Nicotinic receptors partly mediate brainstem autonomic dysfunction evoked by the inhaled anesthetic isoflurane.

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 gamma-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 microm 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 microM 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-beta-erythroidine in an alpha(4)beta(2)-selective concentration (3 microM), was used. Dihydro-beta-erythroidine (3 microM) 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 alpha(4)beta(2) nicotinic receptors.