Am. J. Respir. Crit. Care Med., Volume 164, Number 7, October 2001, 1303-1311

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

HEIDRUN KIWULL-SCHÖNE, MARTIN WIEMANN, STILLA FREDE, DIETER BINGMANN, KLAUS J. WIRTH, UWE HEINELT, HANS-JOCHEN LANG, and PETER KIWULL

Department of Physiology, Ruhr-University, Bochum, Germany; Department of Physiology, University GH Essen, Essen, Germany; and Aventis Pharma, Frankfurt/Main, Germany

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 µg/ml. In response to S8218, the baseline level of IPNA · 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 response was studied at plasma concentrations of S8218 maintained in the range of 0.3 µg/ml (10⁶ M). Although the metabolic acid-base status thereby remained widely unchanged, the group mean apneic threshold Pa_CO2 was significantly 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 nerve 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 compatible with the effects of NHE3 inhibition on chemosensitive brainstem neurons in vitro. Moreover, rhythmogenesis is supported through NHE3 inhibition by lowering the threshold PCO₂ for central apnea.

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