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Role of Brainstem Sodium/Proton Exchanger 3 for Breathing Control during Chronic Acid–Base Imbalance

¹ Department of Physiology, Ruhr-University, Bochum, Germany; and ² Department of Physiology, University of Duisburg-Essen, Essen, Germany

Correspondence and requests for reprints should be addressed to Heidrun Kiwull-Schöne, M.D., Department of Physiology, Ruhr-University, 44780 Bochum, Germany. E-mail: heidrun.kiwull-schoene{at}rub.de

Rationale: The sodium/proton exchanger (NHE) 3 is expressed in brainstem areas with prevalence for central chemosensitivity. Selective NHE3 inhibitors can evoke CO₂ mimetic responses both in vitro and in vivo, demonstrating the functional significance of this pH-regulating protein. Moreover, levels of NHE3 expression are inversely correlated to interindividual differences of baseline ventilation in conscious rabbits.

Objectives: We explored the influence of chronic acid–base disturbances on mRNA levels of brainstem NHE3 in relation to breathing control.

Methods: Alveolar ventilation (A), blood gases, systemic base excess (BE), and metabolic CO₂ were determined in rabbits shortly after exposure to either CO₂-enriched air for 3 days (n = 5) or to ammonium chloride with drinking water for 2 days (n = 6). Untreated animals served as controls (n = 24). NHE3 mRNA within the obex region was quantified by real-time reverse transcription–polymerase chain reaction.

Measurements and Main Results: After chronic hypercapnia, we found a compensatory rise of BE (mean ± SEM) to 5.3 ± 0.5 mmol · L^–1 with slightly elevated Pa_CO2. Brainstem NHE3 mRNA as well as A were not significantly different from control levels. In the NH₄Cl group, arterial pH was 0.09 units lower than control, and BE decreased to –6.5 ± 1.6 mmol · L^–1 with slightly decreased Pa_CO2, but considerably reduced A (by 25%; P < 0.05) and CO₂. Concomitantly, brainstem NHE3 mRNA had increased from control level of 1.45 ± 0.19 to 3.64 ± 0.37 fg cDNA/µg RNA; P < 0.01.

Conclusions: Expression of brainstem NHE3 is up-regulated by chronic metabolic acidosis but not by prolonged hypercapnia. It is proposed that elevated brainstem NHE3 expression contributes to limit maladaptive hyperventilation during metabolic acidosis.

Key Words: brainstem sodium/proton exchange 3 • central chemosensitivity • chronic metabolic acidosis • prolonged hypercapnia • metabolic rate

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Selective sodium/proton exchanger (NHE3) inhibition in chemosensitive brainstem neurons evokes CO2 mimetic responses. Moreover, individual differences of NHE3 expression correlates to baseline ventilation, demonstrating functional significance of NHE3 for breathing control. What This Study Adds to the Field NHE3 mRNA expression in rabbits is significantly up-regulated during chronic metabolic but not respiratory acidosis. Elevated brainstem NHE3 expression likely contributes to limit maladaptive hyperventilation during metabolic acidosis.

 

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