Effects of sevoflurane on excitatory neurotransmission to medullary expiratory neurons and on phrenic nerve activity in a decerebrate dog model

Abstract

Background: Sevoflurane is a new volatile anesthetic with a pronounced respiratory depressant effect. Synaptic neurotransmission in canine expiratory bulbospinal neurons is mainly mediated by excitatory N-methyl-D-aspartatic acid (NMDA) receptor input and modulated by inhibitory γ-aminobutyric acid type A (GABAA) receptors. The authors investigated the effect of sevoflurane on these mechanisms in decerebrate dogs. Methods: Studies were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC; 2.4%) sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the glutamate agonist NMDA and the GABAA receptor blocker bicuculline in a two-part protocol. First, complete blockade of the GABAA ergic mechanism by bicuculline allowed differentiation between the effects of sevoflurane on overall GABAA ergic inhibition and on overall glutamatergic excitation. In a second step, the neuronal response to exogenous NMDA was used to estimate sevoflurane's effect on postsynaptic glutamatergic neurotransmission. Results: One minimum alveolar concentration sevoflurane depressed the spontaneous activity of 16 expiratory neurons by 36.7 ± 22.4% (mean ± SD). Overall glutamatergic excitation was depressed 19.5 ± 16.2%, and GABAA ergic inhibition was enhanced 18.7 ± 20.6%. However, the postsynaptic response to exogenous NMDA was not significantly altered. In addition, 1 MAC sevoflurane depressed peak phrenic nerve activity by 61.8 ± 17.7%. Conclusions: In the authors' in vivo expiratory neuronal model, the depressive effect of sevoflurane on synaptic neurotransmission was caused by a reduction of presynaptic glutamatergic excitation and an enhancement of GABAA ergic inhibition. The effects on expiratory neuronal activity were similar to halothane, but sevoflurane caused a stronger depression of phrenic nerve activity than halothane.