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

From the Department of Neurology (S.M., S.K., K.K., N.T., M.N., S.S., T.H.) and the Second Department of Internal Medicine (K.Y.), Chiba University School of Medicine, Chiba, Japan.

Address correspondence and reprint requests to Dr. Sonoko Misawa, Department of Neurology, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan; e-mail: sonoko.m{at}mb.infoweb.ne.jp.

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.

Disclosure: The authors report no conflicts of interest.

Received October 17, 2005. Accepted in final form January 24, 2006.