Effect of Treating Streptozotocin-Induced Diabetic Rats With Sorbinil, Myo-Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

Abstract

Previously we have demonstrated that diabetes causes impairment in vascular function of epineurial vessels, which precedes the slowing of motor nerve conduction velocity. Treatment of diabetic rats with aldose reductase inhibitors, aminoguanidine or myo-inositol supplementation have been shown to improve motor nerve conduction velocity and/or decreased endoneurial blood flow. However, the effect these treatments have on vascular reactivity of epineurial vessels of the sciatic nerve is unknown. In these studies we examined the effect of treating streptozotocininduced rats with sorbinil, aminoguanidine or myo-inositol on motor nerve conduction velocity, endoneurial blood flow and endotheliumdependent vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve. Treating diabetic rats with sorbinil, aminoguanidine or myo-inositol improved the reduction of endoneurial blood flow and motor nerve conduction velocity. However, only sorbinil treatment significantly improved the diabetes-induced impairment of acetylcholinemediated vasodilation of epineurial vessels of the sciatic nerve. All three treatments were efficacious in preventing the appropriate metabolic derangements associated with either activation of the polyol pathway or increased nonenzymatic glycation. In addition, sorbinil was shown to prevent the diabetes-induced decrease in lens glutathione level. However, other mark-____________________ *Corresponding author: 3 E 17 Veterans Affairs Medical Center, Iowa City, IA 52246; tel: (319) 338-0581 ext. 7629; fax: (319) 339-7025; e-mail: myorek@icva.gov Int. Jnl. Experimental Diab. Res., 3:21-36, 2002 © 2002 Taylor and Francis 1560 ers of oxidative stress were not vividly improved by these treatments. These studies suggest that sorbinil treatment may be more effective in preventing neural dysfunction in diabetes than either aminoguanidine or myoinositol.Key words: diabetes, diabetic neuropathy, endothelium, vascular reactivity, aldose reductase inhibitor, aminoguanidine INTRODUCTIONDiabetic neuropathy is a multifactorial problem likely due to the poor control of hyperglycemia. Two of these perturbations are the activation of the polyol pathway by which glucose is metabolized to sorbitol via aldose reductase contributing to an alteration in the redox balance and a decrease in myo-inositol uptake and content and an increase in non-enzymatic glycation leading to the abnormal glycation of proteins [1,2]. In animal models of diabetes prevention of these defects by treatment with aldose reductase inhibitors, aminoguanidine or supplementation with myo-inositol has been shown to improve peripheral neuropathy.Studies from numerous laboratories have shown that treating diabetic rats with an aldose reductase inhibitor improves nerve function as well as endoneurial blood flow [3][4][5][6][7][8][9][10][11][12]. This has led to wide speculation regarding the potential benefit of aldose reductase inhibitor treatment of diabetic complications [10][11][12][13][14][15][16]. However, clinical tri...

Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes

“…Other studies have found degeneration of sciatic nerve and retina characteristic of early-stage diabetic neuropathy and retinopathy in this model [14,15]. Increased tissue content of AGEs in diabetes leads to impairment of protein function, linked to vascular cell detachment and anoikis [16,17], oxidative stress [18], low-grade inflammation [18,19] and other cell dysfunctions implicated in the development of microvascular complications [20].…”

Aldose Reductase Pathway Inhibition Improved Vascular and C-Fiber Functions, Allowing for Pressure-Induced Vasodilation Restoration During Severe Diabetic Neuropathy

“…Exaggerated glycation processes during diabetes and excessive accumulation of AGEs in endoneurial microvasculature and nerve fibers contribute to the development of peripheral neuropathy (28,29). Accordingly, inhibitors of AGE accumulation were able to prevent or reverse neurovascular dysfunctions in diabetic rats with early or mild neuropathy (11,14,15).…”

“…Hence, aldose reductase inhibition counteracts diabetes-induced peripheral neuropathies as well as endothelial dysfunction (9,13,14).…”

“…These biochemical pathways are involved in the development of diabetic neurovascular disturbance. In fact, inhibitors of the polyol pathway (9,13,14) and AGE accumulation were able to prevent or reverse neurovascular dysfunctions in diabetic rats with early or mild neuropathy (11,14,15). However, it recently appeared that a long-term experimental diabetic mice model mimics human diabetes complications, particularly those related to neuropathy (16,17).…”

“…For this purpose we used sorbinil, an aldose reductase inhibitor (ARI) that decreases aldose reductase activity and thus decreases sorbitol flux. Sorbinil is known to improve neurovascular dysfunctions (9,14). We also used alagebrium, which is an AGE breaker known to improve arterial elasticity in experimental animals (18,19) as well as in clinical studies (20,21) by its ability to reduce the accumulation of AGEs in diabetes (19,22).…”