GAL‐160 Preferentially Increases Respiratory Motor Drive to the Tongue over the Diaphragm during Unobstructed Breathing and Standardized Obstructive Apneas (OA) in Rats

Abstract

GAL‐160, a carotid body (CB) stimulant, decreases spontaneous OA frequency and OA duration in a rodent model of OSA. Mechanistically, we propose that the effect of GAL‐160 on OA frequency is due to increased upper airway respiratory muscle (RMUA) activity during eupnea, and the effect of GAL‐160 on OA duration is due to an increased response of RMUA to obstruction. We evaluated the effects of GAL‐160 on eupneic respiratory drive to the RMUA by recording hypoglossal (HN) and phrenic (PN) neurograms from urethane anesthetized, mechanically ventilated rats before and during IV infusion of vehicle and GAL‐160 (0.24 mg/kg over 30‐min). Baseline neurograms were standardized between rats by setting baseline PaCO2 at 3 mmHg above each animal's apneic threshold to CO2. To evaluate the effects of GAL‐160 on the RMUA response to obstruction, the EMGGG and EMGDIA responses to standardized 10‐s tracheal obstructions were recorded from anesthetized, spontaneously breathing rats, before and during GAL‐160/vehicle infusions.GAL‐160 increased HN activity (67 ± 23% above baseline) without altering PN activity (‐13 ± 20%) during unobstructed breathing. Bilateral CB denervation abolished this effect. GAL‐160 increased the peak EMGGG response to a 10‐s obstruction (pre‐drug: 214 ± 180%; GAL‐160: 589 ± 358%; p<0.01) without altering the EMGDIA response (pre‐drug: 60 ± 31%; GAL‐160: 78 ± 47%). Vehicle infusion had no effect on the neurograms or EMGs recorded. These data demonstrate that GAL‐160 preferentially increases respiratory drive to the RMUA via the CB and during both eupneic breathing and OA. This mechanism may contribute to the efficacy of GAL‐160 in our rodent model of spontaneous OSA.