THE LINKED ROLES OF NITRIC-OXIDE, ALDOSE REDUCTASE AND, (NA-ATPASE INTHE SLOWING OF NERVE-CONDUCTION IN THE STREPTOZOTOCIN-DIABETIC RAT(,K+))

Metabolic and vascular factors have been invoked in the pathogenesis o f diabetic neuropathy but their interrelationships are poorly understo od. Both aldose reductase inhibitors and vasodilators improve nerve co nduction velocity, blood flow, and (Na+,K+)-ATPase activity in the str eptozotocin diabetic rat, implying a metabolic-vascular interaction. N ADPH is an obligate cofactor for both aldose reductase and nitric oxid e synthase such that activation of aldose reductase by hyperglycemia c ould limit nitric oxide synthesis by cofactor competition, producing v asoconstriction, ischemia, and slowing of nerve conduction. In accorda nce with this construct, N-nitro-L-arginine methyl ester, a competitiv e inhibitor of nitric oxide synthase reversed the increased nerve cond uction velocity afforded by aldose reductase inhibitor treatment in th e acutely diabetic rat without affecting the attendant correction of n erve sorbitol and myo-inositol. With prolonged administration, N-nitro -L-arginine methyl ester fully reproduced the nerve conduction slowing and (Na+,K+)-ATPase impairment characteristic of diabetes. Thus the a ldose reductase-inhibitor-sensitive component of conduction slowing an d the reduced (Na+,K+)-ATPase activity in the diabetic rat may reflect in part impaired nitric oxide activity, thus comprising a dual metabo lic-ischemic pathogenesis.