1Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing 100034, China
2Departments of Neurobiology and Molecular and Cellular Pharmacology, Peking University Health Science Center, Beijing 100034, China
3Center for Sleep and Circadian Neurobiology, 4Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

Abstract 

Extracellular pH (pHe) and intracellular pH (pHi) are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na+/ H+ exchanger 3 (NHE-3), a key pHi regulator in the brainstem, decreases the pHi, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus (DVN). Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current (I so) through pH-sensitive K+ channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified pHe and AVE0657 (5 μmol/L) resulted in a stronger effect on firing rate and I so than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pHsensitive K+ current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration.

Keywords

Na+/H+ exchange; potassium channel; dorsal vagal nucleus; in situ hybridization; respiration

[SpringerLink]