the sodium pump in spreading ischemia in rats.
abstract: In rats, spreading depolarization induces vasodilation/hyperemia in naïve tissue but the inverse response when artificial cerebrospinal fluid is topically applied to the brain containing (a) a nitric oxide-lowering agent and (b) elevated K+. The inverse response is characterized by severe vasoconstriction/ischemia. The perfusion deficit runs together with the depolarization in the tissue (=spreading ischemia). Here, we found in male Wistar rats that pre-treatment with artificial cerebrospinal fluid containing elevated K+in vivo led to a selective decline in α2/α3Na+/K+-ATPase activity, determined spectrophotometrically ex vivo. Moreover, spreading ischemia, recorded with laser-Doppler flowmetry and electrocorticography, resulted from artificial cerebrospinal fluid containing a nitric oxide-lowering agent in combination with the Na+/K+-ATPase inhibitor ouabain at a concentration selectively inhibiting α2/α3activity. Decline in α2/α3activity results in increased Ca2+uptake by internal stores of astrocytes, vascular myocytes, and pericytes since Ca2+outflux via plasmalemmal Na+/Ca2+-exchanger declines. Augmented Ca2+mobilization from internal stores during spreading depolarization might enhance vasoconstriction, thus, contributing to spreading ischemia. Accordingly, spreading ischemia was significantly shortened when intracellular Ca2+stores were emptied by pre-treatment with thapsigargin, an inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA). These findings might have relevance for clinical conditions, in which spreading ischemia occurs such as delayed cerebral ischemia after subarachnoid hemorrhage.
authors.affiliation: 1 Department of Experimental Neurology, Charité University Medicine Berlin, Berlin, Germany.|2 Center for Stroke Research Berlin, Charité University Medicine Berlin, Berlin, Germany.|3 Department of Neurology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Major
authors.affiliation: 4 German Center for Neurodegenerative Diseases (DZNE), University Hospital Bonn, Bonn, Germany.|5 Department of Neurology, University Hospital Bonn, Bonn, Germany.
authors.forename: Gabor C
authors.initials: GC
authors.lastname: Petzold
authors.affiliation: 3 Department of Neurology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Reiffurth
authors.affiliation: 6 Department of Psychiatry, Medizinische Hochschule Brandenburg, Ruppiner Kliniken GmbH, Neuruppin, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Windmüller
authors.affiliation: 1 Department of Experimental Neurology, Charité University Medicine Berlin, Berlin, Germany.|2 Center for Stroke Research Berlin, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Foddis
authors.affiliation: 7 Department of Neurosurgery, University of Aachen, Aachen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Lindauer
authors.affiliation: 1 Department of Experimental Neurology, Charité University Medicine Berlin, Berlin, Germany.|2 Center for Stroke Research Berlin, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Eun-Jeung
authors.initials: EJ
authors.lastname: Kang
authors.affiliation: 1 Department of Experimental Neurology, Charité University Medicine Berlin, Berlin, Germany.|2 Center for Stroke Research Berlin, Charité University Medicine Berlin, Berlin, Germany.|3 Department of Neurology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Jens P
authors.initials: JP
authors.lastname: Dreier
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000737:chemistry; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D013181:Cortical Spreading Depression / Q000502:physiology*; D000069280:Electrocorticography; D017078:Laser-Doppler Flowmetry; D008297:Male; D011189:Potassium Chloride / Q000494:pharmacology; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013053:Spectrophotometry; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D011189:Potassium Chloride; C498532:Atp1a2 protein, rat; C541459:Atp1a3 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium
keywords: Na+/K+-ATPase; Spreading depolarization; inverse coupling; migraine; spreading depression; stroke; subarachnoid hemorrhage; vasospasm