Effects Of Etomidate On Calcium Dynamics And Neurotransmitters Release In Rat Cerebrocortical Synaptosomes

Background: Etomidate is an intravenous anesthetic usually used in clinical anesthesia. The previous studies indicated it produced anesthetic effect through its mimic GABA action ,which enhanced central inhibition mediated by postsynaptic GABAa receptors. Recent investigations suggested most general anesthetics had their effects on presynapse, which changed neurotransmitters release from nerve terminals, reducing excitory neurotransmitters release or increasing inhibitory neurotransmitters release, and therefore depressed the central synaptic neurotransmission. The laboratorial investigation was designed to verdict the effects of etomidate on presynapse and deepen understanding its anesthesia mechanism. Methods: The synaptosomes,isolated nerve terminals, is a good tool to study drug effects on presynapse. By using freshly isolated SD rat cerebrocortical synaptosomes and KC1 as chemical stimulant to depolarize, we studied the effects of etomidate on KCl-induced increased intrasynaptosomal calcium concentrations, voltage-gated calcium channel subtypes on presynaptic membrane and neurotransmitters release from synaptosomes respectively, via neurochemical and inverse phase high performance liquid chromatographic(HPLC) methods. Results:1. Etomidate with Various concentrations(fmal concentration was 0.4, 4, 40 and 100uM, respectively) dose-dependently inhibited increasedintrasynaptosomal calcium concentrations induced by 50 mM KC1, in which the inhibitory ratio of peak calcium concentrations was 5+3%, 11+6%, 24+10% and 33+12%,respectively. And 40uM etomidate and above had significant effects (P<0.05) .The results also revealed the anesthetic had a smaller inhibitory action on plateau calcium concentrations than peak ones.2. The P-type (maybe including Q-type) calcium channel accounted for 50% calcium influx into synaptosomes, N-type for about 20%,while L-type didn't change KCl-induced increased intrasynaptosomal calcium concentrations. P/Q-type calcium channel antagonist co-agatoxin IVA had no different effects on increased intrasynaptosomal calcium concentrations with or without 100uM etomidate, but for N- or L-type calcium channel antagonist,it had additional effects when with etomidate.3. The intravenous anesthetic agent etomidate with various concentrations (0.4, 4 and 40uM) inhibited calcium-dependent glutamate (inhibitory ratio was 13%, 25% and 30% compared with control, respectively) and GABA (inhibitory ratio was 7%, 16% and 37% compared with control, respectively) release from rat cerebrocortical synaptosomes.Conclusions: The intravenous anesthetic agent etomidate dose-dependently inhibited voltage-sensitive calcium channels located on presynaptic membrane and 40uM or above has significant effect, which was associated with P-type(and possible Q-type) calcium channel block. It led to reduce in neurotranmitters-Glutamate and GABA-release, which implied etomidate produced its presynaptic effects via neurotransmission down-modulatory resulting in a lower excitory/inhibitory balance on cerebrocortice level.