Na(+)/H(+) exchange subtype 1 inhibition during extracellular acidification and hypoxia in glioma cells

J Neurochem. 2002 Jan;80(1):36-44. doi: 10.1046/j.0022-3042.2001.00661.x.


Lactacidosis is a common feature of ischaemic brain tissue, but its role in ischaemic neuropathology is still not fully understood. Na(+)/H(+) exchange, a mechanism involved in the regulation of intracellular pH (pH(i)), is activated by low pH(i). The role of Na(+)/H(+) exchange subtype 1 was investigated during extracellular acidification and subsequent pH recovery in the absence and presence of (4-isopropyl-3-methylsulphonyl-benzoyl)-guanidine methanesulfonate (HOE642, Cariporid), a new selective and powerful inhibitor of the Na(+)/H(+) exchanger subtype 1 (NHE-1). It was compared for normoxia and hypoxia in two glioma cell lines (C6 and F98). pH(i) was monitored by fluorescence spectroscopy using the intracellularly trapped pH-sensitive dye 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). Alterations in glial cell metabolism were characterized using high-resolution (1)H, (13)C and (31)P NMR spectroscopy of perchloric acid extracts. NHE-1 contributed to glial pH regulation, especially at pathologically low pH(i) values. NHE-1 inhibition with HOE642 during acidification caused exacerbated metabolic disorders which were prolonged during extracellular pH recovery. However, NHE-1 inhibition during hypoxia protected the energy state of glial cells.

MeSH terms

  • Acids / metabolism*
  • Animals
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Extracellular Space / metabolism*
  • Glioma / metabolism*
  • Glioma / pathology
  • Hydrogen-Ion Concentration
  • Hypoxia / metabolism*
  • Intracellular Fluid / metabolism
  • Rats
  • Sodium-Hydrogen Exchangers / metabolism*
  • Tumor Cells, Cultured


  • Acids
  • Sodium-Hydrogen Exchangers
  • growth factor-activatable Na-H exchanger NHE-1