Nicotinic Receptors Partly Mediate Brainstem Autonomic Dysfunction Evoked by the Inhaled Anesthetic Isoflurane

In Brief BACKGROUND: Isoflurane is one of the most commonly used volatile anesthetics, yet the cardiorespiratory depression that occurs with its use remains poorly understood. In this study, the author examined isoflurane modulation of postsynaptic γ-aminobutyric acid (GABA) receptors in parasympathetic cardiac vagal neurons (CVNs) and alterations of GABAergic function by targeting nicotinic acetylcholine receptors on GABAergic presynaptic terminals. METHODS: Rhythmic inspiratory-related activity was recorded from the hypoglossal rootlet of 800 μm medullary sections. CVNs were identified by retrograde fluorescent labeling, and GABAergic neurotransmission to CVNs were examined using patch-clamp electrophysiological techniques. RESULTS: Isoflurane at concentrations of >50 μM significantly suppressed inspiratory bursting frequency, amplitude, and duration. Isoflurane dose-dependently decreased the frequency and increased the decay time of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs. To test whether the inhibition of GABAergic activity to CVNs was mediated by presynaptic nicotinic receptors, the nicotinic antagonist, dihydro-β-erythroidine in an α4β2-selective concentration (3 μM), was used. Dihydro-β-erythroidine (3 μM) prevented the isoflurane-evoked depression of spontaneous GABAergic IPSC frequency, yet isoflurane still increased the IPSC decay time. CONCLUSIONS: These results suggest clinically relevant concentrations of isoflurane inhibit brainstem respiratory rhythmogenesis, prolong inhibitory GABAergic postsynaptic currents and reduce GABA activity in CVNs. The decrease of GABAergic IPSCs frequency is dependent upon inhibition of presynaptic α4β2 nicotinic receptors. IMPLICATIONS: Clinically relevant concentrations of isoflurane inhibit brainstem respiratory rhythmogenesis, prolong γ-aminobutyric acid (GABA)ergic inhibitory postsynaptic currents (IPSC) and, in the meantime, reduce GABAergic IPSC frequency in cardiac vagal neurons. The decrease of the frequency of GABAergic IPSCs is partially dependent upon inhibition of presynaptic α4β2 nicotinic receptors. These mechanisms may contribute to cardiorespiratory homeostatic autonomic regulation impairment induced by isoflurane.