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

Abstract

The sodium/proton exchanger (NHE) 3 is expressed in brainstem areas with prevalence for central chemosensitivity. Selective NHE3 inhibitors can evoke CO(2) 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. We explored the influence of chronic acid-base disturbances on mRNA levels of brainstem NHE3 in relation to breathing control. Alveolar ventilation (Va), blood gases, systemic base excess (BE), and metabolic Vco(2) were determined in rabbits shortly after exposure to either CO(2)-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. After chronic hypercapnia, we found a compensatory rise of BE (mean +/- SEM) to 5.3 +/- 0.5 mmol x L(-1) with slightly elevated Pa(CO(2)). Brainstem NHE3 mRNA as well as Va were not significantly different from control levels. In the NH(4)Cl group, arterial pH was approximately 0.09 units lower than control, and BE decreased to -6.5 +/- 1.6 mmol x L(-1) with slightly decreased Pa(CO(2)), but considerably reduced Va (by approximately 25%; P < 0.05) and Vco(2). Concomitantly, brainstem NHE3 mRNA had increased from control level of 1.45 +/- 0.19 to 3.64 +/- 0.37 fg cDNA/mug RNA; P < 0.01. 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.