GAL‐021 increases CO2‐chemosensitivity at doses that do not stimulate minute ventilation

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GAL‐021 is a novel chemical entity that inhibits BK channels on carotid body glomus type 1 cells and dose‐dependently stimulates ventilation in mice, rats, non‐human primates, and healthy human subjects. As such, GAL‐021 is being developed as a new therapeutic agent to reverse opioid‐induced respiratory depression (OIRD) in people. Here, we evaluated the effects of GAL‐021 on CO2 chemosensitivity at non‐stimulatory plasma concentrations. Minute ventilation was measured using direct tracheal spirometry from urethane‐anesthetized adult rats at three different levels of PaCO2 – baseline, and two levels of hypercapnia: +10 and +20 mmHg above baseline. The slope of the hypercapnic ventilatory responses (HcVR) represented CO2 chemosensitivity. HcVR and CO2 chemosensitivity were measured in each animal before and again during a constant intravenous infusion of GAL‐021, where the dose was titrated in each animal to remain below the threshold that stimulates baseline ventilation. The magnitude of each HcVR and CO2 chemosensitivity was significantly increased during GAL‐021 infusion compared to vehicle control (p<0.001). CO2 chemosensitivity did not change in a time control cohort that received vehicle infusion. Thus, GAL‐021 enhances CO2 chemosensitivity at plasma exposures that do not stimulate baseline breathing. These results suggest that GAL‐021 may have utility as preventative treatment for OIRD and also in the treatment of breathing disorders characterized by intermittent central apneas, such as sleep disordered breathing.