Anesthetic sensitivities to propofol and halothane in mice lacking the R-type (Cav2.3) Ca2+ channel.
Because inhibition of voltage-dependent Ca(2+) channels can be a mechanism underlying general anesthesia, we examined sensitivities to propofol and halothane in mice lacking the R-type (Ca(v)2.3) 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(v)2.3 channel knockouts (Ca(v)2.3(-/-)) than in wild-type (Ca(v)2.3(+/+)) 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 micro M) inhibited PSs by potentiating gamma-aminobutyric acid-ergic inhibition, and this potentiation was markedly smaller at 30 micro M in Ca(v)2.3(-/-) 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(v)2.3(-/-) 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(v)2.3(-/-) mice.


CONCLUSIONS
Because inhibition of neuronal Ca(2+) currents can be a mechanism underlying general anesthesia, we examined anesthetic sensitivities in mice lacking the R-type (Ca(v)2.3) Ca(2+) 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.
Takei
Tetsuhiro
T
Department of Anesthesiology, Graduate School of Medicine, Tokyo Medical and Dental University, Japan.
Saegusa
Hironao
H
Zong
Shuqin
S
Murakoshi
Takayuki
T
Makita
Koshi
K
Tanabe
Tsutomu
T
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D020908:Calcium Channels, R-Type / Q000235:genetics* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006221:Halothane / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D051379:Mice; D018345:Mice, Knockout; D015742:Propofol / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D013997:Time Factors
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D020908:Calcium Channels, R-Type; D006221:Halothane; D015742:Propofol