EFFECT OF THE ALDOSE REDUCTASE INHIBITOR TOLRESTAT ON NERVE-CONDUCTION VELOCITY NA K ATPASE ACTIVITY, AND POLYOLS IN RED-BLOOD-CELLS, SCIATIC-NERVE, KIDNEY CORTEX, AND KIDNEY MEDULLA OF DIABETIC RATS/

Long-term prospective studies comparing the effects of conventional an d intensive insulin therapy have linked diabetic hyperglycemia to the development of diabetic retinopathy, nephropathy, and neuropathy. The mechanisms through which glucose metabolism leads to the development o f these secondary complications, however, are incompletely understood. In animal models of diabetic neuropathy, the loss of nerve function i n myelinated nerve fibers has been related to a series of biochemical changes. Nerve glucose, which is in equilibrium with plasma glucose le vels, rapidly increases during diabetic hyperglycemia because glucose entry is independent of insulin. This excess glucose is metabolized in large part by the polyol pathway. Increased flux through this pathway is accompanied by the depletion of myo-inositol, a loss of Na/K ATPas e activity and the accumulation of sodium. Supportive evidence linking these biochemical changes to the loss of nerve function has come from studies in which aldose reductase inhibitors block polyol pathway act ivity, prevent the depletion of myo-inositol and the accumulation of s odium and presence Na/K ATPase activity, as well as nerve function. Th e kidney and red blood cells (RBCs) are two additional sites of diabet ic lesions that have been reported to develop biochemical changes simi lar to those in the nerve. We observed that polyol levels in the kidne y cortex, medulla, and RBCs increased two- to ninefold in rats followi ng 10 weeks of untreated diabetes. Polyol accumulation was accompanied by a 30% decrease in myo-inositol levels in the kidney cortex, but no change in RBCs or the kidney medulla. Na/K ATPase activity was decrea sed by 59% in RBCs but was unaffected in the kidney cortex or medulla. Aldose reductase inhibitor treatment that preserved myo-inositol leve ls, Na/K ATPase, and conduction velocity in the sciatic nerve also pre served Na/K ATPase activity in RBCs. Our results suggest that the path ophysiologic mechanisms underlying diabetic neuropathy are different f rom those of diabetic nephropathy. Our results also suggest that RBCs maybe a surrogate tissue for the assessment of diabetes-induced change s in nerve Na/K ATPase activity. (C) 1998 Elsevier Science Inc.