Loop diuretic derivative L-644,711 inhibits K(+)-stimulated cellular injury in neonatal guinea pig cortical astrocytes.
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 the anion transport inhibitor, L-644,711, (5,6,-dichloro-2,3, 9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluroen-7-yl)oxyacetic acid. Confluent primary cultures from neonatal guinea pigs, characterized as > 95% astrocytes with antiserum to glial fibrillary acidic protein, were manipulated by incubation in either basal buffer (BB) with the ionic composition of Dulbecco's minimum essential media (DMEM) or one with high extracellular K+ (HiK). Incubation in 27 or 60 mM Hik significantly reduced cell viability and precipitated a time-dose dependent increase in lactate dehydrogenase (LDH) efflux (30 min to 4 h). L-644,711 was not cytotoxic, and significantly inhibited HiK-stimulated LDH efflux. The optimal effective 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.
Thakran
P
P
Joint Division of Newborn Medicine, Creighton University, University of Nebraska Medical Center, Omaha 68131.
Nelson
R M
RM
Leuschen
M P
MP
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology*; D002712:Chlorides / Q000378:metabolism*; D046508:Culture Techniques / Q000379:methods; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000494:pharmacology*; D006168:Guinea Pigs; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D011188:Potassium / Q000037:antagonists & inhibitors / Q000633:toxicity*; D013997:Time Factors
D002712:Chlorides; D004232:Diuretics; D005449:Fluorenes; D007770:L-Lactate Dehydrogenase; D011188:Potassium; C053396:L 644711