Effect of 4-aminopyridine on genioglossus muscle activity during sleep in healthy adults

Luigi Taranto-Montemurro, Scott A. Sands, Ali Azarbarzin, Melania Marques, Camila M. de Melo, Bradley A. Edwards, Danny J. Eckert, Ludovico Messineo, David P. White, Andrew Wellman

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9 Citations (Scopus)

Abstract

Rationale: The reduction in upper airway muscle activity from wakefulness to sleep plays a key role in the development of obstructive sleep apnea. Potassium (K+) channels have been recently identified as the downstream mechanisms through which hypoglossal motoneuron membrane excitability is reduced both in non-rapid eye movement (NREM) sleep and REM sleep. In animal models, the administration of 4-aminopyridine (4-AP), a voltage-gated K+ channel blocker, increased genioglossus activity during wakefulness and across all sleep stages. Objectives: We tested the hypothesis that administration of a single dose of 4-AP 10mgextended release would increase genioglossus activity (electromyography of the genioglossus muscle [EMGGG]) during wakefulness and sleep, and thereby decrease pharyngeal collapsibility. Methods: We performed a randomized controlled crossover proof of concept trial in 10 healthy participants. Participants received active treatment or placebo in randomized order 3 hours before bedtime in the physiology laboratory. Results: EMGGG during wakefulness and NREM sleep and upper airway collapsibility measured during NREM sleep were unchanged between placebo and 4-AP nights. Tonic but not phasic EMGGG during REM sleep was higher on the 4-AP night when measured as a percentage of maximal voluntary activation (median [interquartile range] 0.3 [0.5] on placebo vs. 0.8 [1.9] %max on 4 AP; P = 0.04), but not when measured in mV or as a percentage of wakefulness value. Conclusions: A single dose of 4-AP 10mgextended release showed only a small increase in tonic EMGGG during REM sleep in this group of healthy subjects. We speculate that a higher dose of 4-AP may further increase EMGGG. However, given the potentially severe, dose-related adverse effects of this drug, including seizures, the administration of 4-AP does not appear to be an effective strategy to increase genioglossus activity during sleep in humans.

Original languageEnglish
Pages (from-to)1177-1183
Number of pages7
JournalAmerican Thoracic Society. Annals
Volume14
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017

Keywords

  • obstructive sleep apnea
  • potassium channel blockers
  • Drug Therapy

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    Taranto-Montemurro, L., Sands, S. A., Azarbarzin, A., Marques, M., de Melo, C. M., Edwards, B. A., Eckert, D. J., Messineo, L., White, D. P., & Wellman, A. (2017). Effect of 4-aminopyridine on genioglossus muscle activity during sleep in healthy adults. American Thoracic Society. Annals, 14(7), 1177-1183. https://doi.org/10.1513/AnnalsATS.201701-006OC