Reduced nerve blood flow in diabetic rats: relationship to nitric oxide production and inhibition of aldose reductase

Abstract

This study examined links between impaired nitric oxide production in the sciatic endoneurium, nerve blood flow, and polyol pathway flux, to test the hypothesis that reduced nerve blood flow might be compromised by competition for NADPH between aldose reductase and nitric oxide synthase. Sciatic nerves of streptozotocin-diabetic rats showed reduced laser Doppler flux (by 51 % or 63 %; both pϽ0.05)-indicative of reduced nerve blood flow-and reduced motor nerve conduction velocity (17 % in two experiments; pϽ0.05). Acute interruption of nitric oxide production in the sciatic nerves of control rats, via endoneurial injection of N-nitro-D-arginine methyl ester (L-NAME), caused a local reduction (of 64 %; pϽ0.001) in nerve Doppler flux. This was reversed by either L-arginine or sodium nitroprusside. The response to L-NAME was greatly reduced in diabetic rats (only 22 % reduction; pϽ0. 01), though both L-arginine and SNP caused marked increases in flux. Chronic inhibition of aldose reductase in diabetic rats (with either sorbinil or imirestat at a range of doses) had little effect on resting sciatic nerve Doppler flux, though both inhibitors normalized conduction velocity. Both aldose reductase inhibitors reduced sorbitol pathway intermediates in a dose-related manner. These findings do not support the proposition that aldose reductase inhibitors normalise conduction velocity by mechanisms dependent upon either normalization of endoneurial nitric oxide or nerve blood flow. Instead, a mechanism based upon more direct effects on axon or Schwann cell function is favoured.Data are mean ± 1 standard deviation and were analysed by one-way analysis of variance with Duncan's multiple range tests; pϽ0.05 a vs b and pϽ0.01 ( x vs y ). NM, not measured. Massive differences in body weight and blood glucose were not tested. 580 D.R. TOMLINSON ET AL.

An aldose reductase inhibitor reverses early diabetes‐induced changes in peripheral nerve function, metabolism, and antioxidative defense

“…As expected from previous studies (1,6,20,50,51,52,54), nerve glucose concentrations remained unaffected, whereas both sorbitol and fructose were normalized completely with 65 mg/kg/d of sorbinil. Thus, we achieved a complete inhibition of diabetes-induced sorbitol pathway hyperactivity (that is, met an obligatory criterion for addressing a principal question of this study).…”

“…Our results do not confirm the failure to reverse diabetes-induced MNCV slowing by AR inhibition (11,30). It is important that beneficial effects on nerve conduction have also been observed with suboptimal doses of ARIs (51,54,66,67) and, in particular, with 1 mg/kg SNK-860, the dose equipotent to 20 mg/kg sorbinil (67). A close negative correlation (r=-0.95) was found between MNCV and sciatic nerve sorbitol concentrations in the aforementioned study.…”

“…Ther. 276,[49][50][51][52][53][54][55] 5. Raccah, D., Coste, T., Cameron, N. E., Dufayet, D., Vague, P., and Hohman, T. C. (1998) Effect of the aldose reductase inhibitor tolrestat on nerve conduction velocity, Na/K ATPase activity, and polyols in red blood cells, sciatic nerve, kidney cortex, and kidney medulla of diabetic rats.J.…”

Neural and endothelial control of the microcirculation in diabetic peripheral neuropathy

“…Recent work, demonstrating impaired blood flow response to NO synthase inhibition in streptozotoxin diabetic rats, suggests that impaired production of NO may contribute to the endoneurial ischemia, 8,30 metabolic abnormalities, and nerve conduction slowing in experimental diabetic neuropathy. Reduced nerve blood flow and endoneurial hypoxia have been documented in some 27-29 models of experimental diabetic neuropathy.…”