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Cyclothiazide‐induced persistent increase in respiratory‐related activity in vitro
Author(s) -
Babiec Walter E.,
Faull Kym F.,
Feldman Jack L.
Publication year - 2012
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2012.232421
Subject(s) - ampa receptor , genioglossus , airway , neuroscience , hypoglossal nerve , medicine , anesthesia , glutamate receptor , nmda receptor , tongue , receptor , biology , pathology
Key points• Hypoglossal (XII) motoneurons (MNs) innervate the genioglossus muscle of the tongue, which plays an important role in maintaining upper airway patency and modulating upper airway resistance. • Cyclothiazide (CTZ) is a diuretic, anti‐hypertensive, AMPA receptor modulator. • We show that CTZ induces a profound and long‐lasting increase in the amplitude of respiratory‐related XII nerve activity in rhythmically active neonatal rat medullary slices, with integrated XII nerve burst amplitude rising to 262 ± 23% of pre‐treatment control at 1 h post‐treatment and much of this increase lasting at least 12 h. • This phenomenon is not plasticity and does not depend on AMPA or NMDA receptor activation or on coincident protein kinase A or C activity for its induction. • Electrophysiological and mass spectrometric analyses indicate that the cause is prolonged bioavailability of CTZ. • Discovering methods for inducing long‐term increases in genioglossal motoneuronal excitability to AMPA‐mediated drive may help in the development of therapeutics for upper airway motor disorders such as obstructive sleep apnoea (OSA). These results illustrate a latent residual capacity for potentiating AMPA‐mediated inspiratory drive to XII MNs that might be applied to the treatment of upper airway motor deficits such as OSA.Abstract Hypoglossal (XII) motoneurons (MNs) innervate the genioglossus muscle of the tongue, which plays an important role in maintaining upper airway patency, particularly during sleep, and modulating upper airway resistance. Discovering methods for inducing long‐term increases in genioglossal motoneuronal excitability to AMPA‐mediated drive may help in the development of therapeutics for upper airway motor disorders such as obstructive sleep apnoea. We show that the diuretic, anti‐hypertensive, AMPA receptor modulator cyclothiazide (CTZ) induces a profound and long‐lasting increase in the amplitude of respiratory‐related XII nerve activity in rhythmically active neonatal rat medullary slices. Treatment of the slice with CTZ (90 μ m ) for 1 h increased the integrated XII (∫XII) nerve burst amplitude to 262 ± 23% of pre‐treatment control at 1 h post‐treatment; much of this increase lasted at least 12 h. The amount of CTZ‐induced facilitation (CIF) was dependent upon both CTZ dose and exposure time and was accompanied by a long‐lasting increase in endogenous AMPA‐mediated drive currents to XII MNs. CIF, however, is not a form of plasticity and does not depend on AMPA or NMDA receptor activation for its induction. Nor does it depend on coincident protein kinase A or C activity. Rather, measurement of mEPSCs along with mass spectrometric analysis of CTZ‐treated slices indicates that the cause is prolonged bioavailability of CTZ. These results illustrate a latent residual capacity for potentiating AMPA‐mediated inspiratory drive to XII MNs that might be applied to the treatment of upper airway motor deficits.