ANESTHETIC-INDUCED ALTERATION OF CA2- A TEMPERATURE-SENSITIVE PROCESSTHAT IS ENHANCED BY BLOCKADE OF PLASMA-MEMBRANE CA2+-ATPASE ISOFORMS(HOMEOSTASIS IN NEURAL CELLS )

Background: Many inhalation anesthetics at clinically relevant concent rations inhibit plasma membrane Ca2+-adenosine triphosphatase (PMCA) i on pumping in brain synaptic membranes and in cultured cells of neural origin. In this study, the authors investigated the effect of inhalat ion anesthetics on cytosolic calcium homeostasis in cortical neurons m aintained at physiologic and room temperatures and on cortical neurons and pheochromocytoma cells with antisense blockade of specific PMCA i soforms. Methods: Using Ca2+-specific confocal microfluorimetry, the a nesthetic effects on Ca2+ dynamics were examined in mouse embryonic co rtical neurons in association with ligand-stimulated Ca2+ influx, Stud ies were done at 21 degrees C and 37 degrees C. Mouse embryonic cortic al neurons with oligodeoxyribonucleotide blockade of PMCA2 expression and transfected rat pheochromocytoma cells with blocked expression of PMCA1 were also examined Results: Baseline and poststimulation peak cy tosolic calcium concentrations ([Ca2+](i)) were increased, and Ca2+ cl earance was delayed in cells exposed at 37 degrees C, but not at 21 de grees C, to concentrations less than or equal to 1 minimum alveolar co ncentration (MAC)-equivalent of halothane, isoflurane, and sevoflurane . Nenrons exposed to xenon solutions less than or equal to 0.4, 0.6, a nd 0.8 MAC showed dose-related perturbations of cytosolic Ca2+. Calciu m dynamics were altered in neural cells with blocked PMCA isoform prod uction, but at much lower halothane concentrations: 0.5 MAC for cortic al neurons and 0.1 MAC for pheochromocytoma cells. Conclusions: By ext ruding Ca2+ through the plasma membrane, PMCA maintains resting neuron al [Ca2+]i at low levels and clears physiologic loads of Ca2+ after in flux through calcium channels. Inhalation anesthetics perturb this pro cess and thus may interfere with neurotransmitter release, altering in terneuronal signaling.