Endoneurial vessel abnormalities in diabetic animal models

  • Soroku Yagihashi
  • Kazuhiro Sugimoto
  • Ryu-Ichi Wada
Part of the Rev.Ser.Advs.Research Diab.Animals (Birkhäuser) book series (RSARDA, volume 6)


Neuropathy is a common and serious complication in diabetic patients. Both metabolic and vascular factors are considered to play a crucial role in its pathogenesis. Among the metabolic factors, the enhanced polyol pathway mediated by the enzyme aldose reductase are suggested to induce acutely functional impairments of peripheral nerve fibers and endoneurial microvessels, followed by irreversible structural changes.1–3 Increased nonenzymatic glycation of neural and microvascular proteins may also elicit functional and structural alterations of the peripheral nerve, contributing to the development of neuropathy.4 Thus, the alterations of endoneurial vessel changes may primarily or secondarily facilitate neuropathic changes in the diabetic condition.5 Evaluation of endoneurial microvessels is therefore important not only for determining the role of microvascular lesions in the development of neuropathy, but also for elucidation of the progression of systemic microangiopathy in diabetes.

Key words

neuropathy microangiopathy animal model structure blood flow pathogenesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Winegrad AI. Does a common mechanism induce diverse complications of diabetes? Diabetes 36:396–406, 1989.Google Scholar
  2. 2.
    Greene DA, Sima AAF, Stevens MJ et al. Complications: Neuropathy, pathogenetic considerations. Diabetes Care 15:1902–25, 1992.PubMedCrossRefGoogle Scholar
  3. 3.
    Williamson JR, Chang K, Frangos M et al. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 42:801–13, 1993.PubMedCrossRefGoogle Scholar
  4. 4.
    Brownlee M. Glycation and diabetic complications. Diabetes 43:836–41, 1994.PubMedGoogle Scholar
  5. 5.
    Thomas PK. Diabetic neuropathy: Models, mechanisms and mayhem. Can J Neurol Sci 19:1–7, 1992.PubMedGoogle Scholar
  6. 6.
    Fagerberg SE. Diabetic neuropathy: A clinical and histological study on the significance of vascular affections. Acta Med Scand 164(Suppl 345): 1–97, 1954.Google Scholar
  7. 7.
    Behse F, Buchthal F, Carlsen F. Nerve biopsy and conduction studies in diabetic neuropathy. J Neurol Neurosurg Psychiat 40:1072–82, 1977.PubMedCrossRefGoogle Scholar
  8. 8.
    Yagihashi S, Matsunaga M. Ultrastructural pathology of human diabetic neuropathy. Tohoku J Exp Med 129:357–66, 1979.PubMedCrossRefGoogle Scholar
  9. 9.
    Timperly WR, Ward JD, Preston FE et al. Clinical and histological studies in diabetic neuropathy: A reassessment of vascular factors in relation to vascular coagulation. Diabetologia 12:237–43, 1976.CrossRefGoogle Scholar
  10. 10.
    Williams E, Timperly WR, Ward JD, Duckworth T. Electron microscopical studies of vessels in diabetic peripheral neuropathy. J Clin Pathol 33:462–70, 1980.PubMedCrossRefGoogle Scholar
  11. 11.
    Dyck PJ, Hansen S, Karnes J et al. Capillary number and percentage closed in human diabetic sural nerve. Proc Natl Acad Sci USA 82:2513–17, 1985.PubMedCrossRefGoogle Scholar
  12. 12.
    Dyck PJ, Karnes JL, O’Brien P et al. The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia. Ann Neurol 19:440–9, 1986.PubMedCrossRefGoogle Scholar
  13. 13.
    Dyck PJ, Lais A, Karnes JL et al. Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol 19:425–39, 1986.PubMedCrossRefGoogle Scholar
  14. 14.
    Yasuda H, Dyck PJ. Abnormalities of endoneurial microvessels and sural nerve pathology in diabetic neuropathy. Neurology 37:20–8, 1987.PubMedGoogle Scholar
  15. 15.
    Bradley J, Thomas PK, King RHM et al. Morphometry of endoneurial capillaries in diabetic sensory and autonomic neuropathy. Diabetologia 33:611–18, 1990.PubMedCrossRefGoogle Scholar
  16. 16.
    Sima AAF, Nathaniel V, Prashar A et al. Endoneurial microvessels in human diabetic neuropathy. Endothelial cell dysjunction and lack of treatment effect by aldose reductase inhibitor. Diabetes 40:1090–99, 1991.PubMedCrossRefGoogle Scholar
  17. 17.
    Johnson PC, Doll SC, Cromey DW. Pathogenesis of diabetic neuropathy. Ann Neurol 19:450–7, 1986.PubMedCrossRefGoogle Scholar
  18. 18.
    Llewlyn JG, Thomas PK, Gilbey SG et al. Pattern of myelinated fiber loss in the sural nerve in neuropathy related to type I (insulin dependent) diabetes. Diabetologia 31:162–7, 1988.CrossRefGoogle Scholar
  19. 19.
    Knudsen GH, Jakobsen J, Juhler M, Paulson OB. Decreased blood-brain barrier permeability to sodium in early experimental diabetes. Diabetes 35:1371–73, 1986.PubMedCrossRefGoogle Scholar
  20. 20.
    Rechtland E, Smith QR, Latker CH, Rapoport SI. Altered blood-nerve barrier permeability to small molecules in experimental diabetes mellitus. J Neuropathol Exp Neurol 46:302–14, 1987.CrossRefGoogle Scholar
  21. 21.
    Ohi T, Poduslo JF, Dyck PJ. Increased endoneurial albumin in diabetic polyneuropathy. Neurology 35:1790–91, 1985.PubMedGoogle Scholar
  22. 22.
    Poduslo JF, Curran GL, Dyck PJ. Increase in albumin, IgG, and IgM blood-nerve barrier indices in human diabetic neuropathy. Proc Natl Acad Sci USA 85:4879–83, 1988.PubMedCrossRefGoogle Scholar
  23. 23.
    Lundborg G. Structure and function of the intraneural microvessels as related to trauma, edema formation, and nerve function. J Bone Joint Surg Am 57:938–48, 1975.PubMedGoogle Scholar
  24. 24.
    Myers RR, Powell HC, Shapiro HM, et al. Changes in endoneurial fluid pressure, permeability, and peripheral nerve ultrastructure in experimental lead neuropathy. Ann Neurol 8:392–401, 1980.PubMedCrossRefGoogle Scholar
  25. 25.
    Wadhwani KC, Caspers-Velu LE, Murphy VA et al. Prevention of nerve edema and increased blood-nerve barrier permeability-surface area product in galactosemic rats by aldose reductase or thromboxane synthetase inhibitors. Diabetes 38:1469–77, 1989.PubMedCrossRefGoogle Scholar
  26. 26.
    Myers RR, Powell HC. Galactose neuropathy: Impact of chronic endoneurial edema on nerve blood flow. Ann Neurol 16:587–94, 1984.PubMedCrossRefGoogle Scholar
  27. 27.
    Myers RR, Murakami H, Powell HC. Reduced nerve blood flow in edematous neuropathies: A biochemical mechanism. Microvasc Res 32:145–51, 1986.PubMedCrossRefGoogle Scholar
  28. 28.
    Low PA, Nukada H, Schmelzer JD et al. Endoneurial oxygen tension and radial topography in nerve edema. Brain Res 341:147–54, 1985.PubMedCrossRefGoogle Scholar
  29. 29.
    Lundborg G, Branemark PI. Microvascular structure and function of peripheral nerves. Adv Microcirc 1:66–88, 1968.Google Scholar
  30. 30.
    Bell MA, Weddell AGM. A descriptive study of the blood vessels of the sciatic nerve in the rat, man and other mammals. Brain 107:871–98, 1984.PubMedCrossRefGoogle Scholar
  31. 31.
    Bell MA, Weddell AGM. A morphometric study of intrafascicular vessels of mammalian sciatic nerve. Muscle Nerve 7:524–34, 1984.PubMedCrossRefGoogle Scholar
  32. 32.
    Wadhwani KC, Rapoport SI. Transport properties of vertebrate blood-nerve barrier: Comparison with blood-brain barrier. Prog Neurobiol 43:235–79, 1994.PubMedCrossRefGoogle Scholar
  33. 33.
    Blunt MJ, Stratton K. The immediate effects of ligature of vasa nervorum. J Anat 90:204–16, 1956.PubMedGoogle Scholar
  34. 34.
    Nukada H, Dyck PJ. Microsphere embolization of nerve capillaries and fiber degeneration. Am J Pathol 115:275–87, 1984.PubMedGoogle Scholar
  35. 35.
    Nukada H, Powell HC, Myers RR. Spatial distribution of nerve injury after occlusion of individual major vessels in rat sciatic nerves. J Neuropathol Exp Neurol 52:452–9, 1993.PubMedCrossRefGoogle Scholar
  36. 36.
    Sladky JT, Greenberg JH, Brown MJ. Regional perfusion in normal and ischemic rat sciatic nerves. Ann Neurol 17:191–5, 1985.PubMedCrossRefGoogle Scholar
  37. 37.
    Low PA, Lagerlund TD, McManis PG. Nerve blood flow and oxygen delivery in normal, diabetic, and ischemic neuropathy. Int Rev Neurobiol 31:355–438, 1989.PubMedCrossRefGoogle Scholar
  38. 38.
    Myers RR, Powell HC. Galactose neuropathy: Impact of chronic endoneurial edema on nerve blood flow. Ann Neurol 16:587–94, 1984.PubMedCrossRefGoogle Scholar
  39. 39.
    Greene DA, Lattimer SA. Sodium- and energy-dependent uptake of myo-inositol by rabbit peripheral nerve. Competitive inhibition by glucose and lack of an insulin effect. J Clin Invest 70:1009–18, 1982.PubMedCrossRefGoogle Scholar
  40. 40.
    Smith DR, Kobrine Al, Rizzoli HV. Absence of autoregulation in peripheral nerve blood flow. J Neurol Sci 33:347–52, 1977.PubMedCrossRefGoogle Scholar
  41. 41.
    Kihara M, Low PA. Regulation of rat nerve blood flow: Role of epineurial a-receptors. J Physiol 422:145–52, 1990.PubMedGoogle Scholar
  42. 42.
    Rechtland E, Hervonen A, Sato S, Rapoport SI. Distribution of adrenergic innervation of blood vessels in peripheral nerve. Brain Res 374:185–9, 1986.CrossRefGoogle Scholar
  43. 43.
    Appenzeller O, Dhital KK, Cowen T, Burnstock G. The nerves to blood vessels supplying blood to nerves: The innervation of vasa nervorum. Brain Res 304:383–6, 1984.PubMedCrossRefGoogle Scholar
  44. 44.
    Dhital K, Lincoln J, Appenzeller O, Burnstock G. Adrenergic innervation of vasa and nervi nervorum of optic, sciatic, vagus and sympathetic nerve trunks in normal and streptozotocin-diabetic rats. Brain Res 367:39–44, 1986.PubMedCrossRefGoogle Scholar
  45. 45.
    Koistiraho J, Wadhwani KC, Rapoport SI. Adrenergic innervation of the tibial and vagus nerves in rats of different ages. Mech Ageing Dev 52:195–205, 1990.CrossRefGoogle Scholar
  46. 46.
    Beggs J, Johnson PC, Olafsen A et al. Transperineurial arterioles in human sural nerve. J Neuropathol Exp Neurol 50:704–18, 1991.PubMedCrossRefGoogle Scholar
  47. 47.
    Korthals JK, Gieron MA, Dyck PJ. Intima of epineurial arterioles is increased in diabetic polyneuropathy. Neurology 38:1582–86, 1988.PubMedGoogle Scholar
  48. 48.
    Grover-Johnson NM, Baumann FG, Imparato AM et al. Abnormal innervation of lower limb epineurial arterioles in human diabetes. Diabetologia 20:310–18, 1981.CrossRefGoogle Scholar
  49. 49.
    Yasuda H, Sonobe M, Yamashita M et al. Effect of prostaglandin El analogue TFC 612 on diabetic neuropathy in streptozocin-induced diabetic rats. Comparison with aldose reductase inhibitor ONO 2235. Diabetes 38:832–8, 1989.PubMedCrossRefGoogle Scholar
  50. 50.
    Cameron NE, Cotter MA, Low PA. Nerve blood flow in early experimental diabetes in rats: Relation to conduction deficits. Am J Physiol 261:E1–8, 1991.PubMedGoogle Scholar
  51. 51.
    Moncada S, Palmer MJ, Higgs EA. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–42, 1991.PubMedGoogle Scholar
  52. 52.
    Yanagisawa M, Masaki T. Molecular biology and biochemistry of the endothelins. Trends Pharmacol Sci 10:374–8, 1989.PubMedCrossRefGoogle Scholar
  53. 53.
    Sakurai T, Yanagisawa M, Masaki T. Molecular characterization of endothelin receptors. Trends Pharmacol Sci 13:103–8, 1992.PubMedCrossRefGoogle Scholar
  54. 54.
    Cameron NE, Cotter MA, Robertson S. Angiotensin converting enzyme inhibition prevents development of muscle and nerve dysfunction and stimulates angiogenesis in streptozotocin-diabetic rats. Diabetologia 35:12–18, 1992.PubMedCrossRefGoogle Scholar
  55. 55.
    Maxfield EK, Cameron NE, Cotter MA, Dines KC. Angiotensin II receptor blockade improves nerve function, modulates nerve blood flow and stimulates endoneurial angiogenesis in streptozotocin-diabetic rats. Diabetologia 36:1230–37, 1993.PubMedCrossRefGoogle Scholar
  56. 56.
    Powell HC, Rosoff J, Myers RR. Microangiopathy in human diabetic neuropathy. Acta Neuropathol 68:295–305, 1985.PubMedCrossRefGoogle Scholar
  57. 57.
    Britland ST, Young RJ, Sharma AK, Clarke BF. Relationship of endoneurial capillary abnormalities to type and severity of diabetic polyneuropathy. Diabetes 39:909–13, 1990.PubMedCrossRefGoogle Scholar
  58. 58.
    Malik RA, Newrick PG, Sharma AK et al. Microangiopathy in human diabetic neuropathy: Relationship between capillary abnormalities and the severity of neuropathy. Diabetologia 32:92–102, 1989.PubMedCrossRefGoogle Scholar
  59. 59.
    Malik RA, Veves A, Masson EA, et al. Endoneurial capillary abnormalities in mild human diabetic neuropathy. J Neurol Neurosurg Psychiat 55:557–61, 1992.PubMedCrossRefGoogle Scholar
  60. 60.
    Yagihashi S. Pathogenesis of diabetic neuropathy. Peripheral Nerve 1:43–9, 1990 (in Japanese).Google Scholar
  61. 61.
    Vracko R. A comparison of the microvascular lesions in diabetes mellitus with those of normal aging. J Am Geriat Soc 30:201–5, 1982.PubMedGoogle Scholar
  62. 62.
    Williamson JR, Tilton RG, Chang K, Kilo C. Basement membrane abnormalities in diabetes mellitus: Relationship to clinical microangiopathy. Diabetes Metab Rev 4:339–70, 1988.PubMedCrossRefGoogle Scholar
  63. 63.
    Giannini C, Dyck PJ. Ultrastructural morphometric features of human sural nerve endoneurial microvessels. J Neuropathol Exp Neurol 52:361–9, 1993.PubMedCrossRefGoogle Scholar
  64. 64.
    Giannini C, Dyck PJ. Ultrastructural morphometric abnormalities of sural nerve endoneurial microvessels in diabetes mellitus. Ann Neurol 36:408–15, 1994.PubMedCrossRefGoogle Scholar
  65. 65.
    Vracko R, Benditt EP. Capillary basal lamina thickening. Its relationship to endothelial cell death and replacement. J Cell Biol 47:281–5, 1970.PubMedCrossRefGoogle Scholar
  66. 66.
    Tilton RG, Faller AM, Burkhardt JK et al. Pericyte degeneration and acellular capillaries are increased in the feet of human diabetic patients. Diabetologia 28:895–900, 1985.PubMedCrossRefGoogle Scholar
  67. 67.
    Hotta N, Kakuta H, Fukusawa H et al. Effect of niceritrol on streptozocin-induced diabetic neuropathy in rats. Diabetes 41:587–91, 1992.PubMedCrossRefGoogle Scholar
  68. 68.
    Tilton RG, Chang K, Hasan KS et al. Prevention of diabetic vascular dysfunction by guanidines: Inhibition of nitric oxide synthase versus advanced glycation end product formation. Diabetes 42:221–32, 1993.PubMedCrossRefGoogle Scholar
  69. 69.
    Ido Y, McHowat J, Chang KC et al. Neural dysfunction and metabolic imbalances in diabetic rats. Prevention by acetyl-L-carnitine. Diabetes 43:1469–77, 1994.PubMedCrossRefGoogle Scholar
  70. 70.
    Zochodne DW, Ho LT. Diabetes mellitus prevents capsaicin from inducing hyperemia in the rat sciatic nerve. Diabetologia 36:493–6, 1993.PubMedCrossRefGoogle Scholar
  71. 71.
    Cameron NE, Cotter MA, Robertson S. Essential fatty acid diet supplementation. Effects on peripheral nerve and skeletal muscle function and capillarization in streptozocin-induced diabetic rats. Diabetes 40:532–9, 1991.PubMedCrossRefGoogle Scholar
  72. 72.
    Cameron NE, Cotter MA, Ferguson K et al. Effects of chronic α-adrenergic receptor blockade on peripheral nerve conduction, hypoxic resistance, polyols, Na+-K+-ATPase activity, and vascular supply in STZ-D rats. Diabetes 40:1652–58, 1991.PubMedCrossRefGoogle Scholar
  73. 73.
    Sugimoto K, Nishida N, Yamagishi S et al. Structural changes in endoneurial microvessels in rats with chronic streptozotocin-induced diabetes-morphometric analysis. J Jpn Diab Soc 36:771–8, 1993.Google Scholar
  74. 74.
    Yagihashi S, Sugimoto K, Wada R. Different neuropathic patterns between type I and type II animal models. In: Pathogenesis and treatment of NIDDM and its related problems. Sakamoto N, Alberti KGMM, Hotta N, eds. Elsevier Science, Amsterdam, pp 401–5, 1994.Google Scholar
  75. 75.
    Doukas J, Cutler AH, Baswell CA et al. Reversible endothelial cell relaxation induced by oxygen and glucose deprivation. A model of ischemia in vitro. Am J Pathol 145:211–19, 1994.PubMedGoogle Scholar
  76. 76.
    Powell HC, Myers RR. Axonopathy and microangiopathy in chronic alloxan diabetes. Acta Neuropathol 65:128–37, 1984.PubMedCrossRefGoogle Scholar
  77. 77.
    Sima AAF, Thibert P. Proximal motor neuropathy in the BB-Wistar rat. Diabetes 31:784–8, 1982.PubMedCrossRefGoogle Scholar
  78. 78.
    Cogan DG. Aldose reductase and complications of diabetes. Ann Intern Med 101:527–37, 1984.Google Scholar
  79. 79.
    Hammes HP, Martin S, Federlin K et al. Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc Natl Acad Sci USA 88:11555–558, 1991.PubMedCrossRefGoogle Scholar
  80. 80.
    Chakarabarti S, Sima AAF, Nakajima T et al. Aldose reductase in the BB rat: Isolation, immunological identification and localization in the retina and peripheral nerve. Diabetologia 30:244–51, 1987.CrossRefGoogle Scholar
  81. 81.
    Kador PF, Akagi Y, Takahashi Y et al. Prevention of pericyte ghost formation in retinal capillaries of galactose-fed dogs by aldose reductase inhibitors. Arch Ophthalmol 106:1099–120, 1988.PubMedGoogle Scholar
  82. 82.
    Yagihashi S, Kamijo M, Watanabe K. Reduced myelinated fiber size correlates with loss of axonal neurofilaments in peripheral nerve of chronically streptozotocin diabetic rats. Am J Pathol 136:1365–73, 1990.PubMedGoogle Scholar
  83. 83.
    Goto Y, Kakizaki M, Masaki N. Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc Jpn Acad 51:80–5, 1975.Google Scholar
  84. 84.
    Suzuki K-I, Goto Y, Toyota T. Spontaneously diabetic GK (Goto-Kakizaki) rats. In: Lessons from Animal Diabetes. Shafrir E, ed. Smith Gordon, London, 4:107–16, 1993.Google Scholar
  85. 85.
    Yagihashi S, Goto Y, Kakizaki M, Kaseda N. Thickening of glomerular basement membrane in spontaneously diabetic rats. Diabetologia 15:309–12, 1978.PubMedCrossRefGoogle Scholar
  86. 86.
    Yagihashi S, Tonosaki A, Yamada K-I et al. Peripheral neuropathy in selectively-inbred spontaneously diabetic rats: Electrophysiological, morphometrical and freeze-replica studies. Tohoku J Exp Med 138:39–48, 1982.PubMedCrossRefGoogle Scholar
  87. 87.
    Sima AAF, Nathaniel V, Bril V et al. Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy. J Clin Invest 81:349–64, 1988.PubMedCrossRefGoogle Scholar
  88. 88.
    Yagihashi S, Kamijo M, Nagai K. Peripheral neuropathy in diabetic animals: Heterogeneous expression of neuropathic patterns in different animal models. In: Lessons from animal diabetes. Shafrir E, ed. Smith-Gordon, London, 3:459–63, 1991.Google Scholar
  89. 89.
    Yagihashi S, Wada R, Kamijo M, Nagai K. Peripheral neuropathy in the WBN/Kob rat with chronic pancreatitis and spontaneous diabetes. Lab Invest 68:296–307, 1993.PubMedGoogle Scholar
  90. 90.
    Sugimoto K, Yagihashi S. Peripheral nerve pathology in rats with streptozotocin-induced insulinoma. Acta Neuropathol. 1996 (in press)Google Scholar
  91. 91.
    Yasaki S, Dyck PJ. Spatial distribution of fiber degeneration in acute hypoglycemic neuropathy in rat. J Neuropathol Exp Neurol 50:681–92, 1991.PubMedCrossRefGoogle Scholar
  92. 92.
    Kihara M, Zollman PJ, Smithson IL et al. Hypoxic effect of exogenous insulin on normal and diabetic peripheral nerve. Am J Physiol 266:E980–5, 1994.PubMedGoogle Scholar
  93. 93.
    Stevens MJ, Dananberg J, Feldman EL et al. The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invest 94:853–9, 1994.PubMedCrossRefGoogle Scholar
  94. 94.
    Cameron NE, Cotter MA, Dines KC, Maxfield EK. Pharmacological manipulation of vascular endothelium function in non-diabetic and streptozotocin-diabetic rats: Effects on nerve conduction, hypoxic resistance and endoneurial capillarization. Diabetologia 36:516–22, 1993.PubMedCrossRefGoogle Scholar
  95. 95.
    Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 87:432–8, 1991.PubMedCrossRefGoogle Scholar
  96. 96.
    Yagihashi S, Kamijo M, Baba M, et al. Effect of aminoguanidine on functional and structural abnormalities in peripheral nerve of STZ-induced diabetic rats. Diabetes 41:47–52, 1992.PubMedCrossRefGoogle Scholar
  97. 97.
    Sugimoto K, Nishida N, Wada R. Effects of aminoguanidine on endoneurial vascular abnormalities in experimental diabetic neuropathy. Diabetes 43(Suppl 1):16A, 1994.Google Scholar
  98. 98.
    Kihara M, Schmelzer JD, Poduslo JF et al. Aminoguanidine effect on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals. Proc Natl Acad Sci USA 88:6107–11, 1991.PubMedCrossRefGoogle Scholar
  99. 99.
    Cameron NE, Cotter MA, Dines KC, Love A. Effects of aminoguanidine on peripheral nerve function and polyol pathway metabolites in streptozotocin-diabetic rats. Diabetologia 35:946–50, 1992.PubMedCrossRefGoogle Scholar
  100. 100.
    Corbett JA, Tilton RG, Chang K et al. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes 41:552–6, 1992.PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Boston 1996

Authors and Affiliations

  • Soroku Yagihashi
    • 1
    • 2
  • Kazuhiro Sugimoto
    • 1
  • Ryu-Ichi Wada
    • 1
  1. 1.Department of Pathology, School of MedicineHirosaki UniversityHirosaki 036Japan
  2. 2.Department of PathologyHirosaki University School of MedicineHirosaki 036Japan

Personalised recommendations