The effects of osmotically and sucrose-induced cell volume changes on glutamine and glucose metabolism were investigated in rat lymphocytes and macrophages incubated for 10-60 min at 37 degrees C in Krebs-Henseleit bicarbonate buffer (pH 7.4). Decreasing extracellular osmolarity from 336 to 286 mOsmol by decreasing medium NaCl from 119 to 94 mM increased cell volume and the rates of glutamine metabolism and glycolysis in both cell types. Conversely, increasing extracellular osmolarity from 286 to 386 mOsmol by the addition of 50 and 100 mM D-mannitol progressively decreased both cell volume and the rates of glutamine and glucose metabolism in lymphocytes and macrophages. At the same medium osmolarity of 336 mOsmol, the rates of glutamine metabolism and glycolysis were greater with the addition of 50 mM sucrose than with that of 25 mM NaCl. The sucrose-induced increase in cell volume, which is due to the uptake of sucrose by lymphocytes and macrophages via pinocytosis, is associated with enhanced rates of glutamine metabolism and glycolysis. Our findings suggest that cell volume change may be a hitherto unrecognized mechanism for regulating metabolism in lymphocytes and macrophages. The enhanced glutamine and glucose metabolism in these cells in response to mitogenic stimulation or immunological activation may result, at least in part, from the concomitant increase in cell volume.