Evaluation of an aldose reductase inhibitor on lens metabolism, ATPases and antioxidative defense in streptozotocin-diabetic rats: an intervention study

Aims/hypothesis. Aldose reductase inhibitors (ARIs) prevent biochemical abn ormalities associated with diabetic complications. We evaluated whether a s hort-term intervention with an adequate dose of ARI, introduced at the very early, precataractous stage, reversed diabetes-induced metabolic imbalance s, down-regulation of ATPases and oxidative stress in the lens. Methods. The groups included mature control and streptozotocin-diabetic rat s treated with or without ARI sorbinil (65 mg.kg(-1).day(-1), in the diet, for 2 weeks after 4 weeks of untreated diabetes). Free cytosolic NAD(+):NAD H and NADP(+):NADPH ratios were calculated from the lactate dehydrogenase a nd malic enzyme systems. Concentrations of metabolites and adenine nucleoti des, Na+/K+-ATPase, H+-ATPase and Ca++-independent Mg++-ATPase activities a nd variables of oxidative stress were measured in individual lenses. Results. Sorbinil treatment essentially corrected diabetes-induced sorbitol and fructose accumulation, myo-inositol depletion, decrease in free cytoso lic NAD(+):NADH ratio and energy deficiency. Malondialdehyde accumulation, reduced glutathione depletion and the increase in oxidized glutathione:redu ced glutathione ratio were partially corrected. Free cytosolic NADP(+):NADP H ratio and 4-hydroxyalkenal concentrations were similarly increased in dia betic rats treated with or without ARI. Sorbinil did not counteract diabete s-induced down-regulation of the three ATPase activities. Conclusion/interpretation. All biochemical changes assessed in our study ar e known to be prevented by ARIs. Despite the essential normalization of the sorbitol pathway activity, only part of them were, however, reversed by th e ARI treatment introduced at the very early, i.e. precataractous, stage of diabetes. Therefore, intervention studies can easily underestimate the imp ortance of aldose reductase in the pathogenesis of diabetic complications a nd should be interpreted with caution.