Aldose reductase inhibition alters nodal Na+ currents and nerve conduction in human diabetics.

Background: In diabetic nerves, activation of the polyol pathway via an aldose reductase and the resulting impairment of the Na(+)-K(+) pump would lead to a decreased transaxonal Na+ gradient and thereby reduced nodal Na+ currents.

Objective: To investigate whether the aldose reductase inhibitor (ARI) epalrestat improves nodal Na+ currents and nerve conduction in human diabetic neuropathy.

Methods: The authors conducted a 6-month, open clinical trial with an ARI, epalrestat, in 30 patients with mild-to-moderate diabetic neuropathy. The latent addition technique and measurements of the strength-duration time constant were used to estimate nodal persistent Na+ currents in median motor axons. Excitability testing and extensive nerve conduction studies including F-wave analyses were performed before and 1 and 6 months after the initiation of treatment with oral epalrestat.

Results: Within a month of the start of treatment, there was a significant improvement in nerve conduction, particularly in conduction times across the carpal tunnel and F-wave latencies. The results of latent addition (p < 0.05) and strength-duration time constant (p = 0.06) suggested increased nodal persistent Na+ currents. At 6 months, nerve conduction continued to improve.

Conclusions: Aldose reductase pathway inhibition could rapidly increase nodal Na+ currents and thereby improve the slowing of nerve conduction, presumably because of a restoration of the membranous Na+ gradient.