HALOTHANE, ISOFLURANE, XENON, AND NITROUS-OXIDE INHIBIT CALCIUM-ATPASE PUMP ACTIVITY IN RAT-BRAIN SYNAPTIC PLASMA-MEMBRANES

Background: Perturbation of neuronal calcium homeostasis may alter neu rotransmission in the brain, a phenomenon postulated to characterize t he anesthetic state. Because of the central role of plasma membrane Ca 2+-ATPase (PMCA) in maintaining Ca2+ homeostasis, the authors examined the effect of several inhalational anesthetics on PMCA function in sy naptic plasma membranes (SPM) prepared from rat brain. Methods: Ca2+-A TPase pumping activity was assessed by measurement of ATP-dependent up take of Ca2+ 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, Ca2+ up take or Pi release was measured in SPM exposed to halothane, isofluran e, 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 w ere incubated in a pressure chamber at total pressures sufficient to p rovide anesthetizing partial pressures for each agent. Results: Dose-r elated inhibition of Ca2+-ATPase pumping activity was observed in SPM exposed to increasing concentrations of halothane and isoflurane, conf irmed by ANOVA and multiple comparison testing (P < 0.05). Concentrati ons of halothane and isoflurane equivalent to one minimum effective do se (MED) depressed PMCA pumping approximately 30%, Xenon and nitrous o xide also inhibited Ca2+ uptake by SPM vesicles, At partial pressures of these two gases equivalent to 1.3 MAC, PMCA was inhibited approxima tely 20%. Hydrolysis of ATP by SPM fractions was also inhibited in a d ose-related fashion. An additive effect occurred when 1 vol% of haloth ane was added to xenon or nitrous oxide at partial pressures equivalen t to 0-1.6 MAC for the latter two agents. Conclusions: Plasma membrane s Ca2+-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 activ ity in accordance with their known potencies, and an additive effect w as observed, How inhalational anesthetics inhibit the PMCA pump is not known at this time, It is noteworthy that the only shared characteris tic of this group of agents of widely different structure is anestheti c action, The relevance of this dual commonality, anesthetic action an d PMCA inhibition, to actual production of the anesthetic state remain s to be determined.