ALDOSE REDUCTASE INHIBITION, NERVE PERFUSION, OXYGENATION AND FUNCTION IN STREPTOZOTOCIN-DIABETIC RATS - DOSE-RESPONSE CONSIDERATIONS AND INDEPENDENCE FROM A MYOINOSITOL MECHANISM

We examined the effects of aldose reductase inhibition on nerve bioche mistry and function, blood flow and endoneurial oxygenation in experim ental diabetes mellitus. After 1 month untreated diabetes in rats, tre atment with the novel sulphonylnitromethane aldose reductase inhibitor , ZENECA ZD5522, prevented a progressive increase in sciatic nerve res istance to hypoxic conduction failure (p < 0.05). Motor conduction vel ocity deficits after 4 months untreated diabetes were rapidly returned to normal within 12 days (p < 0.0001) by ZD5522 treatment. Following 2-months untreated diabetes, examination of 1 month ZD5522 treatment d ose-response relationships for correction of nerve sorbitol and fructo se accumulations and reduction in myo-inositol concentration, sciatic motor and saphenous sensory conduction velocity and sciatic blood flow by laser-Doppler flowmetry revealed poor agreement between nerve func tion and biochemical indices. In addition, polyol accumulation differe d between sciatic and saphenous nerves, the latter showing ten-fold lo wer sorbitol concentrations. Laser-Doppler blood flow was 60% decrease d by untreated diabetes (p < 0.001) and there was a strong correlation between ZD5522-mediated increases in blood flow and conduction veloci ty (p < 0.0001). Measurement of nutritive endoneurial blood flow by mi croelectrode polarography and hydrogen clearance showed 44% and 45% de ficits for 1 and 2 months untreated diabetes (p < 0.001) that were pre vented by ponalrestat and ZD5522 treatments, respectively. In contrast , 2 months myo-inositol treatment from diabetes induction did not prev ent reduction in blood flow or sciatic motor conduction velocity. A 37 % reduction in endoneurial oxygen tension after 2 months diabetes (p < 0.001) was completely prevented by ZD5522 treatment (p < 0.001). The data show that a very high degree of polyol pathway blockade is necess ary to correct nerve functional deficits and that aldose reductase inh ibitors have a neurovascular action that does not depend on restoratio n of nerve myo-inositol.