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.
Wang
Xin
X
Departments of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA. xinwang@gwu.ed
D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001933:Brain Stem / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007002:Hypoglossal Nerve / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials; D007530:Isoflurane / Q000633:toxicity*; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D017661:Receptors, Presynaptic / Q000187:drug effects* / Q000378:metabolism; D012125:Respiratory Center / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism
D018685:Anesthetics, Inhalation; D018733:Nicotinic Antagonists; D018079:Receptors, GABA; D011978:Receptors, Nicotinic; D017661:Receptors, Presynaptic; C403531:nicotinic receptor alpha4beta2; D004079:Dihydro-beta-Erythroidine; D007530:Isoflurane