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 ra ts enhanced their bioelectric activity upon intracellular acidification ind uced by inhibition of the Na+/H+ exchanger type 3 (NHE3). Now we detected N HE3 also in the medulla oblongata of adult rabbits. Therefore, this animal model was employed to determine whether NHE3 inhibition also affects centra l respiratory chemosensitivity in vivo. Seven anesthetized (pentobarbital), vagotomized, paralyzed rabbits were artificially ventilated with O-2-enric hed air. From the phrenic nerve compound discharge, integrated burst amplit ude (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 s tudied by comparing respiratory characteristics before and after up to 9.2 +/- 1.1 mg/kg cumulative drug application, yielding average plasma concentr ations of 0.9 +/- 0.2 mug/ml. In response to S8218, the baseline level of I PNA . fR was significantly enhanced by an average of 51.0 +/- 6.4% (n = 27, p < 0.0001). The influence of NHE3 inhibition on the respiratory CO2 respo nse was studied at plasma concentrations of S8218 maintained in the range o f 0.3 <mu>g/ml (10(-6) M). Although the metabolic acid-base status thereby remained widely unchanged, the group mean apneic threshold Pa-CO2 was signi ficantly lowered by 0.45 +/- 0.11 kPa (n = 7, p < 0.01), whereby in four of seven animals even strong hyperventilation failed to suppress phrenic nerv e rhythmicity completely. Likewise, S8218 significantly augmented IPNA . fR , in the range of Pa-CO2 between 1 and 6 kPa above threshold, by an average of 38.0 +/- 8.5% (n = 35, p < 0.0001). These in vivo results are compatibl e with the effects of NHE3 inhibition on chemosensitive brainstem neurons i n vitro. Moreover, rhythmogenesis is supported through NHE3 inhibition by l owering the threshold P-CO2 for central apnea.