Inhibition of central Na+/H+ exchanger type 3 can alleviate sleep apnea in Sprague-Dawley rats

Abstract

Background Recent studies showed the central Na+/H+ exchanger type 3 (NHE3) has a close relationship with ventilation control. The objective of the study is to investigate the role of NHE3 in sleep apnea in Sprague-Dawley (SD) rats. Methods A sleep study was performed on 20 male SD rats to analyze the correlation between the sleep apneic events and total NHE3 protein content and inactive NHE3(pS552) in the brainstem measured by Western blotting. Another 20 adult male SD rats received 3 days of sleep and respiration monitoring for 6 hours a day, with adaption on the first day, 0.5% DMSO microinjection into the fourth ventricle on the second day, and AVE0657 (specific inhibitor of NHE3) microinjection on the third day. Rats were divided into two groups with injection of 5 μmol/L or 8 μmol/L AVE0657 before the sleep study. The effects of AVE0657 on sleep apnea and sleep structure of rats were analyzed through self-control. Results The total post-sigh apnea index (TPSAI) and post-sigh apnea index in non-rapid eye movement (NREM) sleep (NPSAI) and total apnea index (AI) in NREM sleep (NAI) were negatively correlated with NHE3(pS552) protein contents in the brainstem (r=-0.534, -0.547 and -0.505, respectively, P<0.05). The spontaneous apnea index in REM sleep (RSPAI) was positively correlated with the level of NHE3(pS552) protein expression in the brainstem (r=0.556, P<0.05). However, the sleep AI had no relationship with total NHE3 protein. Compared with the blank control and microinjection of 0.5% DMSO, 5 μmol/L AVE0657 significantly reduced the total AI and NPSAI (both P<0.05) without a significant effect on sleep architecture. In contrast to blank control and microinjection of 0.5% DMSO, injection of 8 μmol/L AVE0657 significantly reduced the AI and PSAI in NREM and REM sleep (all P<0.05). Conclusions The severity of sleep apnea was negatively correlated with central inactive NHE3. A specific inhibitor of NHE3 decreased the sleep AI. Thus, our results indicate that central NHE3 might be a molecular target for sleep apnea treatment, whose inhibitors may be potential therapeutic drugs for sleep apnea.