COMPARISON OF THE EFFECTS OF INHIBITORS OF ALDOSE REDUCTASE AND SORBITOL DEHYDROGENASE ON NEUROVASCULAR FUNCTION, NERVE-CONDUCTION AND TISSUE POLYOL PATHWAY METABOLITES IN STREPTOZOTOCIN-DIABETIC RATS

Aldose reductase inhibitors (ARIs) attenuate diabetic complications in several tissues, including lens, retina, kidney, blood vessels, stria ted muscle and peripheral nerve. However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the convers ion of glucose to sorbitol by aldose reductase or indirectly by reduci ng the sorbitol available for subsequent metabolism to fructose by sor bitol dehydrogenase. To identify the polyol pathway step most relevant to complications, particularly neuropathy, we compared the biochemica l effects of a sorbitol dehydrogenase inhibitor, WAY-135706, (250 mg . kg(-1) . day(-1)) and an ARI, WAY-121509, (10 mg . kg(-1) . day(-1)) on a variety of tissues, and their effects on nerve perfusion and cond uction velocity. After 6 weeks of untreated streptozotocin diabetes, r ats were treated for 2 weeks. Sorbitol was elevated 2.1-32.6-fold by d iabetes in lens, retina, kidney, aorta, diaphragm, erythrocytes and sc iatic nerve; this was further increased (1.6-8.2-fold) by WAY-135706 w hereas WAY-121509 caused a marked reduction. Fructose 1.6-8.0-fold ele vated by diabetes in tissues other than diaphragm, was reduced by WAY- 135706 and WAY-121509, except in the kidney. Motor and sensory nerve c onduction velocities were decreased by 20.2 and 13.9%, respectively wi th diabetes. These deficits were corrected by WAY-121509, but WAY-1357 06 was completely ineffective. A 48.6% diabetes-induced deficit in sci atic nutritive endoneurial blood flow was corrected by WAY-121509, but was unaltered by WAY-135706. Thus, despite profound sorbitol dehydrog enase inhibition, WAY-135706 had no beneficial effect on nerve functio n. The data demonstrate that aldose reductase activity, the first step in the polyol pathway, makes a markedly greater contribution to the a etiology of diabetic neurovascular and neurological dysfunction than d oes the second step involving sorbitol dehydrogenase.