The relationship was examined between increased polyol pathway activity and the changes in water content, respiration, and glycolysis that occur when tubular segments of rabbit aortic smooth muscle cells are incubated with elevated glucose concentrations. The presence of 1.0 mmol/L ibuprofen resulted in a 65% reduction in fructose production by tissue incubated with 50 mmol/L glucose. This was associated with an increase in intracellular glucose and decreases in aortic smooth muscle sorbitol and fructose consistent with an inhibition of aldose reductase. Inhibition of increased polyol pathway activity usually observed in tissue incubated with 50 mmol/L glucose, is accompanied by a decrease in tissue water, an increase in oxygen uptake, and a decrease in lactate production. This suggests a causal relationship between increased polyol pathway activity and the changes in the aortic water content and metabolism induced by an elevated medium glucose concentration, although this would not be predicted by the osmotic hypothesis. The mechanism(s) responsible for the prevention of metabolic changes seen in an elevated glucose concentration by the aldose reductase inhibitor remain to be elucidated.