Nitric Oxide and Its Role in Diabetes Mellitus

  • Michael T. Johnstone
  • Todd A. Caulfield
Part of the Contemporary Cardiology book series (CONCARD)


Diabetes mellitus is a major source of morbidity in the United States, affecting between 10 and 15 million people (1). The cause of much of this morbidity and mortality is vascular disease, including both atherosclerosis and microangiopathy (2–4). As discussed elsewhere in this text, atherosclerosis occurs earlier in diabetics than nondiabetics, its severity is often greater, and its distribution is more diffuse (5,6). Vascular disease in diabetics also affects not only large vessels but microvasculature as well, resulting in both diabetic retinopathy and nephropathy (7,8).


Nitric Oxide Nitric Oxide Endothelial Function Acute Hyperglycemia Hypercholesterolemic Rabbit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Diabetes Statistics. National Diabetes Information Clearinghouse. Bethesda, MD. National Institute of Diabetes and Digestive and Kidney Diseases, NIH publication 99–3926, 1999.Google Scholar
  2. 2.
    Kannel WB, McGee DL. Diabetic and cardiovascular disease: the Framingham Study. JAMA 1978; 241:2035–2038.CrossRefGoogle Scholar
  3. 3.
    Garcia MJ, McNamara PM, Gordon T, Kannell WB. Morbidity and mortality in diabetes in the Framingham population. Diabetes 1974;23:105–111.PubMedGoogle Scholar
  4. 4.
    Decker T, Poulsen JE, Larsen M. Prognosis of diabetics with onset before age thirty-one: I and II. Diabetologia 1978;14:363–367.CrossRefGoogle Scholar
  5. 5.
    Beach KW, Strandness DE. Arteriosclerosis obliterans with associated risk factors in insulin-depen-dent and non-insulin-dependent diabetes. Diabetes 1980;29:882–888.PubMedCrossRefGoogle Scholar
  6. 6.
    Keen H, Jarrett RJ. The WHO multinational study of diabetes: 2. Macrovascular disease prevalence. Diabetes Care 1979;2:187–195.PubMedCrossRefGoogle Scholar
  7. 7.
    Merimee TJ. Diabetic retinopathy: a synthesis of perspective. N Engl J Med 1990;322:978–983.PubMedCrossRefGoogle Scholar
  8. 8.
    Zatz R, Brenner BM. Pathogenesis of diabetic microangiopathy: the hemodynamic view. Am J Med 1986;80:443–453.PubMedCrossRefGoogle Scholar
  9. 9.
    Furchgott RF, Zawadzki JV. The obligatory role of the endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;228:373–376.CrossRefGoogle Scholar
  10. 10.
    Furchgott RF. Studies on relaxation of rabbit aorta by sodium nitrate: basis for the proposal that the acid-activatable component of the inhibitory factor from endothelium-derived relaxing factor inorganic nitrate and retractor penis is nitric oxide. In: Vanhoutte PM, ed. Mechanisms of Vasodilation. Raven, New York, 1988, pp. 401–414.Google Scholar
  11. 11.
    Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989;3: 2007–2018.PubMedGoogle Scholar
  12. 12.
    Ignarro LJ Byrns RE, Wood KS. Biochemical and pharmacologic properties of endothelium-derived relaxing factor and its similarity to nitric oxide radical. In: Vanhoutte PM, ed. Mechanisms of Vasodilation. Raven, New York, 1988, pp. 427–435.Google Scholar
  13. 13.
    Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524–526.PubMedCrossRefGoogle Scholar
  14. 14.
    Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possess pharmacoligic and chemical properties identical to those of the nitric oxide radicals. Circ Res 1987;61;866–879.PubMedCrossRefGoogle Scholar
  15. 15.
    Dinerman JL, Lowenstein CJ, Snyder SH. Molecular mechanisms of nitric oxide regulation. Circ Res 1993;73:217–222.PubMedCrossRefGoogle Scholar
  16. 16.
    Waldman SA, Murad F. Cyclic GMP synthesis and function. Pharmacol Rev 1987;39:163–197.PubMedGoogle Scholar
  17. 17.
    Lincoln TM, Cornwell TL, Taylor AE. cGMP-dependent protein kinase mediates the reduction of Ca2+ by cAMP in vascular smooth muscle cells. Am J Physiol 1990;258:C399–C407.Google Scholar
  18. 18.
    Godfraind T. EDRF and cGMP control gating of receptor-operated calcium channels in vascular smooth muscle. Eur J Pharmacol 1986;126:341–343.PubMedCrossRefGoogle Scholar
  19. 19.
    Collins PB, Griffith TM, Henderson AH, et al. Endothelium-derived relaxing factor alters calcium fluxes in rabbit aorta: a cyclic guanosine-mediated effect. J Physiol 1986;381:427–437.PubMedGoogle Scholar
  20. 20.
    Dimmeler S, Lottspeich F, Brune B. Nitric oxide causes ADP-ribosylation and inhibition of glyceraldehyde 3-phosphate dehydrogenase. J Biol Chem 1992;267:16,771–16,774.Google Scholar
  21. 21.
    Rees DD, Palmer RMJ, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 1989;86:3375–3378.PubMedCrossRefGoogle Scholar
  22. 22.
    Vallance P, Collier JG, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989;28:997–1000.CrossRefGoogle Scholar
  23. 23.
    Griffith TM, Edwards DH, Davies RL, et al. EDRF coordinates the behavior of vascular resistance vessels. Nature 1987;329:442–445.PubMedCrossRefGoogle Scholar
  24. 24.
    Stamler JS, Loh E, Roddy M-A, et al. Nitric oxide regulated basal systemic and pulmonary vascular resistance in healthy humans. Circulation 1994;89:2035–2040.PubMedCrossRefGoogle Scholar
  25. 25.
    Lowenstein CJ, Dinerman JL, Snyder SH. Nitric oxide: a physiological messenger. Ann Intern Med 1994;120:227–237.PubMedCrossRefGoogle Scholar
  26. 26.
    Ignarro LJ. Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein. Circ Res 1989;65:1–21.PubMedCrossRefGoogle Scholar
  27. 27.
    Kourembanas S, McQuillan LP, Leung GK, et al. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 1993; 92:99–104.PubMedCrossRefGoogle Scholar
  28. 28.
    Balligand J-L, Kelly RA, Marsden PA, et al. Control of cardiac muscle function by an endogenous nitric oxide signalling system. Proc Natl Acad Sci USA 1993;90:347–351.PubMedCrossRefGoogle Scholar
  29. 29.
    Mellion BT, Ignarro LJ, Ohlstein EH, et al. Evidence for the inhibitory role for guanosine 3′,5′-mono-phosphate in ADP induced human platelet aggregation in the presence of nitric oxide and released vasodilators. Blood 1981;57:946–955.PubMedGoogle Scholar
  30. 30.
    Kubes P, Granger DN. Nitric oxide modulates microvascular permeability. Am J Physiol 1992;262: H611–H615.Google Scholar
  31. 31.
    Garg UC, Hassid A. Nitric oxide generating vasodilators and 8-bromo-cyclic GMP inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1974–1977.CrossRefGoogle Scholar
  32. 32.
    Marks DS, Vita JA, Folts JD, Keaney JF Jr, Welch GN, Loscalzo J. Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide. J Clin Invest 1995;96:2630–2638.PubMedCrossRefGoogle Scholar
  33. 33.
    Taguchi J, Abe J, Okazaki H, et al. L-arginine inhibits neointimal formation following balloon injury. Life Sci 1993;53:387–392.CrossRefGoogle Scholar
  34. 34.
    Cohen RA. The role of nitric oxide and other endothelium-derived vasoactive substances in vascular disease. Prog Cardiovasc Med 1995;38:105–128.CrossRefGoogle Scholar
  35. 35.
    Bossaller C, Habib GB, Yamamoto H, et al. Impaired muscarininc endothelium-dependent relaxation and cyclic guanosine 5′-monophosphate in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest 1987;79:170–174.PubMedCrossRefGoogle Scholar
  36. 36.
    Vereuren TJ, Jordaens FH, Zonnekeyn LL, et al. Effect of hypercholesterolemia on vascular reactivity in the rabbit. 1. Endothelium-dependent and endothelium-independent contractions and relaxations in coronary arteries of control and hypercholesterolemic rabbits. Circ Res 1986;58:552–564.CrossRefGoogle Scholar
  37. 37.
    CookeJP,SingerAH,TsaoPS,etal.AntiatherogeniceffectsofL-arginineinthehypercholesterolemic rabbit. J Clin Invest 1992;90:1168–1172.CrossRefGoogle Scholar
  38. 38.
    De CR, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60–85.CrossRefGoogle Scholar
  39. 39.
    Rajavashisth TB, Andalibi A, Territo MC, et al. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low density lipoproteins. Nature 1990;344: 254–257.PubMedCrossRefGoogle Scholar
  40. 40.
    Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial adhesion molecules: NFKB and cytokine-inducible enhancers. FASEB J 1995;9:899–905.Google Scholar
  41. 41.
    Peng HB, Libby P, Liao JK. Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B. J Biol Chem 1995;270:14,214–14,219.Google Scholar
  42. 42.
    Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic-guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774–1777.PubMedCrossRefGoogle Scholar
  43. 43.
    Almer L, Pandolfi M, Aberg M. The plasminogen activator activity of arteries and veins in diabetes mellitus. Thromb Res 1975;6:177–182.PubMedCrossRefGoogle Scholar
  44. 44.
    Auwerx J, Bouillon R, Collen D, Gebbers J. Tissue-type plasminogen activator inhibitor in diabetes mellitus. Arteriosclerosis 1988;8:68–72.PubMedCrossRefGoogle Scholar
  45. 45.
    Carreras LO, Chamone DA, Klerckx P, Vermylen J. Decreased vascular prostacyclin (PGI2 )in diabetic rats; stimulation of PGI2 release in normal and diabetic rats by antithrombin compound Bay G 675. Thromb Res 1980;19:663–670.PubMedCrossRefGoogle Scholar
  46. 46.
    Umeda F, Inoguchi T, Nawata H. Reduced stimulatory activity on porstacyclin production by cultured endothelial cells in serum from aged and diabetic patients. Atherosclerosis 1980;75:61–66.CrossRefGoogle Scholar
  47. 47.
    Meraji S, Jayakody L, Senarantne P, et al. Endothelium-dependent relaxation in aorta of BB rat. Diabetes 1987;36:978–981.PubMedCrossRefGoogle Scholar
  48. 48.
    Oyama Y, Kawaski H, Hamori Y, Kanno M. Attenuation of endothelium-dependent relaxation in aorta from diabetic rats. Eur J Pharmacol 1986;131:75–78.CrossRefGoogle Scholar
  49. 49.
    Tesfamarian B, Jakubowkski JA, Cohen RA. Contraction of diabetic rabbit aorta due to endotheliumderived PGH2/TXA2. Am J Physiol 1989;257:H:1327–1333.Google Scholar
  50. 50.
    Mayhan W, Simmons LK, Sharpe QM. Mechanisms of impaired responses of cerebral arterioles during diabetes mellitus. Am J Physiol 1991;260:H:319–326.Google Scholar
  51. 51.
    Abiru T, Watanabe Y, Kamara K, Miyata N, Kasuya Y. Decrease in endothelium-dependent relaxation and levels of cyclic nucleotides in aorta from rabbits with alloxan-induced diabetes. Res Commun Chem Pathol Pharmacol 1990;68:13–25.PubMedGoogle Scholar
  52. 52.
    Taylor PD, Oon BB, Thomas CR, et al. Prevention by insulin treatment of endothelial dysfunctin, but not enhanced noradrenaline-induced contractility in mesenteric resistance arteries from streptozocininduced diabetic rats. Br J Pharmacol 1994;111:35–41.PubMedCrossRefGoogle Scholar
  53. 53.
    Fortes ZB, Leme JG, Scivoletto R. Vascular reactivity in diabetes mellitus: possible role of insulin on the endothelial cell. Br J Pharmacol 1984;83:635–643.PubMedCrossRefGoogle Scholar
  54. 54.
    Tesfamaian B, Brown ML, Deykin D, Cohen RA. Elevated glucose promotes generation of endothelium-deprived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest 1990;85:929–932.CrossRefGoogle Scholar
  55. 55.
    Tesfamarian B, Brown ML, Cohen RA. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest 1991;87:1643–1648.CrossRefGoogle Scholar
  56. 56.
    Cohen RA, Tesfamarian B. Diabetes mellitus and the vascular endothelium. In: Ruderman N, ed. Hyperglycemia, Diabetes and Vascular Disease. Oxford University Press, New York, 1992, pp. 44–49.Google Scholar
  57. 57.
    Tesfamarian B, Brown ML, Cohen RA. Aldolase reductase and myo-inositol in endothelial cell dysfunction caused by elevated glucose. J Pharmacol Exp Ther 1992;263:153–157.Google Scholar
  58. 58.
    Cohen RA. Dysfunction of vascular endothelium in diabetes mellitus. Circulation 1993;87(Suppl V): V67–V76.Google Scholar
  59. 59.
    Kamata K, Miyata N, Abiru T, et al. Functional changes in vascular smooth muscle and endothelium of arteries during diabetes mellitus. Life Sci 1992;50:1379–1387.PubMedCrossRefGoogle Scholar
  60. 60.
    Wolff SP, Dean RT. Glucose autoxidation and protein modification: the role of oxididative glycosylation in diabetes. Biochem J 1987;245:243250.Google Scholar
  61. 61.
    Tesfamarian B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 1992;263:H321–H326.Google Scholar
  62. 62.
    Hattori Y, Kawasaki H, Abe K, Kanno M. Superoxide dismutase recovers altered endothelium-depen-dent relaxation in diabetic rat aorta. Am J Physiol 1991;261:H1086–H1094.Google Scholar
  63. 63.
    Saenz de Tejada I, Goldstein I, Azadzoi K, Krane A,Cohen RJ. Impaired neurogenic and endotheliumdependent relaxation of human penile smooth muscle; the pathophysiological basis for impotence in diabetes mellitus. N Engl J Med 1989;320:1025–1030.CrossRefGoogle Scholar
  64. 64.
    Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endotheliumdependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88: 251(-2516.Google Scholar
  65. 65.
    CalverA,CollerJ,VallanceP.Inhibitionandstimulationofnitricoxidesynthesisinthehumanforearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992;90:2648–2654.Google Scholar
  66. 66.
    Elliot TG, Cockroft JR, Groop PH,Viberti GC, Ritter JM. Inhibition of nitric oxide synthesis in forearm arterial vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria. Clin Sci 1993. 85:687–693.Google Scholar
  67. 67.
    Smits P, Kapma JA, Jacobs MC, Lutterman J, Thien T. Endothelium-dependent vascular relaxation in patients with type I diabetes. Diabetes 1993;42:148–153.PubMedCrossRefGoogle Scholar
  68. 68.
    Hallin A, Benjamin N, Doktor HS, Todd D, Viberti G, Ritter JM. Vascular responsiveness and cation exchange in insulin-dependent diabetes. Clin Sci 1991;81:223–232.Google Scholar
  69. 69.
    Lieberman EH, Uehata A, Polak J, et al. Flow mediated vasodilation is impaired in the brachial artery of patients with coronary artery disease or with diabetes mellitus (abstract). Clin Res 1993;41:217A.Google Scholar
  70. 70.
    Zenere BM, Arcaro G, Saggiani F, Rossi L, Muggeo M, Lechi A. Noninvasive detection of functional alterations of the arterial wall in IDDM patients with and without microalbuminuria. Diabetes Care 1995;18:975–982.PubMedCrossRefGoogle Scholar
  71. 71.
    Clarkson P, Celermajer DS, Donald AE, et al. Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J Am Coll Cardiol 1996;28:573–579.PubMedCrossRefGoogle Scholar
  72. 72.
    Makkimaira S, Virkamaki A, Groop PH, et al. Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. Circulation 1996; 94:1276–1282.CrossRefGoogle Scholar
  73. 73.
    Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy MA, Simonson DC. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 1998;97:1695–1701.PubMedCrossRefGoogle Scholar
  74. 74.
    Chowienczyk PJ, Watts GF, Brett SE, Ritter JM. Sex differences in endothelial function in normal and hypercholesterolemic subjects. Lancet 1994;344:305–306.PubMedCrossRefGoogle Scholar
  75. 75.
    Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567–574.PubMedCrossRefGoogle Scholar
  76. 76.
    McVeigh GE, Brennan GM, Johnston GD, et al. Impaired endothelium-dependent and independent vasodilation in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992;35:771–776.PubMedGoogle Scholar
  77. 77.
    Cosentino F, Luscher TF. Endothelial dysfunction in diabetes mellitus. J Cardiovasc Pharmacol 1998; 32(Suppl 3): S54–S61.Google Scholar
  78. 78.
    Bohlen HG, Lash JM. Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation of normal rat arterioles. Am J Physiol 1993;265:H219–H225.Google Scholar
  79. 79.
    Akbari CM, Saouf R, Barnhill DF, et al. Endothelium-dependent vasodilation is impaired in both microcirculation and macrocirculation during acute hyperglycemia. J Vasc Surg 1998;28:687–694.PubMedCrossRefGoogle Scholar
  80. 80.
    Houben AJ, Schaper NC, de Haan CH, et al. Local 24-h hyperglycemia does not affect endotheliumdependent or -independent vasoreactivity in humans. Am J Physiol 1996;270:H2014–H2020.Google Scholar
  81. 81.
    Davies MG, Ramkumar V, Gettys TW, Hagen PO. The expression and function of G-proteins in experimental intimal hyperplasia. J Clin Invest 1994;94:1680–1689.PubMedCrossRefGoogle Scholar
  82. 82.
    Gilligan DM, Guetta V, Panza JA, Garcia CE, Quyyumi AA, Cannon RO. Selective loss of microvascular endothelial function in human hypercholesterolemia. Circulation 1994;90:35–41.PubMedCrossRefGoogle Scholar
  83. 83.
    Mancusi G, Hutter C, Baumgartner-Parzer S, Schmidt K, Schutz W, Sexl V. High glucose incubation of human umbilical-vein endothelial cells does not alter expression and function either of G-protein alpha subunits or of endothelial NO synthase. Biochem J 1996;315:281–287.PubMedGoogle Scholar
  84. 84.
    Pieper GM, Siebeneich W, Moore-Hilton G, Roza AM. Reversal of L-arginine of a dysfunction arginine/ nitric oxide pathway in the endothelium of the genetic diabetic BB rat. Diabetologia 1997;40:910–915.PubMedCrossRefGoogle Scholar
  85. 85.
    Pieper GM, Peltier BA. Amelioration by L-arginine of a dysfunctional arginine/nitric oxide pathway in diabetic endothelium. J Cardiovasc Pharmacol 1995;25:397–403.PubMedCrossRefGoogle Scholar
  86. 86.
    Wu G, Meininger CJ. Impaired arginine metabolism and NO synthesis in coronary endothelial cells of the spontaneously diabetic BB rat. Am J Physiol 1995;269:H1312–H1318.Google Scholar
  87. 87.
    MacAllister RJ, Calver AL, Collier J, et al. Vascular and hormonal responses to arginine:provision of substrate for nitric oxide or non-specific? Clin Sci 1995;89:183–190.PubMedGoogle Scholar
  88. 88.
    Knowles RG, Moncada S. Review article: nitric oxide synthases in mammals. Biochem J 1994;298: 249–258.PubMedGoogle Scholar
  89. 89.
    Asahina T, Kashiwagi A, Nishio Y. Impaired activation of glucose oxidation and NADPH supply in human endothelial cells exposed to H2O2 in high glucose medium. Diabetes 1995;44:520–526.PubMedCrossRefGoogle Scholar
  90. 90.
    Tesfamarian B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med 1994;16: 383–391.CrossRefGoogle Scholar
  91. 91.
    Dohi T, Kawamura K, Morita K, Okamoto H, Tsujimoto A. Alterations of the plasma selenium concentrations and the activities of tissue peroxide metabolism enzymes in streptozocin-induced diabetic rats. Horm Metab Res 1988;20:671–675.PubMedCrossRefGoogle Scholar
  92. 92.
    Wohaieb SA, Godin DV. Alterations in free radical tissue-defense mechanisms in streptozocin-induced diabetes in rat: effects of insulin treatment. Diabetes 1987;36:1014–1018.PubMedCrossRefGoogle Scholar
  93. 93.
    Pieper GM, Gross GJ. Oxygen free radicals abolish endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol 1988;225:H825–H833.Google Scholar
  94. 94.
    Langestroer P, Pieper GM. Regulation of spontaneous EDRF release in diabetic rat aorta by oxygen free radicals. Am J Physiol 1992;263:H257–H265.Google Scholar
  95. 95.
    Auch-Schwelk W, Kapusic ZC, Vanhoutte PM. Contractions to oxygen-derived free radicals are augmented in aorta of spontaneously hypertensive rats. Hypertension 1989;13:859–864.PubMedCrossRefGoogle Scholar
  96. 96.
    Katusie ZS, Schugel J, Cosentino F, Vanhoutte PM. Endothelium-dependent contractions to oxygenderived free radicals in canine basilar artery. Am J Physiol 1993;364:H859–H864.Google Scholar
  97. 97.
    Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes. J Clin Invest 1991;87:432–438.PubMedCrossRefGoogle Scholar
  98. 98.
    Ido y, Kilo C, Williamson JR. Cytosolic NADH/NAD+ free radicals and vascular dysfunction in early diabeties mellitus. Diabetologia 1997;40: S 115-S 117.Google Scholar
  99. 99.
    Williamson JR, Chang K, Frangos M, et al. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 1993;42:801–813.PubMedCrossRefGoogle Scholar
  100. 100.
    Schmidt K, Werner ER, Mayer B, et al. Tetrahydrobiopterin-dependent formation of endotheliumderived relaxing factor (nitric oxide) in aortic endothelial cells. Biochem J 1992;281:297–300.PubMedGoogle Scholar
  101. 101.
    Consentino F, Katusic Z. Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation 1995;91:139–145.CrossRefGoogle Scholar
  102. 102.
    Pieper GM. Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor tetrahydrobiopterin. J Cardiovasc Pharmacol 1997;29:8–15.PubMedCrossRefGoogle Scholar
  103. 103.
    Lee T, MacGregor LC, Fluharty SJ, King GL. Differential regulation of protein kinase C and (Na, K)adenosine triphosphate activities by elevated glucose levels in renal capillary endothelial cells. J Clin Invest 1988;83:90–94.CrossRefGoogle Scholar
  104. 104.
    Lee TS, Saltsman KA, Ohashi H, King GL. Activation of protein kinase C by elevation of glucose concentration: proposal for a mechanism in the development of diabetic vascular complications. Proc Natl Acad Sci USA 1989;86:514–515.Google Scholar
  105. 105.
    Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991;40: 405–412.PubMedCrossRefGoogle Scholar
  106. 106.
    Craven PA, Patterson MC, DeRubertis FR. Role of protein kinase C in A23187 induced glomerular arachidonate release and PGE2 production. Biochem Biophys Res Commun 1987;149:658–664.PubMedCrossRefGoogle Scholar
  107. 107.
    Fujita I, Irita K, Takoshige K, Minakami S. Diacylglycerol 1-oleyl-2-acetyl-glycerol stimulates superoxide generation from human neutrophils. Biochem Biophys Res Commun 1984;120:318–324.PubMedCrossRefGoogle Scholar
  108. 108.
    Dunbar JC, O’Leary DS, Wang G, Wright-Richey J. Mechanisms mediating insulin-induced hypotension in rats: a role for nitric oxide and autonomic mediators. Acta Diabetol 1996;33:263–268.PubMedCrossRefGoogle Scholar
  109. 109.
    Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent; a novel action of insulin to increase nitric oxide release. J Clin Invest 1994;94:1172–1179.PubMedCrossRefGoogle Scholar
  110. 110.
    Balon TW, Nadler JL. Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol 1997;82:359–363.PubMedGoogle Scholar
  111. 111.
    Young ME, Radda GK, Leighton B. Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro. Biochem J 1997;322:223228.Google Scholar
  112. 112.
    Petrie JR, Ueda S, Webb DJ, Elliott HL, Connell JMC. Endothelial nitric oxide production and insulin sensitivity. Circulation 1996;93:1331–1333.PubMedCrossRefGoogle Scholar
  113. 113.
    Cleland SJ, Petrie JR, Small M, Elliott HL, Connell JM. Insulin action is associated with endothelial function in hypertension and type 2 diabetes. Hypertension 2000;35:507–511.PubMedCrossRefGoogle Scholar
  114. 114.
    Utraiainen T, Makimattila S, Virkamaki A, Bergholm R, Yki-Jarvinen H. Dissociation between insulin sensitivity of glucose uptake and endothelial function in normal subjects. Diabetologia 1996;39:1477–1482.CrossRefGoogle Scholar
  115. 115.
    Bursztyn M, Raz I, Mekler J, Ben-Ishay D. Effect of acute N-nitro-L-arginine methyl ester (L-NAME) hypertension on glucose tolerance, insulin levels, and [3H]-deoxyglucose muscle uptake. Am J Hypertens 1997;10:683–686.PubMedCrossRefGoogle Scholar
  116. 116.
    Osborne JA, Siegman MJ, Sedar AW, et al. Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits. Am J Physiol 1989;256:C591–C597.Google Scholar
  117. 117.
    Shimokawa AH, Vanhoutte PM. Hypercholesterolemia causes generalized impairment of endotheliumdependent relaxation to aggregating platelets in porcine arteries. J Am Coll Card 1989;13:1402–1408.CrossRefGoogle Scholar
  118. 118.
    Creager MA, Cooke JP, Mendelsohn ME, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990;86:228–234.PubMedCrossRefGoogle Scholar
  119. 119.
    Simon BC, Cunningham LD, Cohen RA. Oxidized low density lipoproteins cause contraction and inhibit endothelium-dependent relaxation in the pig coronary artery. J Clin Invest 1990;86:75–79.PubMedCrossRefGoogle Scholar
  120. 120.
    Chowienczyk PJ, Watts GF, Cockcroft JR, et al. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolemia. Lancet 1992;340:1430–1432.PubMedCrossRefGoogle Scholar
  121. 121.
    Shiode N, Nakayama K, Morishima N, et al. Nitric oxide production by coronary conductance vessels in hypercholesterolemic patients. Am Heart J 1996;131:1051–1057.PubMedCrossRefGoogle Scholar
  122. 122.
    Quyyumi AA, Mulcahy D, Andrews NP, et al. Coronary vascular nitric oxide activity in hypertension and hypercholesterolemia. Circulation 1997;95:104–110.Google Scholar
  123. 123.
    Creager MA, Gallagher SJ, Girerd XJ, et al. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 1992;90:1248–1253.PubMedCrossRefGoogle Scholar
  124. 124.
    Cooke JP, Singer AH, Tsao P, et al. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest 1992;90:1168–1172.PubMedCrossRefGoogle Scholar
  125. 125.
    Ohara Y, Pederson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide production. J Clin Invest 1993;91:2546–2551.PubMedCrossRefGoogle Scholar
  126. 126.
    Makimattila S, Liu ML, Vakkilainen J, et al. Impaired vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL and antioxidants. Diabetes Care 1999;22:973–981.PubMedCrossRefGoogle Scholar
  127. 127.
    Tan KC, Ai VH, Chow WS, et al. Influence of low density lipoproteins (LDL) subfraction profile and LDL oxidation on endothelium-dependent and independent vasodilation in patients with type 2 diabetes. J Clin Endocrinol Metab 1999;84:3212–3216.PubMedCrossRefGoogle Scholar
  128. 127a.
    O’Brien SF, Watts GF, Playford DA, et al. Low-density lipoprotein size, high-density lipoprotein concentrations, and endothelial dysfunction in non-insulin-dependent diabetics. Diabetes Med 1997; 14:974–948.CrossRefGoogle Scholar
  129. 128.
    Skyrme-Jones RA, O’Brien RC, Luo M, et al. Endothelial vasodilator function is related to low-density lipoproteins particle size and low density lipoprotein vitamin E content in type 1 diabetes. J Am Coll Cardiol 2000;35:292–299.CrossRefGoogle Scholar
  130. 129.
    Hedrick CC, Thorpe SR, Fu MX, et al. Glycation impairs high-density lipoprotein function. Diabetologia 2000;43:312–320.PubMedCrossRefGoogle Scholar
  131. 130.
    Konishi M, Su C. Role of endothelium in dilator responses of spontaneously hypertensive rat arteries. Hypertension 1983;5:881–886.PubMedCrossRefGoogle Scholar
  132. 131.
    Vanhoutte PM, Boulanger CM. Endothelium-dependent responses responses in hypertension. Hypertens Res 1995;18:87–98.PubMedCrossRefGoogle Scholar
  133. 132.
    Dohi XX, et al. Renovascular hypertension impairs formation of endothelium-derived relaxing factors and sensitivity to endothelin-1 in resistance arteries. J Pharmacol 1991;104:349–354.Google Scholar
  134. 133.
    Bell DR. Vascular smooth muscle responses to endothelial autacoids in rats with chronic coarctation hypertension. J Hypertens 1993;11:65–74.PubMedCrossRefGoogle Scholar
  135. 134.
    Tuncer M, Vanhoutte PM. Response to the endothelium-dependent vasodilator acetylcholine in perfused kidneys of normotensive and spontaneously hypertensive rats. Blood Press 1993;2 217–220.PubMedCrossRefGoogle Scholar
  136. 135.
    Panza JA, et al. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 1993;87:1468–1474.PubMedCrossRefGoogle Scholar
  137. 136.
    CalverXX,etal.EffectoflocalintraarterialNG-monomethyl-L-arginineinpatientswithhypertension: the nitric oxide dilator mechanism appears abnormal. J Hypertens 1992;10:1025–1031.Google Scholar
  138. 137.
    Panza JA, et al. Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation 1993;87:1475–1481.PubMedCrossRefGoogle Scholar
  139. 138.
    PanzaJA, et al. Impaired endothelium dependent vasodilation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor level. J Am Coll Cardio11994;23:161(- 1616.Google Scholar
  140. 139.
    Panza JA. Endothelial dysfunction in essential hypertension. Clin Cardiol 1997;20(Suppl II):II26–II33.Google Scholar
  141. 140.
    Panza JA, et al. Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation 1995;91:1732–1738.PubMedCrossRefGoogle Scholar
  142. 141.
    Nakazono XX, et al. Does superoxide underlie the pathogenesis of hypertension? Proc Natl Acad Sci USA 1991;88:10,045–10,048.Google Scholar
  143. 142.
    Wei XX, et al. Superoxide generation and reversal of acetylcholine-induced cerebral arteriolar dilatation after acute hypertension. Circ Res 1985;57:781–787.PubMedCrossRefGoogle Scholar
  144. 143.
    Garcia XX, et al. Effect of copper-zinc superoxide dismutase on endothelium-dependent vasodilation in patients with essential hypertension. Hypertension 1995;26:863–868.PubMedCrossRefGoogle Scholar
  145. 144.
    Cardillo XX, et al. Xanthine oxidase inhibition improves endothelium-dependent vasodilation in hypercholesterolemic but not hypertensive patients. Hypertension 1997;30:57–63.PubMedCrossRefGoogle Scholar
  146. 145.
    Modan M, Halkin H, Almog S, et al. Hyperinsulinemia: a link between hypertension, obesity and glucose intolera nce. J Clin Invest 19 85;75: 809–817.Google Scholar
  147. 146.
    Lucas CP, Estigarriba JA, Darga LL, et al. Insulin and blood pressure in obesity. Hypertension 1985;7: 702–706.PubMedCrossRefGoogle Scholar
  148. 147.
    Ferrannini E, Estigarribia JA, Darga LL, et al. Insulin resistance in essential hypertension. N Engl J Med 1987;15:350–357.CrossRefGoogle Scholar
  149. 148.
    Katakam PV, Ujhelyi MR, Hoenig M, et al. Metformin improves vascular function in insulin-resistant rats. Hypertension 2000;35:108–112.PubMedCrossRefGoogle Scholar
  150. 149.
    Pagano PJ, Griswold MC, Ravel D. Vascular action of the hypoglycemic agent gliclazide in diabetic rabbits. Diabetoligia 1998;41:9–15.CrossRefGoogle Scholar
  151. 150.
    Tack CJJ, Ong MKE, Lutterman JA, et al. Insulin-induced vasodilation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia 1998;41:569–576.PubMedCrossRefGoogle Scholar
  152. 151.
    Steinberg HO, Chaker H, Leaming R, et al. Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Invest 1992;90:2548–2554.CrossRefGoogle Scholar
  153. 152.
    Ohara Y, Sayegh HS, Yamin JJ, Harrison DG. Regulation of endothelial constitutive nitric oxide synthase by protein kinase C. Hypertension 1995;25:415–420.PubMedCrossRefGoogle Scholar
  154. 153.
    Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKCβ inhibitor. Science 1996;272:728–731.PubMedCrossRefGoogle Scholar
  155. 154.
    Vlassara H, Fuh H, Makita Z, Krungkrai S, Cerami A, Bucala R. Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetic and aging complications. Proc Natl Acad Sci USA 1993;90:6434–6438.PubMedCrossRefGoogle Scholar
  156. 155.
    Wohaieb SA, Godin DV. Alterations in free radical tissue-defense mechanisms in streptozotocininduced diabetes in rat. Effects of insulin treatment. Diabetes 1987;36:1014–1018.PubMedCrossRefGoogle Scholar
  157. 156.
    Cunningham JJ, Ellis SL, McVeigh KL, et al. Reduced mononuclear leukocyte ascorbic acid content in adults with insulin-dependent diabetes mellitus consuming adequate dietary vitamin C. Metabolism 1991;40:146–149.PubMedCrossRefGoogle Scholar
  158. 156a.
    Sundaram RK, Bhaskar A, Vijayalingam S, et al. Antioxidant status and lipid peroxidation in type II diabetes mellitus with and without complications. Clin Sci 1996;90:255–260.PubMedGoogle Scholar
  159. 156b.
    Karpen CW, Cataland S, O’Dorisio TM, et al. Interrelation of platelet vitamin E and thromboxane synthesis in type I diabetes mellitus. Diabetes 1984;33:329–343.Google Scholar
  160. 157.
    Timimi FK, Ting HH, Haley EA, et al. Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent mellitus. J Am Coll Cardiol 1998;31:552–557.PubMedCrossRefGoogle Scholar
  161. 158.
    Ting HH, Timimi FK, Boles KS, et al. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent mellitus. J Clin Invest 1996;97:22–28.PubMedCrossRefGoogle Scholar
  162. 159.
    BeckmanJA,GoldfineAB,WoodcomeME,etal.AcuteadministrationofvitaminCrestorestheendothelium-dependent vasodilation of forearm resistance vessels impaired by acute hyperglycemia. Circulation 1998;98:I176.Google Scholar
  163. 160.
    Inoue S, Kawanishi S. Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett 1995;371:86–88.PubMedCrossRefGoogle Scholar
  164. 161.
    Stroes E, Kastelein J, Cosentino F, et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 1997;99:41–46.PubMedCrossRefGoogle Scholar
  165. 162.
    Pieper GM. Acute amelioration of diabetic endothelium dysfunction with a derivative of the nitric oxide synthase cofactor tetrahydrobiopterin. J Cardiovasc Pharmacol 1997;29:8–15.PubMedCrossRefGoogle Scholar
  166. 163.
    Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation 1991;83:1057–1062.PubMedCrossRefGoogle Scholar
  167. 164.
    Boger RH, Bode-Boger SM, Mügge A, et al Supplementation of hypercholesterolemic rabbits with Larginine reduces the vascular release of superoxide anions and restores NO production. Atherosclerosis 1995;117:273–284.PubMedCrossRefGoogle Scholar
  168. 165.
    Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet 1991;338:1546–1550.PubMedCrossRefGoogle Scholar
  169. 166.
    Boger RH, Bode-Boger SM, Thiele W, Junker W, Alexander K, Frölich JC. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997; 95:2068–2074.PubMedCrossRefGoogle Scholar
  170. 167.
    Giugliano D, Marfella R, Coppola L, et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Circulation 1997;95:1783–1790.PubMedCrossRefGoogle Scholar
  171. 168.
    Pieper GM, Peltier BA. Amelioration by L-arginine of a dysfunctional arginine/nitric oxide pathway in diabetic endothelium. J Cardiovasc Pharmacol 1995;25:397–403.PubMedCrossRefGoogle Scholar
  172. 169.
    Bode-Boger SM, Boger RH, Kienke S, Junker W, Frolich JC. Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun 1996;219:598–603.PubMedCrossRefGoogle Scholar
  173. 170.
    Lerman A, Burnett JC, Higano ST, McKinley LJ, Holmes DR. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 1998;97:2123–2128.PubMedCrossRefGoogle Scholar
  174. 170a.
    Cooke JP. Does ADMA cause endothelial dysfunction? ATVB 2000;20:2031–2037.Google Scholar
  175. 170.
    b.Fard A, Tuck C, Donis J, et al. Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. ATVB 2000;20: 2039–2042.Google Scholar
  176. 171.
    Boulanger C, Luscher TF. Release of endothelin from the porcine arota: inhibition by endotheliumderived nitric oxide. J Clin Invest 1990;85:587–590.PubMedCrossRefGoogle Scholar
  177. 172.
    Thorne S, Mullen MJ, Clarkson P, Donald AE, Deanfield JE. Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginine. J Am Coll Cardiol 1998;32:110–116.PubMedCrossRefGoogle Scholar
  178. 173.
    Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J 1986;111:383–390.PubMedCrossRefGoogle Scholar
  179. 174.
    Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991;265:1861–1867.PubMedCrossRefGoogle Scholar
  180. 175.
    Barrett-Connor EL, Cohn BA,Wingard DL, Edelstein SL. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study. JAMA 1991;265:627–631.PubMedCrossRefGoogle Scholar
  181. 176.
    Winocour PD. Platelet abnormalities in diabetes mellitus. Diabetes 1992;41(Supp12):26–31.PubMedGoogle Scholar
  182. 177.
    Gisclard V, Miller VM, Vanhoutte PM. Efect of 17β estradiol on endothelium-dependent responses in the rabbit. J Pharmacol Exp Ther 1988;244:19–22.PubMedGoogle Scholar
  183. 178.
    Keaney JF, Shwaery GT, Xu A, et al. 17β Estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine. Circulation 1994;89:2251–2259.PubMedCrossRefGoogle Scholar
  184. 179.
    Lieberman EH, Gerhard MD, Uehata A, et al. Estrogen improves endothelial dependent flow mediated vasodilation in postmenopausal women. Ann Intern Med 1994;121:936–941.PubMedCrossRefGoogle Scholar
  185. 180.
    Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RO III. Acute vascular effects of estrogen in postmenopausal women. Circulation 1994;90:786–791.PubMedCrossRefGoogle Scholar
  186. 181.
    Pinto S, Virdis A, Ghiadoni L, et al. Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women. Hypertension 1997;29:268–273.PubMedCrossRefGoogle Scholar
  187. 182.
    Skafar DF, Xu R, Morales J, Ram J, Sowers J. Female sex hormones and cardiovascular disease in women. J Clin Endocrinol Metab 1997;82:3913–3918.PubMedCrossRefGoogle Scholar
  188. 183.
    Arora S, Veves A, Cabellero E, Smakoswki P, LoGerfo F. Estrogen improves endothelial function. J Vasc Surg 1998;27:1141–1147.PubMedCrossRefGoogle Scholar
  189. 184.
    Davidge ST, Zhang Y. Estrogen replacement suppresses a prostaglandin H synthase-dependent vasoconstrictor in rat mesenteric arteries. Circ Res 1998;83:388–395.PubMedCrossRefGoogle Scholar
  190. 185.
    Lim SC, Caballero E, Arora S, et al. The effect of hormonal replacement therapy on the vascular reactivity and endothelial function of healthy individuals and individuals with type 2 diabetes. J Clin Endocrinol Metab 1999;84:4159–4164.PubMedCrossRefGoogle Scholar
  191. 186.
    Chobanian AV, Haudenschild CC, Nickerso C, Drago R. Anti-atherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1991;18:558–563.CrossRefGoogle Scholar
  192. 187.
    Becker RHA, Wiener G, Linz W. Preservation of endothelial function by ramipril in rabbits on a longterm atherogenic diet. J Cardiovasc Pharmacol 1991;18:S11(-S115.Google Scholar
  193. 188.
    Heart Outcomes Prevention Evaluation Study Investigators. Effect of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICROHOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;55:253–259.Google Scholar
  194. 189.
    Mancini GBJ, Henry GC, Macaya C, et al. Angiotensin converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: the TREND (Trial on Reversing Endothelial Dysfunction) study. Circulation 1996;94:258–265.PubMedCrossRefGoogle Scholar
  195. 190.
    Mullen MJ, Clarkson P, Donald AE, et al. Effect of enalapril on endothelial function in young insulindependent diabetic patients: a randomized double-blind study. J Am Coll Cardio11998;31:133(-1335.Google Scholar
  196. 191.
    McFarlane R, McCredie RJ, Bonney MA, et al. Angiotensin converting enzyme inhibition and arterial endothelial function in adults with type 1 diabetes mellitus. Diabetes Med 1999;16:62–66.CrossRefGoogle Scholar
  197. 192.
    O’ Driscoll G, Green D, Rankin J, et al. Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus. J Clin Invest 1997;100:678–684.CrossRefGoogle Scholar
  198. 193.
    O’Driscoll G, Green D, Maiorana A, et al. Improvement in endothelial function by angiotensinconverting enzyme inhibition in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1999;33: 1506–1511.PubMedCrossRefGoogle Scholar
  199. 194.
    Nielsen FS, Rossing P, Gall MA, et al. Lisinopril improves endothelial dysfunction in hypertensive NIDDM subjects with diabetic nephropathy. Scand J Clin Invest 1997;57:427–434.PubMedCrossRefGoogle Scholar
  200. 195.
    Bijlstra PJ, Smits P, Lutterman JA, et al. Effect of long-term angiotensin-converting enzyme inhibition on endothelial function in patients with insulin-resistance syndrome. J Cardiovasc Pharmaco11995;25: 658–664.Google Scholar
  201. 196.
    Griendling KK, Minieri CA, 011erenshaw JD, et al. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994;74:1141–1148.PubMedCrossRefGoogle Scholar
  202. 197.
    Wiener G, Scholkens BA, Becker RHA, et al. Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. Hypertension 1991;18:558–563.CrossRefGoogle Scholar
  203. 198.
    Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibition in humans. Circulation 1999;95:1115–1118.CrossRefGoogle Scholar
  204. 199.
    Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332:481–487.PubMedCrossRefGoogle Scholar
  205. 200.
    Anderson TJ, Meredith IT, Yeung AC, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995;332:488–493.PubMedCrossRefGoogle Scholar
  206. 201.
    Evans M, Anderson RA, Graham J, et al. Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation 2000;10:1773–1779.CrossRefGoogle Scholar
  207. 202.
    Sheu WH, Juang BL, Chen YT, et al. Endothelial dysfunction is not reversed by simvastatin treatment in type 2 diabetic patients with hypercholesterolemia. Diabetes Care 1999;22:1224–1225.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Michael T. Johnstone
  • Todd A. Caulfield

There are no affiliations available

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