GAL‐021 –induced respiratory stimulation is associated with increases in carotid sinus nerve and phrenic motoneuron activity in rats

Abstract

GAL‐021 is a novel respiratory stimulant that increases minute ventilation in rats, mice, and Cynomolgus monkeys. We hypothesized that GAL‐021 increases minute ventilation via mechanisms at the level of the carotid body. Using in vivo electrophysiological techniques, we examined the dose‐dependence of the effects of GAL‐021 (0.01 – 3 mg/kg, IV) on carotid sinus nerve (CSN) activity and phrenic motoneuron activity in mechanically ventilated, vagotomized, and neuromuscularly paralyzed adult rats, and on tidal volume (VT) in anesthetized spontaneously breathing rats. GAL‐021 dose‐dependently increased CSN (ED50 0.13 mg/kg) and phrenic nerve neurogram amplitude (ED50 0.08 mg/kg), values in reasonable accord with effects on VT (ED50 0.04 mg/kg). Thus, GAL‐021 is virtually equipotent in stimulating the afferent, efferent and effector components of the ventilatory response. When administered to conscious rats 7 days after either bilateral CSN transection or sham operation, the ventilatory effects (VT and frequency) of GAL‐021 (0.2 mg/kg, IV) were markedly diminished in the CSN transected rats compared to sham‐operated controls. Collectively, these data suggest that GAL‐021 stimulates breathing, at least in part, by effects on the carotid body resulting in increased carotid sinus nerve activity.