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ANESTHETIC PHARMACOLOGY

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

From the Departments of Pharmacology and Physiology, and Anesthesiology and Critical Care Medicine, The George Washington University, Washington, DC.

Address correspondence and reprint requests to Dr. Xin Wang, Departments of Pharmacology and Physiology, and Anesthesiology and Critical Care medicine, The George Washington University, 2300 Eye St., NW, Ross Hall 654, Washington, DC 20037. Address e-mail to xinwang{at}gwu.edu.

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 -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 ₄β₂-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 ₄β₂ nicotinic receptors.