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. 2001 Sep;134(1):21-9.
doi: 10.1038/sj.bjp.0704216.

Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve

L J Coppey  1 , J S Gellett, E P Davidson, J A Dunlap, D D Lund, D Salvemini, M A Yorek
Affiliations

Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve

L J Coppey et al. Br J Pharmacol. 2001 Sep.

Abstract

1. To further explore the effect of antioxidants in preventing diabetes-induced vascular and neural dysfunction we treated streptozotocin-induced diabetic rats daily with subcutaneous injections of 10 mg kg(-1) of M40403 (n=11) and compared the results obtained from 17 control rats and 14 untreated diabetic rats. M40403 is a manganese(II) complex with a bis(cyclo-hexylpyridine)-substituted macrocyclic ligand that was designed to be a selective functional mimetic of superoxide dismutase. Thus, M40403 provides a useful tool to evaluate the roles of superoxide in disease states. 2. Treatment with M40403 significantly improved diabetes-induced decrease in endoneurial blood flow, acetylcholine-mediated vascular relaxation in arterioles that provide circulation to the region of the sciatic nerve, and motor nerve conduction velocity (P<0.05). M40403 treatment also reduced the appearance of superoxide in the aorta and epineurial vessels and peroxynitrite in epineurial vessels. Treating diabetic rats with M40403 reduced the diabetes-induced increase in thiobarbituric acid reactive substances in serum but did not prevent the decrease in lens glutathione level. Treating diabetic rats with M40403 did not improve sciatic nerve Na(+)/K(+) ATPase activity or the sorbitol, fructose or myo-inositol content of the sciatic nerve. 3. These studies provide additional evidence that diabetes-induced oxidative stress and the generation of superoxide and perhaps peroxynitrite may be partially responsible for the development of diabetic vascular and neural complications.

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Figures

Figure 1
Figure 1
Serum triglyceride and free fatty acid levels. Data are presented as the mean±s.e.mean for 17 control rats, 14 untreated diabetic rats and 11 diabetic rats treated with M40403. The * denotes a significant difference compared to control, P<0.05. The+denotes a significant difference compared to untreated diabetic rats, P<0.05.
Figure 2
Figure 2
Serum thiobarbituric acid reactive substances and sciatic nerve conjugated diene level. Serum samples were collected and used to determine thiobarbituric acid reactive substances level (left side of figure). The sciatic nerve was also collected and a portion used to determine the conjugated diene level (right side of figure). Data are presented as the mean±s.e.mean for 17 control rats, 14 untreated diabetic rats and 11 diabetic rats treated with M40403. The * denotes a significant difference compared to control, P<0.05. The+denotes a significant difference compared to untreated diabetic rats, P<0.05.
Figure 3
Figure 3
Detection of superoxide level in arterioles from control, diabetic rats and diabetic rats treated with M40403. The duration of diabetes and treatments for these studies was 3 weeks. Fluorescent photomicrographs of confocal microscopic sections of arterioles that provide circulation to the region of the sciatic nerve from the three individual groups of animals were examined on the same day. Arterioles were labeled with the oxidative dye hydroethidine. Recording of fluorescent were taken at identical laser and photomultiplier settings for both control and untreated and treated diabetic rats. Shown is a representative sample of one set of animals. This experiment was repeated three separate times on separate sets of animals on three different days with similar results.
Figure 4
Figure 4
Detection of peroxynitrite in arterioles from control, diabetic rats, and diabetic rats treated with M40403. Arterioles from control, diabetic rats and diabetic rats treated with M40403 were collected and treated for determination of 3-nitrotyrosine immunostaining. Shown is a representative sample of one set of animals. This experiment was repeated three separate times with similar results.
Figure 5
Figure 5
Determination of endoneurial blood flow. Endoneurial blood flow reported as nutritive flow (left) or conductance (right) was determined. Data are presented as the mean±s.e.mean for 17 control rats, 14 untreated diabetic rats and 11 diabetic rats treated with M40403. The * denotes a significant difference compared to control, P<0.05. The+denotes a significant difference compared to untreated diabetic rats, P<0.05.
Figure 6
Figure 6
Determination of motor nerve conduction velocity. Data are presented as the mean±s.e.mean for 17 control rats, 14 untreated diabetic rats and 11 diabetic rats treated with M40403. The * denotes a significant difference compared to control, P<0.05. The+denotes a significant difference compared to untreated diabetic rats, P<0.05.
Figure 7
Figure 7
Determination of the effect of treatment with M40403 on acetylcholine-mediated vascular relaxation in arterioles that provide circulation to the region of the sciatic nerve. Pressurized arterioles (40 mm Hg) were constricted with U46619 (30 – 50%) and incremental doses of acetylcholine were added to the bathing solution while recording steady state vessel diameter. For control, diabetic and diabetic rats treated with M40403 the number of experimental observations was 17, 14 and 11, respectively. The * denotes that the response to acetylcholine was significantly attenuated in the diabetic rat, P<0.05. The+denotes that the response to acetylcholine was significantly different compared to the untreated diabetic rats, P<0.05.
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References

    1. AMMAR R.F., JR, GUTTERMAN D.D., BROOKS L.A., DELLSPERGER K.C. Free radicals mediate endothelial dysfunction of coronary arterioles in diabetes. Cardiovasc. Res. 2000;47:595–601. - PubMed
    1. ANDREW R., SKYRME-JONES P., O'BRIEN R.C., BERRY K.L., MEREDITH I.T. Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized placebo-controlled study. J. Am. Coll. Cardiol. 2000;36:94–102. - PubMed
    1. BECKMAN J.S. Oxidative damage and tyrosine nitration from peroxynitrite. Chem. Res. Toxicol. 1996;9:836–844. - PubMed
    1. CAKATAY U., TELCI A., KAYALI R., SIVAS A., AKCAY T. Effect of α-lipoic acid supplementation on oxidative protein damage in the streptozotocin-diabetic rat. Res. Exp. Med. 2000;199:243–251. - PubMed
    1. CAMERON N.E., COTTER M.A. Neurovascular dysfunction in diabetic rats: potential contribution of autoxidation and free radicals examined using transition metal chelating agents. J. Clin. Invest. 1995;96:1159–1163. - PMC - PubMed

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