P. Thakran et al., LOOP DIURETIC DERIVATIVE L-644,711 INHIBITS K-STIMULATED CELLULAR INJURY IN NEONATAL GUINEA-PIG CORTICAL ASTROCYTES(), Molecular and chemical neuropathology, 21(1), 1994, pp. 23-39
An early pathological rise in extracellular K+ following acute hypoxia
results in Cl- uptake into astrocytes through the Cl-/HCO3-exchanger
with an osmotic equivalent of water. This study addressed effects of t
he anion transport inhibitor, L-644,711, (5,6,-dichloro-2,3, trahydro-
3-oxo-9a-propyl-1H-fluroen-7-yl)oxyacetic acid. Confluent primary cult
ures from neonatal guinea pigs, characterized as > 95% astrocytes with
antiserum to glial fibrillary acidic protein, were manipulated by inc
ubation in either basal buffer (BB) with the ionic composition of Dulb
ecco's minimum essential media (DMEM) or one with high extracellular K
+ (HiK). Incubation in 27 or 60 mM Hik significantly reduced cell viab
ility and precipitated a time-dose dependent increase in lactate dehyd
rogenase (LDH) efflux (30 min to 4 h). L-644,711 was not cytotoxic, an
d significantly inhibited HiK-stimulated LDH efflux. The optimal effec
tive dose of L-644,711 for preventing injury in guinea pig astrocytes
was 10(-11)M when administered simultaneously with the HiK paradigm or
in reversing injury when administered 30 min after exposing cells to
HiK. These findings indicate the potential usefulness of agents which
modify ion transport processes in hypoxic-ischemic cerebral injury.