—The ouabain‐sensitive K+ uptake and ATPase activities of cultured glioma and neuroblastoma cells were studied. Both cell lines showed ouabain‐sensitive K+ uptake which correlated with the level of [Na++ K+]ATPase activity found in the respective total cell homogenate. The glioma cells had a 2.1‐fold higher rate of K+ uptake than neuroblastoma cells, and a 2.4‐fold higher [Na++ K+]ATPase activity. In the presence of ouabain neuroblastoma cells released K+ and took up Na+ in a 1:1 ratio. These results are compared and contrasted with similar studies on brain tissue and isolated cells. It is suggested that the cultured cell lines may serve as good models for the cation transport properties of their tissue counterparts.

The intact cerebral cortices of cats were exposed in vivo under normothermic conditions and superfused with isotonic artificial cerebrospinal fluid containing added 0.125 mM adenosine. This resulted in chloridecation-rich cerebrocortical swelling which was shown by electron microscopy to be associated with an expanded astroglial compartment. The addition of DCPIB, a non-diuretic acylaryloxyacid analogue of ethacrynic acid and an inhibitor of coupled chloride-cation transport in cerebral cortex in vitro, totally blocked astroglial swelling and the concomitant increases in tissue ion contents. These studies support our previous experiments on the mechanism of formation of astroglial swelling. The pathological consequences of astroglial swelling and the clinical applications of these findings are discussed.

Our initial paper discussed brain edema resulting from traumatic head injury and the need for specific and effective agents to treat the disorder and disclosed a novel approach for the discovery of a drug of this kind. The current study describes the synthesis of a series of [(2,3,9,9a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alk anoic acids and their analogues. These compounds were evaluated in an in vitro cerebrocortical tissue slice assay for their relative potencies in inhibiting K+ + HCO3- induced swelling. Structural modification at a number of sites in the "lead" compound revealed that significant biological activity was inherent only within a very narrow range of structural types. The observation that nearly all the biological activity resided in one of the two enantiomers demonstrated the marked stereospecificity of the most active compounds. One of the most potent compounds, (R)-(+)-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren -7-yl) oxy]acetic acid ((+)-5c), exhibited a dose-response relationship in the in vivo acceleration/deceleration brain edema assay, and the data from the two highest doses were statistically significant. Electron microscopic examination demonstrated that the perivascular astroglial swelling that arises from this procedure is abolished in the animals treated with (+)-5c. This compound is currently being evaluated for its clinical efficacy and safety in the treatment of traumatic head injury.