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Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 lg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P ¼ 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals. [ABSTRACT FROM AUTHOR]

Background: K+ channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and treat obstructive sleep apnea (OSA). However, these findings have not yet been translated to humans.Research Question: Does a novel, potent, TASK 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans and secondarily, what is the optimal dose and mode of topical application?Study Design and Methods: Pre-clinical study: Pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during placebo, 0.3, 3 and 30μg nasal drops of BAY2586116.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 or placebo nasal spray (160μg) prior to sleep via a double-blind, randomized, crossover design. Most participants also returned for three additional overnight visits: 1) nasal drops (160μg), 2) half dose nasal spray (80μg), and 3) direct endoscopic application (160μg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit.Results: There were consistent and sustained improvements in pharyngeal collapsibility to negative pressure with 3 and 30μg of BAY2586116 versus placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of ∼2cmH2O versus placebo regardless of topical application mode and dose (mixed model p<0.008) in participants with OSA.Interpretation: Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiology findings highlight the therapeutic potential to target K+ channel mechanisms to treat OSA.Clinical Trial Registration: NCT04236440. [ABSTRACT FROM AUTHOR]

G-protein-coupled receptor 30 (GPR30) has been reported to act as a membrane-bound estrogen receptor that is involved in the mediation of non-genomic estradiol signalling. In this study, we demonstrated that male, but not female, GPR30-deficient mice suffer from impaired left‑ventricular cardiac function. Left ventricles from male mutant mice were enlarged. There were no malformations in the valves or outflow tract of the heart. Both the contractility and relaxation capacity of the left ventricle were reduced, leading to increased left‑ventricular end-diastolic pressure in GPR30-deficient mice. In conclusion, our data support a role for GPR30 in the gender-specific aspects of heart failure.