Identification of a pharmacological target for genioglossus reactivation throughout sleep.
OBJECTIVE
Obstructive sleep apnea (OSA) is a significant public health problem caused by repeated episodes of upper airway closure that occur only during sleep. Attempts to treat OSA pharmacologically have been unsuccessful because there has not been identification of a target operating at cranial motor nuclei, blockade of which can reactivate pharyngeal muscle activity throughout sleep. Increasing potassium conductance is a common mechanism by which state-dependent neuromodulators reduce motoneuron excitability. Therefore, we aimed to determine if potassium channel blockade is an effective strategy to reactivate the pharyngeal musculature throughout sleep.
In rats chronically instrumented for recording sleep-wake states and respiratory motor activities, we locally microperfused pharmacological agents into the hypoglossal motor pool to modulate potassium channels of three major classes: inwardly rectifying, two-pore domain, and voltage-gated.


RESULTS
Microperfusion of the inwardly rectifying potassium channel blocker, barium, as well as the voltage-gated potassium channel blockers, tetraethylammonium and 4-aminopyridine, increased tonic and respiratory-related genioglossus activities throughout nonrapid eye movement (non-REM) and rapid eye movement (REM) sleep to 133-300% of levels present during baseline wakefulness. In contrast, microperfusion of methanandamide (TWIK-related acid-sensitive potassium [TASK] channel blocker/cannabinoid receptor agonist) activated genioglossus in wakefulness but not in sleep.


CONCLUSIONS
These findings establish proof-of-principle that targeted blockade of certain potassium channels at the hypoglossal motor pool is an effective strategy for reversing upper airway hypotonia and causing sustained reactivation of genioglossus throughout nonrapid eye movement and rapid eye movement sleep. These findings identify an important new direction for translational approaches to the pharmacological treatment of obstructive sleep apnea.
Department of Medicine, University of Toronto, Toronto, Canada.
Kevin P
KP
Grace
Eli Lilly, Erl Wood Manor, Windlesham, Surrey, United Kingdom.
Stuart W
SW
Hughes
Department of Medicine, University of Toronto, Toronto, Canada ; Department of Physiology, University of Toronto, Toronto, Canada.
Richard L
RL
Horner
D000818:Animals; D001464:Barium / Q000008:administration & dosage / Q000494:pharmacology; D007002:Hypoglossal Nerve / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D010609:Pharyngeal Muscles / Q000187:drug effects* / Q000294:innervation* / Q000502:physiology / Q000503:physiopathology; D010614:Pharynx / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D017286:Polysomnography; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D020181:Sleep Apnea, Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology; D014059:Tongue / Q000187:drug effects / Q000294:innervation / Q000502:physiology / Q000503:physiopathology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D001464:Barium
Animal models; genioglossus; obstructive sleep apnea; sleep; upper airway