Intermittent Hypoxia Inhibits Na+-H+ Exchange-Mediated Acid Extrusion Via Intracellular Na+ Accumulation in Cardiomyocytes

• Published in: Cellular physiology and biochemistry Vol. 46; no. 3; pp. 1252 - 1262
• Main Authors: Chang, Huai-Ren, Lien, Chih-Feng, Jeng, Jing-Ren, Hsieh, Jen-Che, Chang, Chen-Wei, Lin, Jian-Hong, Yang, Kun-Ta
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.04.2018; Cell Physiol Biochem Press GmbH & Co KG
• Subjects: Acidosis; Acids; Amiloride - pharmacology; Animals; Cardiomyocytes; Cell Hypoxia; Cells, Cultured; Enzymes; Female; Guanidines - pharmacology; Hydrogen-Ion Concentration; Hypoxia; Intermittent hypoxia; Intracellular Na+; Intracellular pH; Ischemia; Male; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Na+-H+ exchange; Original Paper; Penicillin; Physiology; Protein Kinase C - metabolism; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Reactive oxygen specifies; Rodents; Sodium; Sodium - metabolism; Sodium-Calcium Exchanger - antagonists & inhibitors; Sodium-Calcium Exchanger - metabolism; Sulfones - pharmacology; Superoxide Dismutase - metabolism; United States > US; Intermittent hypoxia; Intracellular pH; Intracellular Na+; Reactive oxygen specifies; Na+-H+ exchange
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000489076

Background/Aims: Intermittent hypoxia (IH) has been shown to exert preconditioning-like cardioprotective effects. It also has been reported that IH preserves intracellular pH (pHi) during ischemia and protects cardiomyocytes against ischemic reperfusion injury. However, the exact mechanism is still unclear. Methods: In this study, we used proton indicator BCECF-AM to analyze the rate of pHi recovery from acidosis in the IH model of rat neonatal cardiomyocytes. Neonatal cardiomyocytes were first treated with repetitive hypoxia-normoxia cycles for 1-4 days. Cells were then acid loaded with NH 4 Cl, and the rate of pHi recovery from acidosis was measured. Results: We found that the pHi recovery rate from acidosis was much slower in the IH group than in the room air (RA) group. When we treated cardiomyocytes with Na + -H + exchange (NHE) inhibitors (Amiloride and HOE642) or Na + -free Tyrode solution during the recovery, there was no difference between RA and IH groups. We also found intracellular Na + concentration ([Na + ] i ) significantly increased after IH exposure for 4 days. However, the phenomenon could be abolished by pretreatment with ROS inhibitors (SOD and phenanathroline), intracellular calcium chelator or Na + -Ca 2+ exchange (NCX) inhibitor. Furthermore, the pHi recovery rate from acidosis became faster in the IH group than in the RA group when inhibition of NCX activity. Conclusions: These results suggest that IH would induce the elevation of ROS production. ROS then activates Ca 2+ -efflux mode of NCX and results in intracellular Na + accumulation. The rise of [Na + ] i further inhibits the activity of NHE-mediated acid extrusion and retards the rate of pHi recovery from acidosis during IH.