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Volume regulation of C6 glial cells was studied in anoxia in vitro to improve the understanding of ischemic cell swelling in the brain. Contrary to in vivo conditions, anoxia or anoxia plus iodoacetate for additional inhibition of anaerobic energy metabolism did not induce glial swelling. However, intracellular K+ was markedly decreased while intracellular Na+ increased. Induction of energy failure by anoxia plus iodoacetate was found to prevent the regulatory volume decrease on hyposmotic exposure of the cells, which is regularly observed in normoxic control conditions. Hyposmotic exposure in anoxia plus iodoacetate led only to an initial tendency of cell volume normalization followed by secondary cell swelling. This was associated with a net increase of intracellular Na+ that may explain the failure of volume regulation under these circumstances. Maintenance of a normal glial cell size during complete energy deprivation by anoxia plus iodoacetate in isotonic medium strongly indicates that energy failure per se does not suffice to induce cell swelling. Cell swelling in cerebral ischemia in vivo thus is likely to require additional mechanisms, most likely an increase of membrane permeability to Na+, which may be caused by release and accumulation of excitotoxins such as glutamate or by an extracellular release of K+. Such a mechanism would hardly influence the extracellular homeostasis in vitro due to the large medium-to-cell volume ratio. The findings demonstrate, nonetheless, the significance of a competent energy metabolism to support cell volume regulation. This is concluded from the failure of regulatory volume decrease of hypotonically suspended glial cells in anoxia plus iodoacetate.(ABSTRACT TRUNCATED AT 250 WORDS)