Proceedings of The Physiological Society

Sleep Sleep and Circadian Rhythms (London, UK) (2018) Proc Physiol Soc 42, SA11

Research Symposium

Strategic Decision Making and Potential Drug Targets for Obstructive Sleep Apnea Pharmacotherapy

R. Horner1

1. Medicine, and Physiology, University of Toronto, Toronto, Ontario, Canada.

The root cause of some of the most common and serious sleep problems is impaired breathing. Of the sleep-related breathing disorders, obstructive sleep apnea (OSA) is the most prevalent and is associated with significant clinical, social and economic consequences. OSA is ultimately caused by closure of the pharyngeal airspace during sleep due largely to relaxation of the tongue muscles whose activity normally keeps the airspace open. The hypoglossal motoneuron pool is the source of motor output to the tongue, and in theory strategies to modulate its activity may lead to identification, development and testing of new pharmacological treatments for OSA. The first part of this symposium presentation will identify the four principal factors underpinning the pathophysiology of OSA. Two of these factors are strongly influenced by upper airway muscle activity, and as such are amenable to targeted manipulation. The presentation will then identify the two major mechanisms operating at the hypoglossal motoneuron pool in rats to modulate tongue muscle activity across natural sleep-wake states. Such studies have identified that there is a functional endogenous noradrenergic drive to the hypoglossal motoneuron pool that activates motor output to the tongue muscle in wakefulness via an α1 receptor mechanism, with this drive being withdrawn in sleep. The presentation will also identify the mechanism of tongue muscle inhibition in REM sleep in rats, this being an acetylcholine mediated G protein-coupled inwardly-rectifying potassium (GIRK) channel mechanism. In addition, modulation of certain K+ channels can reactivate tongue muscle activity throughout sleep in rats. Others have manipulated (with success) such mechanisms as potential OSA pharmacotherapies in humans (e.g., trial IDs: NCT02428478, NCT02656160, NCT02908529 at The presentation will conclude with the identification and description of a resource of potential drug targets for OSA pharmacotherapy. Some of these targets and their pharmacological agents (e.g., thyrotropin releasing hormone analogs) have been studied in pre-clinical rodent models. Overall, these basic science findings inform current and future studies in humans to identify the potential beneficial effects of pharmacological agents for breathing during sleep and OSA.

Where applicable, experiments conform with Society ethical requirements