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Perturbation of neuronal calcium homeostasis may alter neurotransmission in the brain, a phenomenon postulated to characterize the anesthetic state. Because of the central role of plasma membrane Calcium2+ -ATPase (PMCA) in maintaining Calcium2+ homeostasis, the authors examined the effect of several inhalational anesthetics on PMCA function in synaptic plasma membranes (SPM) prepared from rat brain.Calcium2+ -ATPase pumping activity was assessed by measurement of ATP-dependent uptake of Calcium2+ by SPM vesicles. ATPase hydrolytic activity was assessed by spectrophotometric measurement of inorganic phosphate (Pi) released from ATP. For studies of anesthetic effects on PMCA activity, Calcium2+ uptake or Pi release was measured in SPM exposed to halothane, isoflurane, xenon, and nitrous oxide at partial pressures ranging from 0 to 1.6 MAC equivalents. Halothane and isoflurane exposures were carried out under a gassing hood. For xenon and nitrous oxide exposures, samples were incubated in a pressure chamber at total pressures sufficient to provide anesthetizing partial pressures for each agent.Dose-related inhibition of Calcium2+ -ATPase pumping activity was observed in SPM exposed to increasing concentrations of halothane and isoflurane, confirmed by ANOVA and multiple comparison testing (P < 0.05). Concentrations of halothane and isoflurane equivalent to one minimum effective dose (MED) depressed PMCA pumping approximately 30%. Xenon and nitrous oxide also inhibited Calcium2+ uptake by SPM vesicles. At partial pressures of these two gases equivalent to 1.3 MAC, PMCA was inhibited approximately 20%. Hydrolysis of ATP by SPM fractions was also inhibited in a dose-related fashion. An additive effect occurred when 1 vol% of halothane was added to xenon or nitrous oxide at partial pressures equivalent to 0–1.6 MAC for the latter two agents.Plasma membranes Calcium2+ -ATPase is significantly inhibited, in a dose-related manner, by clinically relevant partial pressures of halothane, isoflurane, xenon, and nitrous oxide. Furthermore, these anesthetics inhibit PMCA activity in accordance with their known potencies, and an additive effect was observed. How inhalational anesthetics inhibit the PMCA pump is not known at this time. It is noteworthy that the only shared characteristic of this group of agents of widely different structure is anesthetic action. The relevance of this dual commonality, anesthetic action and PMCA inhibition, to actual production of the anesthetic state remains to be determined.