Abnormal axonal inward rectifier in streptozocin-induced experimental diabetic neuropathy.

In order to explore the pathophysiology of diabetic neuropathy, we studied serial changes of axonal excitability in 20 adult Wistar rats with streptozocin-induced diabetes using the technique of threshold electrotonus (TE). After persistent hyperglycaemia had developed, rats were divided into two groups: nine were fed a diet containing aldose reductase inhibitor (Epalrestat 30 mg/kg/day) (ARI(+) group) and 11 were fed a diet without the inhibitor (ARI(-) group). Eight normal control rats of similar age (NC group) were also studied. We monitored membrane properties of motor axons in the tail for 3 months using TE to measure the changes in excitability induced by subthreshold polarizing currents while recording compound muscle action potentials (CMAPs) in the tail muscle. The ARI(-) group showed a significant increase in CMAP latency 1 month after streptozocin injection, and by 3 months there was significantly lower excitability after hyperpolarization for 100 ms compared with the NC group. A similar change in TE was reproduced by injection of caesium chloride, an inhibitor of inward rectification. By contrast, the ARI(+) group exhibited no significant change in TE or latency at 3 months, although they showed significant body weight loss and hyperglycaemia. These findings indicate that inward rectification is reduced in an experimental model, as in human diabetes, and that blocking the polyol pathway with an ARI prevents this reduction. Reduced inward rectification potentiates conduction block caused by activity-dependent hyperpolarization and may underlie the decreased vibratory sensation seen in the early stage of diabetic neuropathy.