A Novel Inhibitor of the Na+/ H+ Exchanger Type 3 Activates the Central Respiratory CO2 Response and Lowers the Apneic Threshold

Cultured CO2-sensitive neurons from the ventrolateral medulla of newborn rats enhanced their bioelectric activity upon intracellular acidification induced by inhibition of the Na+/ H+ exchanger type 3 (NHE3). Now we detected NHE3 also in the medulla oblongata of adult rabbits. Therefore, this animal model was employed to determine whether NHE3 inhibition also affects central respiratory chemosensitivity in vivo. Seven anesthetized (pentobarbital), vagotomized, paralyzed rabbits were artificially ventilated with O2-enriched air. From the phrenic nerve compound discharge, integrated burst amplitude (IPNA), respiratory rate (fr), and phrenic minute activity (IPNA · fr) were taken as measures of central respiratory rhythm and drive. Effects of potent NHE3 inhibition with the novel brain permeant substance S8218 were studied by comparing respiratory characteristics before and after up to 9.2 ± 1.1 mg / kg cumulative drug application, yielding average plasma concentrations of 0.9 ± 0.2 μ g / ml. In response to ...