Role of brainstem sodium/proton exchanger 3 for breathing control during chronic acid-base imbalance

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 (V-A), blood gases, systemic base excess (BE), and metabolic V-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 V-A were not significantly different from control levels. In the NH4Cl group, arterial pH was similar to 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 VA (by similar to 25%; P < 0.05) and V-CO2., Concomitantly, brainstem NHE3 mRNA had increased from control level of 1.45 +/- 0.19 to 3.64 +/- 0.37 fg cDNA/mu g 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.