Effects of Hyperglycemia on Vascular Endothelium Nitric Oxide Metabolism

  • Steven B. Magill
  • Jamie Dananberg
Part of the Contemporary Endocrinology book series (COE, volume 1)


Vascular complications remain the leading cause of increased mortality in the diabetic population. There are many theories as to the etiology of these effects, but vascular endothelial dysfunction appears to play an extremely important role. Accumulating data suggests that exposure to increased concentrations of glucose leads to endothelial dysfunction. Studies in diabetes have demonstrated elevations in plasma von Willebrand’s factor (1), diminished release of prostacyclin (PGI) (2), a vasodilatory prostaglandin (PG), enhanced secretion of endothelin (3), and lowered lipoprotein lipase activity (4) as evidence of abnormal endothelial function.


Nitric Oxide Aldose Reductase Nicotinamide Adenine Dinucleotide Phosphate Nitric Oxide Nitric Oxide Hyperglycemic Environment 
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  1. 1.
    Bensousan D, Levy-Toledano S, Passa P, Caen J, Canivet J. Platelet hyperaggregation and increased plasma level of von Willebrand factor in diabetic patients with retinopathy. Diabetologia 1975;11:307–312.CrossRefGoogle Scholar
  2. 2.
    Harrison HE, Reece AH, Johnson M. Decreased vascular PGI in experimental diabetes. Life Sci 1978;23:351–356.CrossRefPubMedGoogle Scholar
  3. 3.
    Yamauchi T, Ohnaka K, Takayanagi R, Umeda F, Nawata H. Enhanced secretion of endothelin-1 by elevated glucose levels from cultured bovine aortic endothelial cells. FEBS Lett 1990;267:16–18.CrossRefPubMedGoogle Scholar
  4. 4.
    Steiner G. Diabetes and atherosclerosis. Diabetes 1981;30(Suppl. 2):1–7.PubMedGoogle Scholar
  5. 5.
    Oyama Y, Kawasaki H, Hattori Y, Kanno M. Attenuation of endothelium-dependent relaxation in aorta from diabetic rats. Eur J Pharmacol 1986;131:75–78.CrossRefGoogle Scholar
  6. 6.
    Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, Gruetter CA. Mechanism of VSMC relaxation by organic nitrates, nitrites, nitroprusside and NO: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981;218:739–749.PubMedGoogle Scholar
  7. 7.
    Meraji S, Jayakody L, Senaratne MPJ, Thompson ABR, Kappagoda T. Endothelium-dependent relaxation in aorta of BB rat. Diabetes 1987;36:978–981.CrossRefPubMedGoogle Scholar
  8. 8.
    Durante W, Sen AK, Sunahara FA. Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats. Br J Pharmacol 1988;94:463–468.CrossRefPubMedGoogle Scholar
  9. 9.
    Abiru T, Watanabe Y, Kamata K, Kasuya Y. Changes in endothelium-dependent relaxation and levels of cyclic nucleotides in the perfused mesenteric arterial bed from streptozotocin-induced diabetic rats. Life Sci 1993;53:PL7–PL12.CrossRefPubMedGoogle Scholar
  10. 10.
    Calver A, Collier J, Valiance P. Inhibition and stimulation of NO synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992;90:2548–2554.CrossRefPubMedGoogle Scholar
  11. 11.
    Elliot TG, Cockcroft JR, Groop P, Viberti GC, Ritter M. Inhibition of NO synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria. Clin Sci 1993;85:687–693.Google Scholar
  12. 12.
    McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, Andrews JW, Hayes JR. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (noninsulin-dependent) diabetes mellitus. Diabetologia 1992;35:771–776.PubMedGoogle Scholar
  13. 13.
    Chang KSK, Stevens WC. Endothelium-dependent increase in vascular sensitivity to phenylephrine in long-term streptozotocin diabetic rat aorta. Br J Pharmacol 1992;107:983–990.CrossRefPubMedGoogle Scholar
  14. 14.
    Taylor PD, McCarthy AL, Thomas CR, Poston L. Endothelium-dependent relaxation and noradrenaline sensitivity in mesenteric resistance arteries of streptozotocin-induced diabetic rats. Br J Pharmacol 1992;107:393–399.CrossRefPubMedGoogle Scholar
  15. 15.
    Tesfamariam B, Brown ML, Deykin D, Cohen RA. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest 1990;85:929–932.CrossRefPubMedGoogle Scholar
  16. 16.
    Tesfamariam B, Brown ML, Cohen RA. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest 1991;87:1643–1648.CrossRefPubMedGoogle Scholar
  17. 17.
    Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Phys 1992;263:H321–H326.Google Scholar
  18. 18.
    Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med 1994;16:383–391.CrossRefPubMedGoogle Scholar
  19. 19.
    Gupta S, Sussman I, McCarthur CS, Tomheim K, Cohen RA, Ruderman NB. Endothelium-dependent inhibition of Na/K-ATPase activity in rabbit aorta by hyperglycemia. J Clin Invest 1992;90:727–732.CrossRefPubMedGoogle Scholar
  20. 20.
    Stevens MJ, Dananberg J, Feldman EL, Lattimer SA, Kamijo M, Thomas TP, Shindo H, Sima AF, Greene DA. The linked roles of NO, aldose reductase and, (Na+, K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invest 1994;94:853–859.CrossRefPubMedGoogle Scholar
  21. 21.
    Hogan M, Cerami A, Bucala R. Advanced glycosylation endproducts block the antiproliferative effect of NO. Role in the vascular and renal complications of diabetes mellitus. J Clin Invest 1992;90:1110–1115.CrossRefPubMedGoogle Scholar
  22. 22.
    Valiance P, Collier J, Moncada S. Effects of endothelium-dependent NO on peripheral arteriolar tone in man. Lancet 1989;ii:997–1000.CrossRefGoogle Scholar
  23. 23.
    Radomski MW, Palmer RMJ, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 1990;87:5193–5197.CrossRefPubMedGoogle Scholar
  24. 24.
    Kubes P, Suzuki M, Granger DN. NO: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88:4651–4656.CrossRefPubMedGoogle Scholar
  25. 25.
    Garg UC, Hassid A. NO generating vasodilation and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat VSMC cells. J Clin Invest 1989;83:1774–1777.CrossRefPubMedGoogle Scholar
  26. 26.
    Kamata K, Miyata N, Kasuya Y. Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in aorta from streptozotocin-induced diabetic rats. Br J Pharmacol 1989;97:614–618.CrossRefPubMedGoogle Scholar
  27. 27.
    Tesfamariam B, Jakabowsky JA, Cohen RA. Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TXA2. Am J Physiol 1989;257:H1327–H1333.PubMedGoogle Scholar
  28. 28.
    Saenz de Tejada IS, Goldstein J, Azadzoik K, Krane K, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989;320:1025–1030.CrossRefPubMedGoogle Scholar
  29. 29.
    Johnstone MT, Creager SJ, Scales KM, Casco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circ 1993;88:2510–2516.CrossRefGoogle Scholar
  30. 30.
    Moncada S, Palmer RMJ, Higgs EA. NO, physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109–142.PubMedGoogle Scholar
  31. 31.
    Marietta MA. NOS structure and mechanism. J Biol Chem 1993;268:12,231–12,234.Google Scholar
  32. 32.
    Forstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H. Nitric oxide synthase isozymes: characterization, purification, molecular cloning, and functions. Hypertension 1994;23(part 2): 1121–1131.CrossRefPubMedGoogle Scholar
  33. 33.
    Radomski MW, Palmer RMJ, Moncada S. Endogenous NO inhibits platelet adhesion to vascular endothelium. Lancet 1987;ii:1057,1058.CrossRefGoogle Scholar
  34. 34.
    Mayhan WG. Impairment of endothelium-dependent dilatation of cerebral arterioles during diabetes mellitus. Am J Physiol 1989;256:H621–H625.PubMedGoogle Scholar
  35. 35.
    Abiru T, Watanabe Y, Kamata K, Miyata N, Kasuya Y. Decrease in endothelium-dependent relaxation and levels of cyclic nucleotide in aorta from rabbits with alloxan-induced diabetes. Res Comm Chem Pathol Pharmacol 1990;68:13–25.Google Scholar
  36. 36.
    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.CrossRefPubMedGoogle Scholar
  37. 37.
    Orie N, Aloamaka C, Iyawe VI. Duration-dependent attenuation of acetylcholine but not histamine-induced relaxation of the aorta in diabetes mellitus. Gen Pharmacol 1993;24:329–332.CrossRefPubMedGoogle Scholar
  38. 38.
    Tesfamariam B, Palacino JJ, Weisbrod RM, Cohen RA. Aldose reductase inhibition restores endothelial cell function in diabetic rabbit aorta. J Cardiovasc Pharmacol 1993;21:205–211.CrossRefPubMedGoogle Scholar
  39. 39.
    Craven PA, Studer RK, DeRubertis FR. Impaired NO-dependent cyclic guanosine monophosphate generation in glomeruli from diabetic rats. Evidence for protein kinase C-mediated suppression of the cholinergic response. J Clin Invest 1994;93:311–320.CrossRefPubMedGoogle Scholar
  40. 40.
    Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench NO and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 1991;87:432–438.CrossRefPubMedGoogle Scholar
  41. 41.
    Rosen P, Schror K. Increased PGI release from perfused hearts of acutely diabetic rats. Diabetologia 1980;18:391–394.PubMedGoogle Scholar
  42. 42.
    Tesfamariam B, Cohen RA. Role of superoxide anion and endothelium in vasoconstrictor action of PG endoperoxide. Am J Physiol 1992;262:H1915–H1919.PubMedGoogle Scholar
  43. 43.
    Weisbrod RM, Brown ML, Cohen RA. Elevated glucose alters endothelial cell NO and prostanoid circulation. Circ 1991;84(Suppl. II):II43.Google Scholar
  44. 44.
    Wolff SP, Dean RT. Glucose autooxidation and protein modification: the role of oxidative glycosylation in diabetes. Biochem J 1987;245:234–250.Google Scholar
  45. 45.
    Hattori Y, Kawasaki H, Abe K, Kanno M. Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol 1991;261:H1086–H1094.PubMedGoogle Scholar
  46. 46.
    Mugge A, Elwell JH, Peterson TE, Harrison OG. Release of intact endothelium dependent derived relaxing factor depends on endothelial superoxide dismutase. Am J Physiol. 1991;260: C219–C225.PubMedGoogle Scholar
  47. 47.
    Omar HA, Cherry PD, Mortelliti MP, Burke-Wolin T, Wolin MS. Inhibition of coronary artery superoxide dismutase attenuates endothelium-dependent and -independent nitrovasodilator relaxation. Circ Res 1991;69:601–608.CrossRefPubMedGoogle Scholar
  48. 48.
    Pieper GM, Gross GJ. Oxygen free radicals abolish endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol 1988;255:H825–H833.PubMedGoogle Scholar
  49. 49.
    Brownlee MA, Cerami A, Vlassara H. Advanced glycosylation endproducts in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988;318:1315–1321.CrossRefPubMedGoogle Scholar
  50. 50.
    Corbett JA, Tilton RG, Chang K, Hasan KS, Ido Y, Wang JL, Sweetland MA, Lancaster JR, Williamson JR, McDaniel ML Aminoguanidine, a novel inhibitor of NO formation, prevents diabetic vascular dysfunction. Diabetes 1992;41:552–556.CrossRefPubMedGoogle Scholar
  51. 51.
    Cameron NE, Cotter MA. Impaired contraction and relaxation in aorta from streptozotocin-diabetic rats: role of polyol pathway. Diabetologia 1992;35:1011–1019.CrossRefPubMedGoogle Scholar
  52. 52.
    Hodgson WC, King RG. Effects of glucose, insulin or aldose reductase inhibition on responses to endothelin1 of aortic rings from streptozotocin-induced diabetic rats. Br J Pharmacol 1992;106:644–649.CrossRefPubMedGoogle Scholar
  53. 53.
    Yamashita T, Umeda F, Hashimoto T, Inoguchi T, Yamauchi T, Mimura K, Watanabe J, Nawata H. Effect of glucose on Na, K-ATPase activity in cultured bovine aortic endothelial cells. Endocrinol Jpn 1992;39:1–7.CrossRefPubMedGoogle Scholar
  54. 54.
    Kern TS, Engerman RL. Immunohistochemical distribution of aldose reductase. Histochem J 1982;14:507–515.CrossRefPubMedGoogle Scholar
  55. 55.
    Gonzalez RG, Barnett P, Aguayo J, Cheng HM, Chylack LT. Direct measurement of polyol pathway activity in the ocular lens. Diabetes 1984;33:196–199.CrossRefPubMedGoogle Scholar
  56. 56.
    Stevens MJ, Lattimer SA, Kamijo M, Van Huysen C, Sima AAF, Greene DA. Osmotically induced nerve taurine depletion and the compatible osmolyte hypothesis in experimental diabetic neuropathy. Diabetologia 1993;36:608–614.CrossRefPubMedGoogle Scholar
  57. 57.
    Greene DA, Lattimer SA, Sima AAF. Sorbitol, phosphoinositides and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 1987;316:599–606.CrossRefPubMedGoogle Scholar
  58. 58.
    Tilton RG, Chang K, Hasan KS, Smith SR, Petrash JM, Misko TP, Moore WM, Currie MG, Corbett JA, McDaniel ML, Williamson JR. Prevention of diabetic vascular dysfunction by guanidines: inhibition of NOS versus advanced glycation end-product formation. Diabetes 1993;42:221–232.CrossRefPubMedGoogle Scholar
  59. 59.
    Greene DA, Sima AAF, Stevens MJ, Feldman EL, Killen PD, Henry DN, Thomas T, Dananberg J, Lattimer SA. Aldose reductase inhibitors: an approach to the treatment of diabetic nerve damage. Diab Metab Rev 1993;9:189–217.CrossRefGoogle Scholar
  60. 60.
    Wolf BA, Williamson JR, Easom RA, Chang K, Sherman WR, Turk J. Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels. J Clin Invest 1991;87:31–38.CrossRefPubMedGoogle Scholar
  61. 61.
    Craven PA, Davidson CM, DeRubertis FR. Increase in diacylglycerol mass in isolated glomeruli by glucose from de novo synthesis of glycerolipids. Diabetes 1990;39:667–674.CrossRefPubMedGoogle Scholar
  62. 62.
    Pugliese G, Tilton RG, Williamson JR. Glucose-induced metabolic imbalances in the pathogenesis of diabetic vascular disease. Diab Metab Rev 1991;7:35–39.CrossRefGoogle Scholar
  63. 63.
    Okumura K, Nishiura T, Awaji Y, Kondo J, Hashimoto H, Ito T. 1, 2 diacylglycerol content and its fatty acid composition in thoracic aorta of diabetic rats. Diabetes 1991;40:820--824.CrossRefPubMedGoogle Scholar
  64. 64.
    Williams B, Schrier RW. Characterization of glucose-induced in situ protein kinase C activity in cultured vascular smooth cells. Diabetes 1992;41:464–472.CrossRefGoogle Scholar
  65. 65.
    Pfeilschifter J, Bauer C. Role of phospholipase C and protein kinase C in vasoconstrictor-induced PG synthesis in cultured rat mesangial cells. Biochem J 1986;236:289–294.PubMedGoogle Scholar
  66. 66.
    Wu KK, Hatzakis H, Lo SS, Seong DC, Sanduja SK, Tai HH. Stimulation of de novo synthesis of PG G/H synthase in human endothelial cells by phorbol ester. J Biol Chem 1988;263:19,043–19,047.PubMedGoogle Scholar
  67. 67.
    Robinson JM, Badwey JA, Kamovsky ML, Karnovsky MJ. Superoxide release by neutrophils: synergistic effects of a phorbol ester and a calcium ionophore. Biochem Biophys Res Comm 1984;122:734–739.CrossRefPubMedGoogle Scholar
  68. 68.
    Craven PA, DeRubertis FR. Protein kinase C is activated in glomeruli from streptozotocin diabetic rats. Possible mechanisms by glucose. J Clin Invest 1989;83:1667–1675.CrossRefPubMedGoogle Scholar
  69. 69.
    Greene DA, Lattimer-Greene S, Sima AAF. Pathogenesis of diabetic neuropathy: role of altered phosphoinositide metabolism. Clin Rev Neurobiol 1989;5:143–219.Google Scholar
  70. 70.
    Thomas TP, Porcellati F, Kato K, Stevens MJ, Sherman WR, Greene DA. Effects of glucose on sorbitol pathway activation, cellular redox, and metabolism of myo-inositol, phosphoinositide, and diacylglycerol in cultured human retinal pigment epithelial cells. J Clin Invest 1994;93:2718–2724.CrossRefPubMedGoogle Scholar
  71. 71.
    Shiba T, Inoguchi T, Sportsman JR, Heath WF, Bursell S, King GI. Correlation of diacylglycerol level and protein kinase C activation in rat retina to retinal circulation. Am J Physiol 1993;265:E783–E793.PubMedGoogle Scholar
  72. 72.
    Bredt DS, Ferris CD, Snyder SH. NOS regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites. J Biol Chem 1992;267:10,976–10,981.PubMedGoogle Scholar
  73. 73.
    Brune B, Lapetina EG. Phosphorylation of NOS by protein kinase A. Biochem Biophys Res Comm 1991;181:921–926.CrossRefPubMedGoogle Scholar
  74. 74.
    Michel T, Li GK, Busconi L.Phosphorylation and subcellular translocation of endothelial NOS. Proc Natl Acad Sci, USA 1993;90:6252–6256.CrossRefGoogle Scholar
  75. 75.
    Tsukahara H, Gordienko DV, Goligorsky MS. Continuous monitoring of NO release from human umbilical vein endothelial cells. Biochem Biophys Res Comm 1993;193:722–729.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Steven B. Magill
  • Jamie Dananberg

There are no affiliations available

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