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ANESTHETIC PHARMACOLOGY

Ketamine Stereoselectively Inhibits Spontaneous Ca²⁺-Oscillations in Cultured Hippocampal Neurons

Barbara Sinner, MD^*, Oliver Friedrich, MD, PhD, Wolfgang Zink, MD^*, Eike Martin, MD^*, Rainer H. A. Fink, PhD, and Bernhard M. Graf, MD, PhD^*

*Department of Anesthesiology, and Institute for Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany

Address correspondence and reprint requests to Bernhard M. Graf, MD, PhD, Department of Anesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Address e-mail to Bernhard_graf{at}med.uni-heidelberg.de.

Spontaneous Ca²⁺-oscillations are a result of periodic increases and decreases of cytosolic Ca²⁺. In neurons, they are thought to possess integrative properties because amplitude and frequency influence axon outgrowth, neuronal growth cone migration, and long distant wiring within the developing cortex. Ketamine stereoisomers differ in their affinities for the N-methyl-d-aspartic acid receptor and analgesic and anesthetic effects. Using a dual-excitation Ca²⁺ ratiometric fluorescence technique with the Ca²⁺-sensitive dye fura-2 AM, we detected spontaneous Ca²⁺-oscillations in neurons of hippocampal cell cultures. Spontaneous Ca²⁺-oscillations development is dependent on external Ca²⁺, and their amplitude and frequency increased in Mg²⁺-free solution. Ca²⁺-oscillations are glutamate dependent because blocking of the N-methyl-d-aspartic acid, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic, or kainate receptor resulted in a complete disruption of the oscillations. The ketamine stereoisomers dose-dependently and reversibly suppressed the amplitude and frequency of the spontaneous Ca²⁺-oscillations. This effect was highly stereoselective with the S(+) isomer being nearly four times more potent than the R(–) enantiomer. These results correlate well with the clinical anesthetic and analgesic potency of the stereoisomers and therefore our experimental approach might represent a model system to study mechanisms of anesthetic action on Ca²⁺-dependent integration of neuronal information.

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999