Deep Isoflurane Anesthesia Is Associated with Alterations in Ion Homeostasis and Specific Na+/K+-ATPase Impairment in the Rat Brain

Author:

Reiffurth Clemens1,Berndt Nikolaus2,Gonzalez Lopez Adrian3,Schoknecht Karl4,Kovács Richard5,Maechler Mathilde6,grote Lambers Mirja7,Dreier Jens P.8,Friedman Alon9,Spies Claudia10,Liotta Agustin11

Affiliation:

1. 1Center for Stroke Research and Department of Experimental Neurology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Berlin, Germany.

2. 2Institute of Computer-Assisted Cardiovascular Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany, and Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Berlin, Germany.

3. 3Department of Anesthesiology and Intensive Care, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Berlin, Germany.

4. 4Carl-Ludwig-Institute for Physiology, Medical Faculty, University of Leipzig, Leipzig, Germany.

5. 5Institute of Neurophysiology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Berlin, Germany.

6. 6Department of Anesthesiology and Intensive Care and Institute of Neurophysiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

7. 7Institute of Neurophysiology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Berlin, Germany.

8. 8Center for Stroke Research, Department of Experimental Neurology, and Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Berlin, Germany; Bernstein Center for Computational Neuroscience Berlin, Humboldt–Universität zu Berlin, Germany; and Einstein Center for Neurosciences Berlin, Berlin, Germany.

9. 9Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Canada; and Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

10. 10Department of Anesthesiology and Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; and Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.

11. 11Department of Experimental Neurology, Department of Anesthesiology and Intensive Care, Institute of Neurophysiology, and Neuroscience Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany, and Institute of Computer-assisted Cardiovascular Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany.

Abstract

BackgroundMaintenance of ion homeostasis is essential for normal brain function. Inhalational anesthetics are known to act on various receptors, but their effects on ion homeostatic systems, such as sodium/potassium-adenosine triphosphatase (Na+/K+-ATPase), remain largely unexplored. Based on reports demonstrating global network activity and wakefulness modulation by interstitial ions, the hypothesis was that deep isoflurane anesthesia affects ion homeostasis and the key mechanism for clearing extracellular potassium, Na+/K+-ATPase.MethodsUsing ion-selective microelectrodes, this study assessed isoflurane-induced extracellular ion dynamics in cortical slices of male and female Wistar rats in the absence of synaptic activity, in the presence of two-pore-domain potassium channel antagonists, during seizures, and during spreading depolarizations. The specific isoflurane effects on Na+/K+-ATPase function were measured using a coupled enzyme assay and studied the relevance of the findings in vivo and in silico.ResultsIsoflurane concentrations clinically relevant for burst suppression anesthesia increased baseline extracellular potassium (mean ± SD, 3.0 ± 0.0 vs. 3.9 ± 0.5 mM; P < 0.001; n = 39) and lowered extracellular sodium (153.4 ± 0.8 vs. 145.2 ± 6.0 mM; P < 0.001; n = 28). Similar changes in extracellular potassium and extracellular sodium and a substantial drop in extracellular calcium (1.5 ± 0.0 vs. 1.2 ± 0.1 mM; P = 0.001; n = 16) during inhibition of synaptic activity and two-pore-domain potassium suggested a different underlying mechanism. After seizure-like events and spreading depolarization, isoflurane greatly slowed extracellular potassium clearance (63.4 ± 18.2 vs. 196.2 ± 82.4 s; P < 0.001; n = 14). Na+/K+-ATPase activity was markedly reduced after isoflurane exposure (greater than 25%), affecting specifically the α2/3 activity fraction. In vivo, isoflurane-induced burst suppression resulted in impaired extracellular potassium clearance and interstitial potassium accumulation. A computational biophysical model reproduced the observed effects on extracellular potassium and displayed intensified bursting when Na+/K+-ATPase activity was reduced by 35%. Finally, Na+/K+-ATPase inhibition with ouabain induced burst-like activity during light anesthesia in vivo.ConclusionsThe results demonstrate cortical ion homeostasis perturbation and specific Na+/K+-ATPase impairment during deep isoflurane anesthesia. Slowed potassium clearance and extracellular accumulation might modulate cortical excitability during burst suppression generation, while prolonged Na+/K+-ATPase impairment could contribute to neuronal dysfunction after deep anesthesia.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Anesthesiology and Pain Medicine

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