Large clinical trials have determined that hydroxymethylglutaryl-coenzyme A reductase inhibitors ("statins") significantly reduce cardiovascular morbidity and mortality. Furthermore, lipid-lowering therapy has been shown to improve endothelial function in several studies (204,205). Attempts to ameliorate the impaired endothelium-dependent vascular relaxation that occurs in diabetic patients with dyslipidemia are few and the results mixed. Impaired endothelium-dependent vasodilation in patients with type 2 DM with dyslipidemia has been reported to improve with fibrate therapy (206) (which lowers the serum triglyceride level) but not with simvastatin (206,207).
The normal endothelium plays an important role in the prevention of atherosclerosis and microvascular disease. DM is an important cause of both macro- and microvascular disease. Animal and clinical studies have demonstrated a decrease in endothelium-de-pendent vasodilation in both type 1 and type 2 DM. Possible mechanisms include abnormalities in signal transduction, reduced synthesis of NO, accelerated inactivation of NO, or production of vasoconstrictor prostanoids, probably through the relative increase of oxygen-derived free radicals (Table 1). The mediators of this abnormality include hyperinsulinemia, insulin resistance, or hyperglycemia. Improved glucose control, supplementation with either tetrahydrobiopterin, L-arginine, or vitamin C, or the addition of ACE inhibitors have been shown to improve endothelial function. Further research is required to determine whether restoring endothelial function in patients with either type 1 or type 2 diabetes will translate into an overall reduction in diabetic vascular disease.
1. Cohen AM, Rosenmann E, Rosenthal T. The Cohen diabetic (non-insulin-dependent) hypertensive rat model. Description of the model and pathologic findings. Am J Hypertens 1993;6(12):989-995.
2. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241(19):2035-2038.
3. Garcia MJ, et al. Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes 1974;23(2):105-111.
4. Deckert T, et al. Natural history of diabetic complications: early detection and progression. Diabet Med 1991;8(Spec No):S33-S37.
5. Deckert T, et al. [Microalbuminuria as predictor of atherosclerotic cardiovascular disease in IDDM]. Ugeskr Laeger 1997;159(20):3010-3014.
6. Beach KW, Strandness DE Jr. Arteriosclerosis obliterans and associated risk factors in insulin-dependent and non-insulin-dependent diabetes. Diabetes 1980;29(11):882-888.
7. Keen H, Jarrett RJ. The WHO multinational study of vascular disease in diabetes: 2. Macrovascular disease prevalence. Diabetes Care 1979;2(2):187-195.
8. Zatz R, Brenner BM. Pathogenesis of diabetic microangiopathy. The hemodynamic view. Am J Med 1986;80(3):443-453.
9. Merimee TJ. Diabetic retinopathy. A synthesis of perspectives. N Engl J Med 1990;322(14):978-983.
10. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288(5789):373-376.
11. Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. Faseb J 1989;3(9):2007-2018.
12. Ignarro LJ, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987;84(24):9265-9269.
13. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327(6122):524-526.
14. Forstermann U, et al. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension 1994;23(6 Pt 2):1121-1131.
15. Dinerman JL, Lowenstein CJ, Snyder SH. Molecular mechanisms of nitric oxide regulation. Potential relevance to cardiovascular disease. Circ Res 1993;73(2):217-222.
16. 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(3 Pt 1):C399-C407.
17. Waldman SA, Murad F. Cyclic GMP synthesis and function. Pharmacol Rev 1987;39(3):163-196.
18. Dimmeler S, Lottspeich F, Brune B. Nitric oxide causes ADP-ribosylation and inhibition of glyceral-dehyde-3-phosphate dehydrogenase. J Biol Chem 1992;267(24):16,771-16,774.
19. Rees DD, Palmer RM, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 1989;86(9):3375-2278.
20. Duplain H, et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 2001;104(3):342-245.
21. McQuillan LP, et al. Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol 1994;267(5 Pt 2):H1921-H1027.
22. Griffith TM, et al. EDRF coordinates the behaviour of vascular resistance vessels. Nature 1987; 329(6138):442-445.
23. Stamler JS, et al. Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 1994;89(5):2035-2040.
24. Lowenstein CJ, Dinerman JL, Snyder SH. Nitric oxide: a physiologic messenger. Ann Intern Med 1994;120(3):227-237.
25. Ignarro LJ. Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein. Circ Res 1989;65(1):1-21.
26. Kourembanas S, 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(1):99-104.
27. Balligand JL, et al. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci USA 1993;90(1):347-351.
28. Joe EK, et al. Regulation of cardiac myocyte contractile function by inducible nitric oxide synthase (iNOS): mechanisms of contractile depression by nitric oxide. J Mol Cell Cardiol 1998;30(2):303-315.
29. Mellion BT, et al. Evidence for the inhibitory role of guanosine 3' 5'-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood 1981;57(5): 946-955.
30. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989;2(8670):997-1000.
31. Kubes P, Granger DN. Nitric oxide modulates microvascular permeability. Am J Physiol 1992;262(2 Pt 2):H611-H615.
32. 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(5):1774-1777.
33. Marks DS, et al. 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(6):2630-2638.
34. Taguchi J, et al. L-arginine inhibits neointimal formation following balloon injury. Life Sci 1993;53(23):PL387-PL392.
35. Cohen RA. The role of nitric oxide and other endothelium-derived vasoactive substances in vascular disease. Prog Cardiovasc Dis 1995;38(2):105-128.
36. Bossaller C, et al. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest 1987;79(1):170-174.
37. Cooke JP, et al. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest 1992;90(3):1168-1172.
38. De Caterina R, 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(1):60-68.
39. Rajavashisth TB, et al. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature 1990;344(6263):254-257.
40. Collins T, et al. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. Faseb J 1995;9(10):899-909.
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(23):14,214-14,219.
42. Almer LO, Pandolfi M, Aberg M. The plasminogen activator activity of arteries and veins in diabetes mellitus. Thromb Res 1975;6(2):177-182.
43. Auwerx J, et al. Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. Arteriosclerosis 1988;8(1):68-72.
44. Carreras LO, et al. Decreased vascular prostacyclin (PGI2) in diabetic rats. Stimulation of PGI2 release in normal and diabetic rats by the antithrombotic compound Bay g 6575. Thromb Res 1980;19(4-5): 663-670.
45. Umeda F, Inoguchi T, Nawata H. Reduced stimulatory activity on prostacyclin production by cultured endothelial cells in serum from aged and diabetic patients. Atherosclerosis 1989;75(1):61-66.
46. Meraji S, et al. Endothelium-dependent relaxation in aorta of BB rat. Diabetes 1987;36(8):978-981.
47. Oyama Y, et al. Attenuation of endothelium-dependent relaxation in aorta from diabetic rats. Eur J Pharmacol 1986;132(1):75-78.
48. Mayhan WG, Simmons LK, Sharpe GM. Mechanism of impaired responses of cerebral arterioles during diabetes mellitus. Am J Physiol 1991;260(2 Pt 2):H319-H326.
49. Abiru T, et al. 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(1):13-25.
50. Fortes ZB, Garcia Leme J, Scivoletto R. Vascular reactivity in diabetes mellitus: possible role of insulin on the endothelial cell. Br J Pharmacol 1984;83(3):635-643.
51. Taylor PD, et al. Prevention by insulin treatment of endothelial dysfunction but not enhanced norad-renaline-induced contractility in mesenteric resistance arteries from streptozotocin-induced diabetic rats. Br J Pharmacol 1994;111(1):35-41.
52. Tesfamariam B, et al. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest 1990;85(3):929-932.
53. Tesfamariam B, Brown ML, Cohen RA. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest 1991;87(5):1643-1648.
54. Tesfamariam B, Brown ML, Cohen RA. Aldose reductase and myo-inositol in endothelial cell dysfunction caused by elevated glucose. J Pharmacol Exp Ther 1992;263(1):153-157.
55. Cohen RA. Dysfunction of vascular endothelium in diabetes mellitus. Circulation 1993;87 (Suppl V):V67-V76.
56. Kamata K, et al. Functional changes in vascular smooth muscle and endothelium of arteries during diabetes mellitus. Life Sci 1992;50(19):1379-1387.
57. Wolff SP, Dean RT. Glucose autoxidation and protein modification. The potential role of 'autoxidative glycosylation' in diabetes. Biochem J 1987;245(1):243-250.
58. Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 1992;263(2 Pt 2):H321-H326.
59. Hattori Y, et al. Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol 1991;261(4 Pt 2):H1086-H1094.
60. Saenz de Tejada I, et al. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989;320(16):1025-1030.
61. Johnstone MT, et al. Impaired endothelium-dependent vasodilation in patients with insulin- dependent diabetes mellitus. Circulation 1993;88(6):2510-2516.
62. Smits P, et al. Endothelium-dependent vascular relaxation in patients with type I diabetes. Diabetes 1993;42(1):148-153.
63. 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(6):2548-2554.
63a. Johnstone MT, Veves A. (Eds.) Diabetes and cardiovascular disease. Humana Press, Totowa, NJ:2001.
64. Halkin A, et al. Vascular responsiveness and cation exchange in insulin-dependent diabetes. Clin Sci (Lond) 1991;81(2):223-232.
65. Zenere BM, et al. Noninvasive detection of functional alterations of the arterial wall in IDDM patients with and without microalbuminuria. Diabetes Care 1995;18(7):975-982.
66. Clarkson P, 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(3):573-579.
67. Makimattila S, et al. Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. Circulation 1996;94(6):1276-1282.
68. Williams SB, et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 1998;97(17):1695-1701.
69. Chowienczyk PJ, et al. Sex differences in endothelial function in normal and hypercholesterolaemic subjects. Lancet 1994;344(8918):305-306.
70. Williams SB, et al. Impaired nitric oxide-mediated vasodilation in patients with non- insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27(3):567-574.
71. McVeigh GE, et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992;35(8):771-776.
72. Cosentino F, Luscher TF. Endothelial dysfunction in diabetes mellitus. J Cardiovasc Pharmacol 1998;32(Suppl 3):S54-S61.
73. Bohlen HG, Lash JM. Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation of normal rat arterioles. Am J Physiol 1993;265(1 Pt 2):H219-H225.
74. Akbari CM, et al. Endothelium-dependent vasodilatation is impaired in both microcirculation and macrocirculation during acute hyperglycemia. J Vasc Surg 1998;28(4):687-694.
75. Houben AJ, et al. Local 24-h hyperglycemia does not affect endothelium-dependent or -independent vasoreactivity in humans. Am J Physiol 1996;270(6 Pt 2):H2014-H2020.
76. Davies MG, et al. The expression and function of G-proteins in experimental intimal hyperplasia. J Clin Invest 1994;94(4):1680-1689.
77. Gilligan DM, et al. Selective loss of microvascular endothelial function in human hypercholesterolemia. Circulation 1994;90(1):35-41.
78. Mancusi G, et al. 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 ( Pt 1):281-287.
79. Cooke JP, et al. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation 1991;83(3):1057-1062.
80. Boger RH, et al. Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production. Atherosclerosis 1995;117(2):273-284.
81. Boger RH, et al. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997;95(8):2068-2074.
82. Drexler H, et al. Correction of endothelial dysfunction in coronary microcirculation of hyper-cholesterolaemic patients by L-arginine. Lancet 1991;338(8782-8783):1546-1550.
83. Pieper GM, Peltier BA. Amelioration by L-arginine of a dysfunctional arginine/nitric oxide pathway in diabetic endothelium. J Cardiovasc Pharmacol 1995;25(3):397-403.
84. Pieper GM, et al. Reversal by L-arginine of a dysfunctional arginine/nitric oxide pathway in the endothelium of the genetic diabetic BB rat. Diabetologia 1997;40(8):910-915.
85. 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(4 Pt 2):H1312-H1318.
86. MacAllister RJ, et al. Vascular and hormonal responses to arginine: provision of substrate for nitric oxide or non-specific effect? Clin Sci (Lond) 1995;89(2):183-190.
87. Giugliano D, et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia. Circulation 1997;95(7):1783-1790.
88. Thorne S, et al. Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginine. J Am Coll Cardiol 1998;32(1):110-116.
89. Boulanger C, Luscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 1990;85(2):587-590.
90. Bell MR, et al. The changing in-hospital mortality of women undergoing percutaneous transluminal coronary angioplasty. JAMA 1993;269(16):2091-2095.
91. Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J 1994;298 ( Pt 2):249-258.
92. Asahina T, et al. Impaired activation of glucose oxidation and NADPH supply in human endothelial cells exposed to H2O2 in high-glucose medium. Diabetes 1995;44(5):520-526.
93. Bode-Boger SM, et al. Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun 1996;219(2):598-603.
94. Lerman A, et al. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 1998;97(21):2123-2128.
95. Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 2000;20(9): 2032-2037.
96. Xiong Y, et al. Elevated levels of the serum endogenous inhibitor of nitric oxide synthase and metabolic control in rats with streptozotocin-induced diabetes. J Cardiovasc Pharmacol 2003;42(2):191-196.
97. Fard A, 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. Arterioscler Thromb Vasc Biol 2000;20(9):2039-2044.
98. Boger RH, et al. Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. Clin Sci (Lond) 2001;100(2):161-167.
99. Paiva H, et al. Plasma concentrations of asymmetric-dimethyl-arginine in type 2 diabetes associate with glycemic control and glomerular filtration rate but not with risk factors of vasculopathy. Metabolism 2003;52(3):303-307.
100. Xu B, et al. Impairment of vascular endothelial nitric oxide synthase activity by advanced glycation end products. Faseb J 2003;17(10):1289-1291.
101. Bucala, R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 1991;87(2): 432-438.
102. Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med 1994;16(3):383-391.
103. Dohi T, et al. Alterations of the plasma selenium concentrations and the activities of tissue peroxide metabolism enzymes in streptozotocin-induced diabetic rats. Horm Metab Res 1988;20(11):671-675.
104. Wohaieb SA, Godin DV. Alterations in free radical tissue-defense mechanisms in streptozocin-induced diabetes in rat. Effects of insulin treatment. Diabetes 1987;36(9):1014-1018.
105. Pieper GM, Gross GJ. Oxygen free radicals abolish endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol 1988;255(4 Pt 2):H825-H833.
106. Langenstroer P, Pieper GM. Regulation of spontaneous EDRF release in diabetic rat aorta by oxygen free radicals. Am J Physiol 1992;263(1 Pt 2):H257-H265.
107. Auch-Schwelk W, Katusic ZS, Vanhoutte PM. Contractions to oxygen-derived free radicals are augmented in aorta of the spontaneously hypertensive rat. Hypertension 1989;13(6 Pt 2):859-864.
108. Katusic ZS, et al. Endothelium-dependent contractions to oxygen-derived free radicals in the canine basilar artery. Am J Physiol 1993;264(3 Pt 2):H859-H864.
109. Ido Y, Kilo C, Williamson JR. Cytosolic NADH/NAD+, free radicals, and vascular dysfunction in early diabetes mellitus. Diabetologia 1997;40 Suppl 2:S115-S117.
110. Williamson JR, et al. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 1993;42(6): 801-813.
111. Schmidt K, et al. Tetrahydrobiopterin-dependent formation of endothelium-derived relaxing factor (nitric oxide) in aortic endothelial cells. Biochem J 1992;281 ( Pt 2):297-300.
112. Cosentino F, Katusic ZS. Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation 1995;91(1):139-144.
113. Pieper GM. Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol 1997;29(1):8-15.
114. Lee TS, et al. Differential regulation of protein kinase C and (Na,K)-adenosine triphosphatase activities by elevated glucose levels in retinal capillary endothelial cells. J Clin Invest 1989;83(1):90-94.
115. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999;48(1):1-9.
116. Craven PA, Patterson MC, DeRubertis FR. Role for protein kinase C in A23187 induced glomerular arachidonate release and PGE2 production. Biochem Biophys Res Commun 1987;149(2):658-664.
117. Fujita I, et al. Diacylglycerol 1-oleoyl-2-acetyl-glycerol, stimulates superoxide-generation from human neutrophils. Biochem Biophys Res Commun 1984;120(2):318-324.
118. Dunbar JC, et al. Mechanisms mediating insulin-induced hypotension in rats. A role for nitric oxide and autonomic mediators. Acta Diabetol 1996;33(4):263-268.
119. Zeng G, et al. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 2000;101(13):1539-1545.
120. Steinberg HO, et al. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996;97(11):2601-2610.
121. Balon TW, Nadler JL. Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol 1997;82(1):359-363.
122. Young ME, Radda GK, Leighton B. Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro. Biochem J 1997;322 ( Pt 1):223-228.
123. Petrie JR, et al. Endothelial nitric oxide production and insulin sensitivity. A physiological link with implications for pathogenesis of cardiovascular disease. Circulation 1996;93(7):1331-1333.
124. Cleland SJ, et al. Insulin action is associated with endothelial function in hypertension and type 2 diabetes. Hypertension 2000;35(1 Pt 2):507-511.
125. Utriainen T, et al. Dissociation between insulin sensitivity of glucose uptake and endothelial function in normal subjects. Diabetologia 1996;39(12):1477-1482.
126. Bursztyn M, et al. 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(6):683-686.
127. Creager MA, Lusher T. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation 2003;108:1527-1532.
128. Kelley DE, Simoneau JA. Impaired free fatty acid utilizaiton by skeletal muscle in non-insulin-dependent diabetes mellitus. J Clin Invest 1994;94:2349-2356.
129. Boden G. Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians 1999;111:241-248.
130. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impari endot-helium-dependent vasodilation. J Clin Invest 1997;100:1230-1239.
131. Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999;103:253-259.
132. Dichtl W, Nilsson L, Goncalves I, et al. Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells. Circ Res 1999;84:1085-1094.
133. Inoguchi T, Li P, Umeda F, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000;49:1939-1945.
134. de Man FH, Weverling-Rijnsburger AW, van der Laarse A, et al. Not acute but chronic hypertri-glyceridemia is associated with impaired endothelium-dependent vasodilation: reversal after lipid-lowering therapy by atorvastatin. Arteroscler Thromb Vasc Biol 2000;20:744-750.
135. Kuhn FE, Mohler ER, Satler LF, et al. Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity. Am J Cardiol 1991;68:1425-1430.
136. Osborne JA, et al. Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits. Am J Physiol 1989;256(3 Pt 1):C591-C597.
137. 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(1):75-79.
138. Shimokawa H, Vanhoutte PM. Hypercholesterolemia causes generalized impairment of endothelium-dependent relaxation to aggregating platelets in porcine arteries. J Am Coll Cardiol 1989;13(6):1402-1408.
139. Creager MA, et al. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemia humans. J Clin Invest 1992;90(4):1248-1253.
140. Chowienczyk PJ, et al. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet 1992;340(8833):1430-1432.
141. Quyyumi AA, et al. Coronary vascular nitric oxide activity in hypertension and hypercholesterolemia. Comparison of acetylcholine and substance P. Circulation 1997;95(1):104-110.
142. Shiode N, et al. Nitric oxide production by coronary conductance and resistance vessels in hypercholesterolemia patients. Am Heart J 1996;131(6):1051-1057.
143. Ohara, Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 1993;91(6):2546-2551.
144. Makimattila S, et al. Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants. Diabetes Care 1999;22(6):973-981.
145. Tan KC, et al. Influence of low density lipoprotein (LDL) subfraction profile and LDL oxidation on endothelium-dependent and independent vasodilation in patients with type 2 diabetes. J Clin Endocrinol Metab 1999;84(9):3212-3216.
146. O'Brien SF, et al. Low-density lipoprotein size, high-density lipoprotein concentration, and endothelial dysfunction in non-insulin-dependent diabetes. Diabet Med 1997;14(11):974-978.
147. Skyrme-Jones RA, et al. Endothelial vasodilator function is related to low-density lipoprotein particle size and low-density lipoprotein vitamin E content in type 1 diabetes. J Am Coll Cardiol 2000;35(2):292-299.
148. Hedrick CC, et al. Glycation impairs high-density lipoprotein function. Diabetologia 2000;43(3): 312-320.
149. Konishi M, Su C. Role of endothelium in dilator responses of spontaneously hypertensive rat arteries. Hypertension 1983;5(6):881-886.
150. Dohi Y, Criscione L, Luscher TF. Renovascular hypertension impairs formation of endothelium-derived relaxing factors and sensitivity to endothelin-1 in resistance arteries. Br J Pharmacol 1991;104(2):349-354.
151. Tuncer M, Vanhoutte PM. Response to the endothelium-dependent vasodilator acetylcholine in perfused kidneys of normotensive and spontaneously hypertensive rats. Blood Press 1993;2(3):217-220.
152. Bell DR. Vascular smooth muscle responses to endothelial autacoids in rats with chronic coarctation hypertension. J Hypertens 1993;11(1):65-74.
153. Vanhoutte PM, Boulanger CM. Endothelium-dependent responses in hypertension. Hypertens Res 1995;18(2):87-98.
154. 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(5):1468-1474.
155. 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(5):1475-1481.
156. Panza JA, 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 Cardiol 1994;23(7): 1610-1616.
157. Panza JA. Endothelial dysfunction in essential hypertension. Clin Cardiol 1997;20(11 Suppl 2):II-26-II-33.
158. 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(6):1732-1738.
159. Wei EP, et al. Superoxide generation and reversal of acetylcholine-induced cerebral arteriolar dilation after acute hypertension. Circ Res 1985;57(5):781-787.
160. Nakazono K, et al. Does superoxide underlie the pathogenesis of hypertension? Proc Natl Acad Sci USA 1991;88(22):10,045-10,048.
161. Garcia CE, et al. Effect of copper-zinc superoxide dismutase on endothelium-dependent vasodilation in patients with essential hypertension. Hypertension 1995;26(6 Pt 1):863-868.
162. Cardillo C, et al. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension 1997;30(1 Pt 1):57-63.
163. Lucas CP, et al. Insulin and blood pressure in obesity. Hypertension 1985;7(5):702-706.
164. Modan M, et al. Hyperinsulinemia. A link between hypertension obesity and glucose intolerance. J Clin Invest 1985;75(3):809-817.
165. Katakam PV, et al. Metformin improves vascular function in insulin-resistant rats. Hypertension 2000;35(1 Pt 1):108-112.
166. Pagano PJ, et al. Vascular action of the hypoglycaemic agent gliclazide in diabetic rabbits. Diabetologia 1998;41(1):9-15.
167. Tack CJ, et al. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia 1998;41(5):569-576.
168. Pistrosch F, et al. In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control. Diabetes Care 2004;27(2):484-490.
169. Ishii H, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996;272(5262):728-731.
170. Beckman JA, et al. Inhibition of protein kinase Cbeta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res 2002;90(1):107-111.
171. Vlassara H, et al. Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetic and aging complications. Proc Natl Acad Sci USA 1992;89(24):12,043-12,047.
172. Wohaieb SA, Godin DV. Alterations in tissue antioxidant systems in the spontaneously diabetic (BB Wistar) rat. Can J Physiol Pharmacol 1987;65(11):2191-2195.
173. Sundaram RK, et al. Antioxidant status and lipid peroxidation in type II diabetes mellitus with and without complications. Clin Sci (Lond) 1996;90(4):255-260.
174. Cunningham JJ, et al. Reduced mononuclear leukocyte ascorbic acid content in adults with insulin-dependent diabetes mellitus consuming adequate dietary vitamin C. Metabolism 1991;40(2):146-149.
175. Karpen CW, et al. Interrelation of platelet vitamin E and thromboxane synthesis in type I diabetes mellitus. Diabetes 1984;33(3):239-243.
176. Timimi FK, et al. Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol 1998;31(3):552-557.
177. Ting HH, et al. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996;97(1):22-28.
178. Beckman JA, et al. Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 2001;103(12):1618-1623.
179. Inoue S, Kawanishi S. Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett 1995;371(1):86-88.
180. Stroes E, et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 1997;99(1):41-46.
181. 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(2):383-390.
182. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. Jama 1991;265(14): 1861-1867.
183. Winocour PD. Platelet abnormalities in diabetes mellitus. Diabetes 1992;41 Suppl 2:26-31.
184. Keaney JF Jr, et al. 17 beta-estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine. Circulation 1994;89(5):2251-2259.
185. Gisclard V, Miller VM, Vanhoutte PM. Effect of17 beta-estradiol on endothelium-dependent responses in the rabbit. J Pharmacol Exp Ther 1988;244(1):19-22.
186. Lieberman EH, et al. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med 1994;121(12):936-941.
187. Gilligan DM, et al. Acute vascular effects of estrogen in postmenopausal women. Circulation 1994;90(2):786-791.
188. Pinto S, et al. Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women. Hypertension 1997;29(1 Pt 2):268-273.
189. Arora S, et al. Estrogen improves endothelial function. J Vasc Surg 1998;27(6):1141-1146; discussion 1147.
190. Davidge ST, Zhang Y. Estrogen replacement suppresses a prostaglandin H synthase-dependent vasoconstrictor in rat mesenteric arteries. Circ Res 1998;83(4):388-395.
191. Lim SC, 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(11):4159-4164.
192. Chobanian AV, et al. Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1990;15(3):327-331.
193. Becker RH, Wiemer G, Linz W. Preservation of endothelial function by ramipril in rabbits on a long-term atherogenic diet. J Cardiovasc Pharmacol 1991;18 (Suppl 2):S110-S115.
194. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355(9200):253-259.
195. Mancini GB, 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(3):258-265.
196. McFarlane R, et al. Angiotensin converting enzyme inhibition and arterial endothelial function in adults with Type 1 diabetes mellitus. Diabet Med 1999;16(1):62-66.
197. Mullen MJ, et al. Effect of enalapril on endothelial function in young insulin-dependent diabetic patients: a randomized, double-blind study. J Am Coll Cardiol 1998;31(6):1330-1335.
198. O'Driscoll G, et al. Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus. J Clin Invest 1997;100(3):678-684.
199. Nielsen FS, et al. Lisinopril improves endothelial dysfunction in hypertensive NIDDM subjects with diabetic nephropathy. Scand J Clin Lab Invest 1997;57(5):427-434.
200. Bijlstra PJ, et al. Effect of long-term angiotensin-converting enzyme inhibition on endothelial function in patients with the insulin-resistance syndrome. J Cardiovasc Pharmacol 1995;25(4):658-664.
201. Griendling KK, et al. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994;74(6):1141-1148.
202. Wiemer G, et al. Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. Hypertension 1991;18(4):558-563.
203. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation 1997;95(5):1115-1118.
204. Anderson TJ, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-depen-dent coronary vasomotion. N Engl J Med 1995;332(8):488-493.
205. Treasure CB, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332(8):481-487.
206. Evans M, et al. Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation 2000;101(15):1773-1779.
207. Sheu WH, et al. Endothelial dysfunction is not reversed by simvastatin treatment in type 2 diabetic patients with hypercholesterolemia. Diabetes Care 1999;22(7):1224-1225.
Was this article helpful?
I can't believe I'm actually writing the book that is going to help you achieve the level of health and fitness that you always dreamed of. Me, little scrawny sickly Darlene that was always last picked in gym class. There's power in a good story here so get this book now.