Effect of 4-Aminopyridine on Genioglossus Muscle Activity during Sleep in Healthy Adults

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 10 mg extended 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 μV or as a percentage of wakefulness value.

Conclusions: A single dose of 4-AP 10 mg extended 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. Clinical Trial registered with clinicaltrials.gov (NCT02656160).

Keywords: drug therapy; obstructive sleep apnea; potassium channel blockers.

Figures

Figure 1.

Flowchart of the trial. 4-AP = 4-aminopyridine.

Figure 2.

Genioglossus activity and epiglottic pressure across sleep stages during placebo and 4-aminopyridine (4-AP) nights. Group data representing tonic (upper), phasic (middle) genioglossus activity (EMGGG), and epiglottic pressure swings (lower). There was no significant difference between placebo and 4-AP in EMGGG for any sleep stage analyzed when measured as a percentage of wakefulness value. The EMGGG was matched for the same range of epiglottic pressure swings (median value during placebo night ± 1 cm H2O). Dots indicate median values, and lines indicate 25th (low) and 75th (top) percentiles. Rapid eye movement (REM) passive refers to periods of relative atonia during REM sleep, whereas REM active refers to periods characterized by prolonged muscle twitches. NREM1, NREM2, and NREM3 = non-rapid eye movement sleep stages 1, 2, and 3.

Figure 3.

Individual data showing a significant increase of tonic genioglossus activity (EMGGG) on 4-aminopyridine (4-AP) compared with placebo in eight participants in whom REM sleep was recorded on both study nights. This finding was limited to EMGGG expressed as percentage of maximal voluntary activity (%max, see Table 2 and text for explanation). Horizontal lines indicate median values.

Figure 4.

Individual data showing genioglossus muscle responsiveness on placebo (P) and 4-aminopyridine (4-AP). Although there was no statistically significant effect of 4-AP as a group, seven of 10 subjects had an improvement in genioglossus muscle responsiveness to progressively greater epiglottic pressure swings evaluated during slow continuous positive airway pressure dial down. However, with the exception of one participant, the improvement was minimal.