INHIBITION OF SORBITOL DEHYDROGENASE - EFFECTS ON VASCULAR AND NEURALDYSFUNCTION IN STREPTOZOCIN-INDUCED DIABETIC RATS

These experiments were undertaken to assess the role of sorbitol dehyd rogenase in mediating sorbitol pathway-inked neural and vascular dysfu nction in rats with streptozocin-induced diabetes. thyl-4-[N,N-methyls ulfamoyl-piperazino]-pyrimidine (S-0773), a putative inhibitor of sorb itol dehydrogenase, was given in the drinking water to control and dia betic rats. After 5 weeks of diabetes, glycosylated hemoglobin levels were increased twofold and were unaffected by S-0773. Sorbitol levels in diabetic rats were increased 11- to 14-fold in ocular tissues and s ciatic nerve; S-0773 increased sorbitol levels another 4-fold or more in these same tissues but had much smaller effects in other tissues. D iabetes-associated increases in fructose levels and lactate:pyruvate r atios in retina and in sciatic nerve were markedly attenuated by S-077 3. S-0773 also attenuated, but did not completely normalize, impaired caudal nerve conduction and vascular dysfunction in ocular tissues, sc iatic nerve, and aorta in diabetic rats. These observations, together with other evidence, suggest that sorbitol pathway-linked vascular dys function (in ocular tissues, peripheral nerve, and aorta) and electrop hysiological dysfunction (in peripheral nerve) induced by diabetes are more closely linked to increased oxidation of sorbitol to fructose th an to putative osmotic effects of elevated sorbitol levels or redox an d metabolic imbalances associated with reduction of glucose to sorbito l by aldose reductase.