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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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 animalmodels, the administration of 4-aminopyridine (4-AP), a voltage-gatedK+ 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 releasewould 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 proofofconcept 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 whenmeasured 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 tonicEMGGG duringREMsleep 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
JournalAnnals of the American Thoracic Society
Volume14
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017

Keywords

  • Drug therapy
  • Obstructive sleep apnea
  • Potassium channel blockers

Cite this

Taranto-Montemurro, Luigi ; Sands, Scott A. ; Azarbarzin, Ali ; Marques, Melania ; De Melo, Camila M. ; Edwards, Bradley A. ; Eckert, Danny J ; Messineo, Ludovico ; White, David P. ; Wellman, Andrew. / Effect of 4-aminopyridine on genioglossus muscle activity during sleep in healthy adults. In: Annals of the American Thoracic Society. 2017 ; Vol. 14, No. 7. pp. 1177-1183.
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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 animalmodels, the administration of 4-aminopyridine (4-AP), a voltage-gatedK+ 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 releasewould 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 proofofconcept 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 whenmeasured 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 tonicEMGGG duringREMsleep 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.",
keywords = "Drug therapy, Obstructive sleep apnea, Potassium channel blockers",
author = "Luigi Taranto-Montemurro and Sands, {Scott A.} and Ali Azarbarzin and Melania Marques and {De Melo}, {Camila M.} and Edwards, {Bradley A.} and Eckert, {Danny J} and Ludovico Messineo and White, {David P.} and Andrew Wellman",
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Taranto-Montemurro, L, Sands, SA, Azarbarzin, A, Marques, M, De Melo, CM, Edwards, BA, Eckert, DJ, Messineo, L, White, DP & Wellman, A 2017, 'Effect of 4-aminopyridine on genioglossus muscle activity during sleep in healthy adults', Annals of the American Thoracic Society, vol. 14, no. 7, pp. 1177-1183. https://doi.org/10.1513/AnnalsATS.201701-006OC

Effect of 4-aminopyridine on genioglossus muscle activity during sleep in healthy adults. / Taranto-Montemurro, Luigi; Sands, Scott A.; Azarbarzin, Ali; Marques, Melania; De Melo, Camila M.; Edwards, Bradley A.; Eckert, Danny J; Messineo, Ludovico; White, David P.; Wellman, Andrew.

In: Annals of the American Thoracic Society, Vol. 14, No. 7, 01.07.2017, p. 1177-1183.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effect of 4-aminopyridine on genioglossus muscle activity during sleep in healthy adults

AU - Taranto-Montemurro, Luigi

AU - Sands, Scott A.

AU - Azarbarzin, Ali

AU - Marques, Melania

AU - De Melo, Camila M.

AU - Edwards, Bradley A.

AU - Eckert, Danny J

AU - Messineo, Ludovico

AU - White, David P.

AU - Wellman, Andrew

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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 animalmodels, the administration of 4-aminopyridine (4-AP), a voltage-gatedK+ 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 releasewould 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 proofofconcept 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 whenmeasured 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 tonicEMGGG duringREMsleep 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.

AB - 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 animalmodels, the administration of 4-aminopyridine (4-AP), a voltage-gatedK+ 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 releasewould 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 proofofconcept 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 whenmeasured 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 tonicEMGGG duringREMsleep 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.

KW - Drug therapy

KW - Obstructive sleep apnea

KW - Potassium channel blockers

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U2 - 10.1513/AnnalsATS.201701-006OC

DO - 10.1513/AnnalsATS.201701-006OC

M3 - Article

VL - 14

SP - 1177

EP - 1183

JO - Annals of the American Thoracic Society

JF - Annals of the American Thoracic Society

SN - 2325-6621

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