Topical Potassium Channel Blockage Improves Pharyngeal Collapsibility: A Translational, Placebo-Controlled Trial.

BACKGROUND: Potassium (K+) channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and to treat OSA. However, these findings have not yet been translated to humans.RESEARCH QUESTION: Does a novel, potent, tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK) 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans, and secondarily, what is the optimal dose and method of topical application?STUDY DESIGN AND METHODS: In the preclinical study, pharyngeal muscle activity and upper -airway collapsibility via transient negative pressure application was quantified in 13 anes-thetized pigs during administration of placebo, 0.3 mu g, 3 mu g, and 30 mu g nasal drops of BAY2586116. In the clinical study, 12 people with OSA instrumented with polysomnography equipment, an epiglottic pressure catheter, pneumotachograph, and nasal mask to monitor sleep and breathing performed up to four detailed upper airway sleep physiology studies. Participants received BAY2586116 (160 mu g) or placebo nasal spray before sleep via a double-masked, randomized, crossover design. Most participants also returned for three additional overnight visits: (1) nasal drops (160 mu g), (2) half-dose nasal spray (80 mu g), and (3) direct endoscopic application (160 mu g). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit. RESULTS: Consistent and sustained improvements in pharyngeal collapsibility to negative pressure were found with 3 and 30 mu g of BAY2586116 vs placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of approximately 2 cm H2O vs placebo, regardless of topical application method and dose (P < .008, mixed model) in participants with OSA.INTERPRETATION: Acute topical application of BAY2586116 improves upper-airway collaps-ibility in anesthetized pigs and sleeping humans with OSA. These novel physiologic findings highlight the therapeutic potential to target potassium channel mechanisms to treat OSA.TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04236440; URL: www.clinicaltrials.govCHEST 2023; 163(4):953-965