Cerebral edema in various disease states may result from astroglial swelling due to increased NaCl uptake mediated by enhanced ClHC0 3 exchange. We evaluated this mechanism in the pathogenesis of cerebral edema in acute hyponatremia by administering L-644, 711, a fluorenyloxyacetate derivative that functions as an anion exchange inhibitor, to guinea pigs with severe reductions in serum Na + concentration. Acute hyponatremia was induced for 54 hr by daily injections of arginine vasopressin (10 U/day) and 5% dextrose in water (7.5% body wt/day). Experimental animals received L-644, 711, 20 mg/kg/day, while controls were given an equal volume of the diluent. This regimen lowered the serum Na + from normal levels to 108 ± 3 and 109 ± 4 mM in experimental and control animals, respectively. Drug treatment resulted in less cerebral edema characterized by a reduction in brain total tissue water 432 ± 4 vs 466 ± 8 ml/100 g dry wt experimental vs control, p < 0.005. This difference was composed mainly of less expansion of the intracellular water space, 287 ± 11 vs 323 ± 9 ml/100 g dry wt experimental vs control, p < 0.005. The cerebral cortical Na ++Cl content was reduced from 55.5 ± 1.3 (control) to 39.5 ± 1.1 mEq/100 g dry wt (experimental), p < 0.01. These results indicate that treatment of guinea pigs with L-644, 711 decreases brain NaCl content and attenuates cerebral edema during severe acute hypotnatremia without normalizing the serum Na + concentration.