L-type calcium channel blockade modifies anesthetic actions on aged hippocampal neurons

Previous studies in our laboratory demonstrated a reversal of anesthetic actions on aged neurons by decreasing extracellular [Ca2+] in hippocampal slices. Such maneuver indirectly attenuated Ca2+ influx, hence decreased exogenous intraneuronal Ca2+ loads during neuronal activity and consequently improved intracellular Ca2+ concentration homeostasis. Therefore, in the present study we hypothesized that decreasing exogenous Ca2+ loads by blocking voltage-gated calcium influx in aged neurons would oppose isoflurane actions. Conversely, increasing endogenous Ca2+ loads by suppressing calcium efflux during forced reversal of Na+/Ca2+ exchanger function would enhance anesthetic effects. Hippocampal slices were prepared from young (2-4 months) and old (24-26 months) Fischer 344 rats. Isoflurane depressed the evoked dendritic field excitatory postsynaptic potentials by approximately 45% in slices taken from old animals. However, application of isoflurane in addition with COCl2 or nifedipine opposed the anesthetic actions, which then depressed the evoked dendritic field postsynaptic potentials by only 15%. Selective blockade of the N-type and P/Q-type calcium channels with omega-conotoxin GVIA and (omega-conotoxin MVIIC respectively caused rapid but partial depression of synaptic transmission in slices taken from old Fischer 344 rats. However, isoflurane actions in these aged slices were not affected compared with slices perfused only with normal artificial cerebrospinal fluid. Young and aged slices were then exposed to a low sodium perfusate that forces the Na+/Ca2+ exchanger protein into a reverse mode, thus increasing intracellular Ca2+ concentration. Isoflurane actions under such conditions were profoundly potentiated in aged slices but were not altered in young hippocampi. The current results show that in aged central neurons, selectively blocking L-type calcium channels opposes anesthetic-induced depression of excitatory synaptic transmission. On the contrary, increasing calcium loads in aged neurons potentiates these actions. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.