Na(+)/H(+) exchange subtype 1 inhibition during extracellular acidification and hypoxia in glioma cells.
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.
Glunde
Kristine
K
Department of Chemistry, University of Bremen, Bremen, Germany.
Düssmann
Heiko
H
Juretschke
Hans-Paul
HP
Leibfritz
Dieter
D
D000143:Acids / Q000378:metabolism*; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D005110:Extracellular Space / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000143:Acids; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1