Effects of NIDDM on Vascular Tone Regulation

  • Alain D. Baron
  • Helmut O. Steinberg
Part of the Contemporary Biomedicine book series (CB, volume 15)


The maintenance of vascular tone is extremely complex. Neural, endocrine, paracrine, and mechanical depressor and pressor forces all participate in a delicate balancing act to regulate vascular tone. The purpose of this chapter is to review the effect of noninsulin-dependent diabetes mellitus (NIDDM) on the regulation of vascular tone in humans. This issue is of great clinical importance because NIDDM is associated with an increased risk for hypertension and macrovascular disease, and is thus a major contributing factor to both cardiovascular morbidity and mortality (1). Importantly, both the risk and pattern of macrovascular disease in patients with NIDDM cannot be completely attributed to either the height of the blood pressure elevation or quantitative or qualitative abnormalities in circulating lipoprotein particles, suggesting that other factors, such as vascular wall integrity, might play an important role (1,2). NIDDM is characterized by insulin resistance, abnormal insulin secretion, and hyperglycemia (3). Because abnormalities in insulin secretion are not likely to play a direct role on the vasculature, these will not be discussed. In contrast, both insulin resistance and hyperglycemia are potentially critical factors in the dysregulation of vascular tone in NIDDM, and therefore, their effects on the vasculature will be discussed in some detail. The common phenotype of NIDDM is usually accompanied by obesity. Therefore, special attention will be paid to the effect of obesity per se on vascular tone. Finally, the biology of the vasculature is both organ- and tissue-specific, such that factors controlling vascular tone in the coronary vessels may be different than those in peripheral vessels. Because the greatest body of knowledge in this area has been garnered in peripheral limb arteries, the discussion will therefore largely focus on those vessels.


Nitric Oxide Vascular Tone Total Peripheral Vascular Resistance Skeletal Muscle Blood Flow NIDDM Subject 
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  1. 1.
    Kannel WB, McGee DL. Diabetes and cardiovascular disease. DAMA 1979; 241: 2035–2038.Google Scholar
  2. 2.
    Uusitupa MIJ, Niskanen LK, Siitonen O, Voutilainen E, Pyörälä K. Ten-year mortality in relation to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia 1993; 36: 1175–1184.PubMedCrossRefGoogle Scholar
  3. 3.
    DeFronzo RA. The triumvirate: beta cell muscle, liver. A collusion responsible for NIDDM. Diabetes 1988; 37: 667–687.PubMedGoogle Scholar
  4. 4.
    Rocchini AP, Moorehead C, Katch V, Key J, Finta KM. Forearm resistance vessel abnormalities and insulin resistance in obese adolescents. Hypertension 1992; 19: 615–620.PubMedCrossRefGoogle Scholar
  5. 5.
    Raison JM, Safar ME, Cambien FA, London GM. Forearm haemodynamcies in obese normotensive and hypertensive patients. J Hypertension 1988; 6: 299–303.CrossRefGoogle Scholar
  6. 6.
    Dustan HP. Mechanisms of hypertension associated with obesity. Ann Int Med 1983; 98: 860–864.PubMedGoogle Scholar
  7. 7.
    Frohlich ED, Messerli FM, Reisin E, Dunn FG. The problem of obesity and hypertension. Hypertension 1984; 5 (Suppl III): III-71—III-78.Google Scholar
  8. 8.
    Messerli FH, Christie B, DeCarvalho JGR, Aristimuno GG, Suarez DH, Dreslinski GR, Frohlich ED. Obesity and essential hypertension. Hemodynamics, intravascular volume, sodium excretion, and plasma renin activity. Arch Intern Med 1981; 141: 81–85.PubMedCrossRefGoogle Scholar
  9. 9.
    Mujais SK, Tarazi RC, Dustan HP, Fouad FM, Bravo EL. Hypertension in obese patients: hemodynamic and volume studies. Hypertension 1982; 4: 84–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Cowley AW, Liard JF, Guyton AC. Role of the baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs. Circ Res 1973; 32: 564–576.PubMedCrossRefGoogle Scholar
  11. 11.
    Scherrer U, Randin D, Tappy L, Vollenweider P, Jequier E, Nicod P. Body fat and sympathetic nerve activity in healthy subjects. Circulation. 1994; 89: 2634–2640.PubMedCrossRefGoogle Scholar
  12. 12.
    Spraul M, Ravussin E, Fontvieille AM, Rising R, Larson ED, Anderson EA. Reduced sympathetic nervous activity. A potential mechanism predisposing to body weight gain. J Clin Invest 1993; 92: 1730–1735.PubMedCrossRefGoogle Scholar
  13. 13.
    Anderson EA, Hoffman RP, Balon 1W, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 1991; 87: 2246–2252.PubMedCrossRefGoogle Scholar
  14. 14.
    Scherrer U, Vollenweider P, Randin D, Jequier E, Nicod P, Tappy L. Suppression of insulin-induced sympathetic activation and vasodilation by dexamethasone in humans. Circulation 1993; 88: 388–394.PubMedCrossRefGoogle Scholar
  15. 15.
    Berne C, Fagius J, Pollare T, Hjemdahl P. The sympathetic response to euglycaemic hyperinsulinemia. Diabetologia 1992; 35: 873–879.PubMedCrossRefGoogle Scholar
  16. 16.
    Lembo G, Rendina V, Iaccarino G, Lamenza F, Volpe M, Trimarco B. Insulin reduces reflex forearm sympathetic vasoconstriction in healthy humans. Hypertension 1993; 21: 1015–1019.PubMedCrossRefGoogle Scholar
  17. 17.
    Lembo G, Rendina V, Iaccarino G, Lamenza F, Condorelli G, Rosiello G, Trimarco B. Insulin does not modulate reflex forearm sympathetic vasoconstriction in patients with essential hypertension. JHypertension 1993; 11 (Suppl. 5): S272, S273.Google Scholar
  18. 18.
    Baron AD, Brechtel G, Johnson A, Fineberg N, Henry DP, Steinberg HO. Interactions between insulin and norepinephrine on blood pressure and insulin sensitivity. J Clin Invest 1994; 93: 2453–2462.PubMedCrossRefGoogle Scholar
  19. 19.
    Ferri C, Pittoni V, Piccoli A, Laurenti O, Cassone MR, Bellini C, Properzi G, Valesini G, De Mattia G, Santucci A. Insulin stimulates endothelin-1 secretion from human endothelial cells and modulates its circulating levels in vivo. J Clin Endocrinol Metab 1994; 80: 829–835.CrossRefGoogle Scholar
  20. 20.
    Ferri C, Carolomagno A, Coassin S, Roberta B, Cassone Faldetta MR, Laurenti O, Properzi G, Santucci A, De Mattia G. Circulating endothelin-1 levels increase during euglycemic hyperinsulinemic clamp in lean NIDDM men. Diabetes Care 1995; 18: 226–233.PubMedCrossRefGoogle Scholar
  21. 21.
    Uriu K, Kaizo K, Hashimoto O, Komine N, Etoch S. Acute and chronic effects of thromboxane A2 inhibition on the renal hemodynamics in streptozotocin-induced diabetic rats. Kidney Int 1994; 45: 794–802.PubMedCrossRefGoogle Scholar
  22. 22.
    Shimizu K, Muramatsu M, Kakegawa Y, Asano H, Toki Y, Miyazaki Y, Okumura K, Hashimoto H, Ito T. Role of prostaglandin H2 as an endothelium-derived contracting factor in diabetic state. Diabetes 1993; 42: 1246–1252.PubMedCrossRefGoogle Scholar
  23. 23.
    Liao JK, Shin WS, Lee WY, Clark SL. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 1995; 270: 319–324.PubMedCrossRefGoogle Scholar
  24. 24.
    Creager MA, Cooke JP, Mendelsohn MP, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodiliation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990; 86: 228–234.PubMedCrossRefGoogle Scholar
  25. 25.
    Chin JH, Azhar S, Hoffman BB. Inactivation of endothelial derived relaxing factor by oxidized lipoproteins. J Clin Invest 1992; 89: 10–18.PubMedCrossRefGoogle Scholar
  26. 26.
    Reaven GM, Chen Y-DI, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles. J Clin Invest 1993; 92: 141–146.PubMedCrossRefGoogle Scholar
  27. 27.
    Galle J, Ochslen M, Schollmeyer P, Wanner C. Oxidized lipoproteins inhibit endothelium-dependent vasodilation. Effects of pressure and high-density lipoprotein. Hypertension 1994; 23: 556–564.PubMedCrossRefGoogle Scholar
  28. 28.
    Galle J, Bengen J, Schollmeyer P, Wanner C. Oxidized lipoprotein(a) inhibits endothelium-dependent dilation: prevention by high density lipoprotein. Eur J Pharmacol 1994; 265: 111–115.PubMedCrossRefGoogle Scholar
  29. 29.
    Bowie A, Ownes D, Collins P, Johnson A, Tomkin GH. Glycosylated low density lipoprotein is more sensitive to oxidation: implications for the diabetic patient? Atherosclerosis 1993; 102: 63–67.PubMedCrossRefGoogle Scholar
  30. 30.
    Jacobs M, Plane F, Bruckdorfer KR. Native and oxidized low-density lipoproteins have different inhibitory effects on endothelium-derived relaxing factor in the rabbit aorta. Br J Pharmacol 1990; 100: 21–26.PubMedCrossRefGoogle Scholar
  31. 31.
    Plane F, Bruckdorfer KR, Kerr P, Steuer A, Jacobs M. Oxidative modification of low-density lipoproteins and the inhibition of relaxation mediated by endothelium-derived nitric oxide in rabbit aorta. Br J Pharmacol 1992; 105: 216–222.PubMedCrossRefGoogle Scholar
  32. 32.
    Plane F, Kerr P, Bruckdorfer KR, Jacobs M. Inhibition of endothelium-dependent relaxation by oxidized low-density lipoproteins. Biochem Soc Trans 1990; 18: 1177, 1178.Google Scholar
  33. 33.
    Rodriguez-Manas L, Arribas S, Giron C, Villamor J, Sanchez-Ferrer CF, Marin J. Interference of glycosylated human hemoglobin with endothelium-dependent responses. Circulation 1993; 88: 2111–2116.PubMedCrossRefGoogle Scholar
  34. 34.
    Stepniakowski KT, Goodfriend TL, Egan BM. Fatty acids enhance vascular alpha-adrenergic sensitivity Hypertension. 1995; 25 (4 part 2): 774–778.PubMedCrossRefGoogle Scholar
  35. 35.
    Grekin RJ, Vollmer AP, Sider RS. Pressor effects of portal venous oleate infusion. A proposed mechanism for obesity hypertension. Hypertension 1995; 26: 193–198.PubMedCrossRefGoogle Scholar
  36. 36.
    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
  37. 37.
    Laakso M, Edelman SV, Brechtel, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese men. J Clin Invest 1990; 85: 1844–1852.PubMedCrossRefGoogle Scholar
  38. 38.
    Laakso M, Edelman SV, Brechtel G, Baron AD. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 1992; 41: 1076–1083.PubMedCrossRefGoogle Scholar
  39. 39.
    Baron AD, Laakso M, Brechtel G, Edelman SV. Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow. J Clin Endocrinol Metab 1991; 73: 637–643.PubMedCrossRefGoogle Scholar
  40. 40.
    Furchgott RR Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373–382.PubMedCrossRefGoogle Scholar
  41. 41.
    Moncada S, Radomski MW, Palmer RMJ. Endothelium derived relaxing factor: identification as nitric oxide and role in the control of vascular tone and platelet function. Biochem Pharmacol 1988; 37: 2495–2501.PubMedCrossRefGoogle Scholar
  42. 42.
    Palmer RMJ, Ferrige AJ, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524–526.PubMedCrossRefGoogle Scholar
  43. 43.
    Ignarro LJ. Nitric oxide-a novel signal transduction mechanism for transcellular communication. Hypertension 1990; 16: 477–483.PubMedCrossRefGoogle Scholar
  44. 44.
    Vanhoutee PM, Miller VM. Heterogeneity of endothelium-dependent responses in mammalian blood vessels. J Cardiovas Pharmacol 1985; 7 (Suppl. 3): S12 - S23.CrossRefGoogle Scholar
  45. 45.
    D’Orleans-Juste P, Dion S, Mizrahi J, Regoli D. Effects of peptides and non-peptides on isolated arterial smooth muscles: role of endothelium. Eur J Pharmacol 1985; 114: 9–21.PubMedCrossRefGoogle Scholar
  46. 46.
    Palmer RMJ, Rees DD, Ashton DS, Moncada S. L-Arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun 1988; 153: 1251–1256.PubMedCrossRefGoogle Scholar
  47. 47.
    Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333 (524–6).Google Scholar
  48. 48.
    Suzuki H, Ikenaga H, Hishikawa K, Nakaki T, Kato R, Saruta T. Increases in NO2-/NO3excretion in the urine as an indicator of the release of endothelium-derived relaxing factor during elevation of blood pressure. Clin Sci 1992; 82: 631–634.PubMedGoogle Scholar
  49. 49.
    Rees, DD, Palmer RMJ, Hodson HF, Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium dependent relaxation. Br J Pharmacol 1989; 96: 418–424.PubMedCrossRefGoogle Scholar
  50. 50.
    Valiance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. The Lancet 1989; 2: 997–1000.CrossRefGoogle Scholar
  51. 51.
    Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 1992; 90: 278–281.PubMedCrossRefGoogle Scholar
  52. 52.
    Navarro J, Sanchez A, Saiz J, Ruilope LM, Garcia-Estan J, Romero JC, Lahera V. Hormonal, renal, and metabolic alterations during hypertension induced by chronic inhibition of NO in rats. Am J Physiol 1994; 267: R1516 - R1521.PubMedGoogle Scholar
  53. 53.
    Stammler JS, Loh E, Roddy M-A, Currie KE, Creager MA. Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 1994; 89: 2035–2040.CrossRefGoogle Scholar
  54. 54.
    Steinberg HO, Brechtel G, Johnson A, Fienberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. J Clin Invest 1994; 94: 1172–1179.PubMedCrossRefGoogle Scholar
  55. 55.
    Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod R Nitric oxide release accounts for insulin’s vascular effects in humans. J Clin Invest 1994; 94: 2511–2515.PubMedCrossRefGoogle Scholar
  56. 56.
    Panza JA, Quyyumy A, Brush JE, Epstein SE. Abnormal endothelium dependent vascular relaxation in patients with essential hypertension. New Engl J Med 1990; 323: 22–27.PubMedCrossRefGoogle Scholar
  57. 57.
    Taddei S, Virdis A, Maffei P, Arzilli F, Salvetti A. Endothelium-dependent forearm vasodilation is reduced in normotensive subjects with familial history of hypertension. J Cardiovasc Pharmacol 1992; 20 (Supp112): 193–195.CrossRefGoogle Scholar
  58. 58.
    Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. 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
  59. 59.
    Calver A, Collier J, Moncada S, Vallance P. Effect of local intra-arterial NG-monomethyl-Larginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal. I Hypertension 1992; 10: 1025–1031.Google Scholar
  60. 60.
    Smits P, Kapma J-A, Jacobs M-C, Lutterman J, Thien T. Endothelium-dependent vascular relaxation in patients with type 1 diabetes. Diabetes 1993; 42: 148–153.PubMedCrossRefGoogle Scholar
  61. 61.
    Johnstone MT, Craeger SJ, Scales KM, Cusco JA, Lee BK, Craeger MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993; 88: 2510–2516.PubMedCrossRefGoogle Scholar
  62. 62.
    Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992; 90: 2548–2554.PubMedCrossRefGoogle Scholar
  63. 63.
    McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, 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
  64. 64.
    Angus JA, Lew M. Interpretation of the acetycholine test of endothelial dysfunction in hypertension. J Hypertension 1992; 10 (Suppl 7): S179 - S186.CrossRefGoogle Scholar
  65. 65.
    Panza JA, Casino PR, Badar DM, Quyyumi AA. Effect of increased availability of endotheliumderived-nitric-oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation 1993; 87: 1475–1481.PubMedCrossRefGoogle Scholar
  66. 66.
    Castillo L, Sanchez M, Vogt J, Chapman TE, DeRojas-Walker TC, Tannenbaum SR, Ajami AM, Young VR. Plasma arginine, citrulline, and ornithine kinetics in adults, with observation on nitric oxide synthesis. Am J Physiol 1995; 268: E360 - E367.PubMedGoogle Scholar
  67. 67.
    Steinberg HO, Chaker H, Learning R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996; 97: 2001–2010.CrossRefGoogle Scholar
  68. 68.
    Gupta S, McArthur C, Grady C, Ruderman NB. Role of endothelium-derived nitric oxide in stimulation of Na(+)-K(+)-ATPase activity by endothelin in rabbit aorta. Am J Physiol 1994; 266: H577 - H582.PubMedGoogle Scholar
  69. 69.
    Bohlen G, Lash IM. Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation of normal rat arterioles. Am J Physiol 1993; 265: H219 - H225.PubMedGoogle Scholar
  70. 70.
    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: 7–12.CrossRefGoogle Scholar
  71. 71.
    Mayhan WG. Impairment of endothelium-dependent dilation of the basilar artery during diabetes mellitus. Brain Res 1992; 580: 297–302.PubMedCrossRefGoogle Scholar
  72. 72.
    Sikorski BW, Hodgson WC, King RG. Effects of haemoglobin and N-nitro-L-arginine on constrictor and dilator responses of aortic rings from streptozotocin diabetic rats. Eur J Pharmacol 1993; 242: 275–282.PubMedCrossRefGoogle Scholar
  73. 73.
    The Hypertension in Diabetes Study Group. Hypertension in diabetes I. Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertension 1993; (11): 309–317.Google Scholar
  74. 74.
    United Kingdom Prospective Diabetes Study (UKPDS) XI. Biochemical risk facators in type 2 diabetic patients at diagnosis compared with age-matched normal subjects. Diabetic Med 1993; 11: 534–544.CrossRefGoogle Scholar
  75. 75.
    Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607.PubMedCrossRefGoogle Scholar
  76. 76.
    Radomski MW, Palmer RMJ, Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol 1987; 92: 639–646.PubMedCrossRefGoogle Scholar
  77. 77.
    Mollace V, Salvemini D, Anggard E, Vane J. Nitric oxide from vascular smooth muscle cells: regulation of platelet reactivity and smooth muscle cell guanylate cycicase. Br J Pharmacol 1991; 104: 633–638.PubMedCrossRefGoogle Scholar
  78. 78.
    Kanner J, Harel S, Granit R. Nitric oxide, an inhibitor of lipid oxidation by lipoxygenase, cyclooxygenase and hemoglobin. Lipids 1992; 27: 43–49.CrossRefGoogle Scholar
  79. 79.
    Kopalkov V, Gordon D, Kulik TJ. Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells. Circ Res 1995; 76: 305–309.CrossRefGoogle Scholar
  80. 80.
    Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphaste inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83: 1774–1777.PubMedCrossRefGoogle Scholar
  81. 81.
    Cooke JP, Tsao P. Cellular mechanisms of atherogenesis and the effect of nitric oxide. Curr Opinions Cardiol 1992; 7: 799–804.Google Scholar
  82. 82.
    Reaven GM, Laws A. Insulin resistance, compensatory hyperinsulinemia, and coronary heart disease. Diabetologia 1994; 37: 948–952.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Alain D. Baron
  • Helmut O. Steinberg

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