D 2d Da

Figure 3 Reversal of sciatic nutritive endoneurial blood flow (A) and motor conduction velocity (B) deficits in diabetic rats by treatment with the probucol analogue BM 150639. Groups (n = 9-10); C, nondiabetic control; ID, 2D, 1-month, and 2-month streptozotocin-diabetic; DA, 1-month untreated diabetes followed by 1-month BM 150639 (400 mg/kg/day) treatment; DAN, as for DA but cotreated with the nitric oxide synthase inhibitor, A'°-nitro-L-arginine (10 mg/kg/day) during the second month. Data are mean ± SEM. The diabetic deficits in blood flow and motor conduction velocity were well developed after 1 month. BM 150639 treatment was highly effective in reversing these defects, blood flow being approximately 33% supranormal and conduction velocity in the nondiabetic range. The effects of BM 150639 on blood flow and conduction velocity were almost completely blocked by iVG-nitro-l,-arginine, which suggests that blood flow modulates conduction velocity and that antioxidant treatment corrects a diabetic deficit in the vasa nervorum nitric oxide mechanism. (See Ref. 24 for further details.)

angiotensin-converting enzyme activity suggest increased activation of the vasoconstrictor renin-angiotensin system in diabetes, and studies with angiotensin-converting enzyme inhibitors and angiotensin AT, receptor antagonists have shown that this is important for vasa nervorum; these inhibitors correct blood flow, endoneurial hypoxia, and NCV defects in diabetic rats (60). Increased local angiotensin II also causes upregulation of endothelial NADH oxidase, which may exacerbate dysfunction by increasing ROS production (30). Furthermore, oxidative stress also stimulates endothelial endothelin-l synthesis, and this interacts with the angiotensin II system to increase vasa nervorum vasoconstriction (61). Thus, ROS cause a self-reinforcing cycle that compromises vasodilation by NO and increases local vasoconstrictor mechanisms. This cycle may be interrupted by antioxidant treatment.

B. Antioxidant Dose Considerations

The normal dietary intake of natural antioxidants could in theory influence NCV and blood flow in diabetic rats. However, high doses that far exceed normal availability are required in practice; for example, 0.62 g/kg/day of a-tocopherol was necessary to give —50% protection of sciatic motor NCV in diabetic rats (50). For ascorbic acid, 150 mg/kg/day gave an optimal level of protection that was relatively modest (—35%). At high doses (500 mg/kg/ day), protection was less, probably because ascorbic acid is susceptible to autoxidation, acting as a prooxidant (50,62). Under physiological conditions, ascorbic acid may aid the recycling of a-tocopherol from its tocopheroxyl radical form (63); however, with the pharmacological doses used in diabetic rats, there was no evidence of a synergy between ascorbic acid and a-tocopherol cotreatment on NCV. Instead, their effects were simply additive, as if they were acting independently in lipid and aqueous phases (50).

C. Studies Using Transition Metal Chelators

As an alternative to scavenging ROS, it may be therapeutically preferable to prevent their formation by autoxidation, the Fenton reaction, and the advanced glycation process, all of which are catalyzed by free transition metal ions. This can be accomplished using transition metal chelators. Low doses of deferoxamine (relatively specific for iron) and trientine (relatively specific for copper) completely corrected sciatic nerve blood flow and motor and sensory NCV deficits in diabetic rats (64). In vessels such as aorta, chronic trientine and deferoxamine treatment prevented the development of defective NO-mediated, endothelium-dependent relaxation (65,66). For diabetic rat vasa nerv-

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