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ANESTHETIC PHARMACOLOGY

Anesthetic Sensitivities to Propofol and Halothane in Mice Lacking the R-Type (Ca_v2.3) Ca²⁺ Channel

Tetsuhiro Takei, MD^*, Hironao Saegusa, PhD, Shuqin Zong, MD PhD, Takayuki Murakoshi, MD PhD, Koshi Makita, MD PhD^*, and Tsutomu Tanabe, PhD

*Department of Anesthesiology and Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; and CREST, Japan Science and Technology Corp., Kawaguchi-shi, Japan

Address correspondence and reprint requests to Tsutomu Tanabe, PhD, Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Address e-mail to t-tanabe.mphm{at}tmd.ac.jp

Because inhibition of voltage-dependent Ca²⁺ channels can be a mechanism underlying general anesthesia, we examined sensitivities to propofol and halothane in mice lacking the R-type (Ca_v2.3) channel widely expressed in neurons. Sleep time after propofol injection (26 mg/kg IV) and halothane MAC_RR and MAC (50% effective concentrations for the loss of the righting reflex and for the tail pinch/withdrawal response, respectively) were determined. Significantly shorter propofol-induced sleep time (291.6 ± 16.8 s versus 344.4 ± 12.1 s) and larger halothane MAC_RR (1.11% ± 0.04% versus 0.98% ± 0.03%) were observed in Ca_v2.3 channel knockouts (Ca_v2.3^-/-) than in wild-type (Ca_v2.3^+/+) litter mates. To investigate the basis of the decreased anesthetic sensitivities in vivo, field excitatory postsynaptic potentials and population spikes (PSs) were recorded from Schaffer collateral CA1 synapses in hippocampal slices. Propofol (10–30 µM) inhibited PSs by potentiating -aminobutyric acid-ergic inhibition, and this potentiation was markedly smaller at 30 µM in Ca_v2.3^-/- mice, possibly accounting for the decreased propofol sensitivity in vivo. Halothane (1.4%–2.2%) inhibited field excitatory postsynaptic potentials similarly in both genotypes, whereas 1%–2% halothane depressed PSs more in Ca_v2.3^-/- mice, suggesting the postsynaptic role of the R-type channel in the propagation of excitation and other mechanisms underlying the increased halothane MAC_RR in Ca_v2.3^-/- mice.

IMPLICATIONS: Because inhibition of neuronal Ca²⁺ currents can be a mechanism underlying general anesthesia, we examined anesthetic sensitivities in mice lacking the R-type (Ca_v2.3) Ca²⁺ channels both in vivo and in hippocampal slices. Decreased sensitivities in mutant mice imply a possibility that agents blocking this channel may increase the requirements of anesthetics/hypnotics.

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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