Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus
SB Williams,
JA Cusco,
MA Roddy,
MT Johnstone,
and
MA Creager
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
OBJECTIVES: This study sought to determine whether nitric oxide-mediated vasodilation is abnormal in patients with non-insulin-dependent diabetes mellitus. BACKGROUND: Multiple investigations, both in experimental models and in patients with insulin-dependent diabetes mellitus, demonstrate impaired endothelium-dependent vasodilation. Decreased availability of endothelium-derived nitric oxide may contribute to the high prevalence of vascular disease in diabetes. METHODS: Vascular reactivity was measured in the forearm resistance vessels of 21 patients with non-insulin-dependent diabetes mellitus and 23 matched healthy control subjects. No patient had hypertension or hypercholesterolemia. Each subject was pretreated with aspirin to inhibit endogenous production of vasoactive prostanoids. Methacholine chloride (0.3 to 10 microg/min) was administered through a brachial artery cannula to assess vasodilation to endothelium-derived nitric oxide. Sodium nitroprusside (0.3 to 10 microg/min) was infused to evaluate vasodilation to an exogenous nitric oxide donor. Verapamil (10 to 300 microg/min) was administered to distinguish impaired nitric-oxide-mediated vasodilation from general dysfunction of vascular smooth muscle. Forearm blood flow was determined by venous occlusion plethysmography, and dose-response curves were generated for each agent. To assess the role of vasoconstrictor prostanoids, a subset of eight diabetic subjects were reexamined in the absence of aspirin treatment. RESULTS: Basal forearm blood flow in diabetic and nondiabetic subjects was comparable. The forearm blood flow responses to both methacholine chloride and nitroprusside were significantly attenuated in diabetic compared with nondiabetic subjects (p < 0.005 by analysis of variance for both agents). In contrast, the response to verapamil was not significantly different between the groups (p > 0.50). The forearm blood flow responses to these agents were not significantly affected by cyclooxygenase inhibition. CONCLUSIONS: Nitric oxide-mediated vasodilation is impaired in non-insulin-dependent diabetes mellitus. Vasoconstrictor prostanoids do not contribute significantly to vascular dysfunction. The attenuated response to exogenous as well as endogenous nitric oxide donors suggests that the abnormality is due to increased inactivation of nitric oxide or to decreased reactivity of the vascular smooth muscle to nitric oxide.
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Uncontrolled Hypertension, Uncompensated Type II Diabetes, and Smoking Have Different Patterns of Vascular Dysfunction
Chest,
March 1, 2004;
125(3):
823 - 830.
[Abstract]
[Full Text]
[PDF]
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V. Fonseca, C. Desouza, S. Asnani, and I. Jialal
Nontraditional Risk Factors for Cardiovascular Disease in Diabetes
Endocr. Rev.,
February 1, 2004;
25(1):
153 - 175.
[Abstract]
[Full Text]
[PDF]
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P. A. Economides, A. Caselli, E. Tiani, L. Khaodhiar, E. S. Horton, and A. Veves
The Effects of Atorvastatin on Endothelial Function in Diabetic Patients and Subjects at Risk for Type 2 Diabetes
J. Clin. Endocrinol. Metab.,
February 1, 2004;
89(2):
740 - 747.
[Abstract]
[Full Text]
[PDF]
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F. Pistrosch, J. Passauer, S. Fischer, K. Fuecker, M. Hanefeld, and P. Gross
In Type 2 Diabetes, Rosiglitazone Therapy for Insulin Resistance Ameliorates Endothelial Dysfunction Independent of Glucose Control
Diabetes Care,
February 1, 2004;
27(2):
484 - 490.
[Abstract]
[Full Text]
[PDF]
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S. F. Yan, R. Ramasamy, Y. Naka, and A. M. Schmidt
Glycation, Inflammation, and RAGE: A Scaffold for the Macrovascular Complications of Diabetes and Beyond
Circ. Res.,
December 12, 2003;
93(12):
1159 - 1169.
[Abstract]
[Full Text]
[PDF]
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J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, J. F. Keaney Jr., and M. A. Creager
Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus
Am J Physiol Heart Circ Physiol,
December 1, 2003;
285(6):
H2392 - H2398.
[Abstract]
[Full Text]
[PDF]
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R. T. Hurst and R. W. Lee
Increased Incidence of Coronary Atherosclerosis in Type 2 Diabetes Mellitus: Mechanisms and Management
Ann Intern Med,
November 18, 2003;
139(10):
824 - 834.
[Abstract]
[Full Text]
[PDF]
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D. Tousoulis, C. Antoniades, C. Tountas, E. Bosinakou, M. Kotsopoulou, P. Toutouzas, and C. Stefanadis
Vitamin C Affects Thrombosis/ Fibrinolysis System and Reactive Hyperemia in Patients With Type 2 Diabetes and Coronary Artery Disease
Diabetes Care,
October 1, 2003;
26(10):
2749 - 2753.
[Abstract]
[Full Text]
[PDF]
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Z. Bagi, A. Koller, and G. Kaley
Superoxide-NO interaction decreases flow- and agonist-induced dilations of coronary arterioles in Type 2 diabetes mellitus
Am J Physiol Heart Circ Physiol,
October 1, 2003;
285(4):
H1404 - H1410.
[Abstract]
[Full Text]
[PDF]
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M. A. Creager, T. F. Luscher, F. Cosentino, and J. A. Beckman
Diabetes and Vascular Disease: Pathophysiology, Clinical Consequences, and Medical Therapy: Part I
Circulation,
September 23, 2003;
108(12):
1527 - 1532.
[Full Text]
[PDF]
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M. Guazzi, G. Tumminello, M. Matturri, and M. D. Guazzi
Insulin ameliorates exercise ventilatory efficiency and oxygen uptake in patients with heart failure-type 2 diabetes comorbidity
J. Am. Coll. Cardiol.,
September 17, 2003;
42(6):
1044 - 1050.
[Abstract]
[Full Text]
[PDF]
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W. C. Levy and I. B. Hirsch
Diabetes and heart failure: is insulin therapy the answer?
J. Am. Coll. Cardiol.,
September 17, 2003;
42(6):
1051 - 1053.
[Full Text]
[PDF]
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J. G Regensteiner, S. Popylisen, T. A Bauer, J. Lindenfeld, E. Gill, S. Smith, C. K Oliver-Pickett, J. E. Reusch, and J. V Weil
Oral L-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes
Vascular Medicine,
August 1, 2003;
8(3):
169 - 175.
[Abstract]
[PDF]
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S. Vigili de Kreutzenberg, E. Kiwanuka, A. Tiengo, and A. Avogaro
Visceral obesity is characterized by impaired nitric oxide-independent vasodilation
Eur. Heart J.,
July 1, 2003;
24(13):
1210 - 1215.
[Abstract]
[Full Text]
[PDF]
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K.-H. Mak and D. P. Faxon
Clinical studies on coronary revascularization in patients with type 2 diabetes
Eur. Heart J.,
June 2, 2003;
24(12):
1087 - 1103.
[Abstract]
[Full Text]
[PDF]
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S. R. Colberg, H. K. Parson, D. R. Holton, T. Nunnold, and A. I. Vinik
Cutaneous Blood Flow in Type 2 Diabetic Individuals After an Acute Bout of Maximal Exercise
Diabetes Care,
June 1, 2003;
26(6):
1883 - 1888.
[Abstract]
[Full Text]
[PDF]
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K. Alagiakrishnan, A. Juby, D. Hanley, W. Tymchak, and A. Sclater
Role of Vascular Factors in Osteoporosis
J. Gerontol. A Biol. Sci. Med. Sci.,
April 1, 2003;
58(4):
M362 - 366.
[Abstract]
[Full Text]
[PDF]
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K. Dunder, L. Lind, B. Zethelius, L. Berglund, and H. Lithell
Increase in blood glucose concentration during antihypertensive treatment as a predictor of myocardial infarction: population based cohort study
BMJ,
March 29, 2003;
326(7391):
681 - 681.
[Abstract]
[Full Text]
[PDF]
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B. A. Kingwell, M. Formosa, M. Muhlmann, S. J. Bradley, and G. K. McConell
Type 2 Diabetic Individuals Have Impaired Leg Blood Flow Responses to Exercise: Role of endothelium-dependent vasodilation
Diabetes Care,
March 1, 2003;
26(3):
899 - 904.
[Abstract]
[Full Text]
[PDF]
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J. C. Baldi, J. L. Aoina, H. C. Oxenham, W. Bagg, and R. N. Doughty
Reduced exercise arteriovenous O2 difference in Type 2 diabetes
J Appl Physiol,
March 1, 2003;
94(3):
1033 - 1038.
[Abstract]
[Full Text]
[PDF]
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S. Ulker, P. P. McKeown, and U. Bayraktutan
Vitamins Reverse Endothelial Dysfunction Through Regulation of eNOS and NAD(P)H Oxidase Activities
Hypertension,
March 1, 2003;
41(3):
534 - 539.
[Abstract]
[Full Text]
[PDF]
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W. G. Haynes
Triglyceride-Rich Lipoproteins and Vascular Function
Arterioscler Thromb Vasc Biol,
February 1, 2003;
23(2):
153 - 155.
[Full Text]
[PDF]
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M. G. Clark, M. G. Wallis, E. J. Barrett, M. A. Vincent, S. M. Richards, L. H. Clerk, and S. Rattigan
Blood flow and muscle metabolism: a focus on insulin action
Am J Physiol Endocrinol Metab,
February 1, 2003;
284(2):
E241 - E258.
[Abstract]
[Full Text]
[PDF]
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W. H. Capell, C. A. DeSouza, P. Poirier, M. L. Bell, B. L. Stauffer, K. M. Weil, T. L. Hernandez, and R. H. Eckel
Short-Term Triglyceride Lowering With Fenofibrate Improves Vasodilator Function in Subjects With Hypertriglyceridemia
Arterioscler Thromb Vasc Biol,
February 1, 2003;
23(2):
307 - 313.
[Abstract]
[Full Text]
[PDF]
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A. Kjaer, C. Meyer, F. S. Nielsen, H.-H. Parving, and B. Hesse
Dipyridamole, Cold Pressor Test, and Demonstration of Endothelial Dysfunction: A PET Study of Myocardial Perfusion in Diabetes
J. Nucl. Med.,
January 1, 2003;
44(1):
19 - 23.
[Abstract]
[Full Text]
[PDF]
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R. C. Hickner, G. Kemeny, K. McIver, K. Harrison, and M. E. Hostetler
Lower Skeletal Muscle Nutritive Blood Flow in Older Women Is Related to eNOS Protein Content
J. Gerontol. A Biol. Sci. Med. Sci.,
January 1, 2003;
58(1):
B20 - 25.
[Abstract]
[Full Text]
[PDF]
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K. J. Stewart, W. R. Hiatt, J. G. Regensteiner, and A. T. Hirsch
Exercise Training for Claudication
N. Engl. J. Med.,
December 12, 2002;
347(24):
1941 - 1951.
[Full Text]
[PDF]
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J. M. Fernandez-Real, G. Penarroja, A. Castro, F. Garcia-Bragado, A. Lopez-Bermejo, and W. Ricart
Blood Letting in High-Ferritin Type 2 Diabetes: Effects on vascular reactivity
Diabetes Care,
December 1, 2002;
25(12):
2249 - 2255.
[Abstract]
[Full Text]
[PDF]
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N. N. Wahab, E. A. Cowden, N. J. Pearce, M. J. Gardner, H. Merry, J. L. Cox, and ICONS Investigators
Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era?
J. Am. Coll. Cardiol.,
November 20, 2002;
40(10):
1748 - 1754.
[Abstract]
[Full Text]
[PDF]
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K. J. Stewart
Exercise Training and the Cardiovascular Consequences of Type 2 Diabetes and Hypertension: Plausible Mechanisms for Improving Cardiovascular Health
JAMA,
October 2, 2002;
288(13):
1622 - 1631.
[Abstract]
[Full Text]
[PDF]
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G. M. London, S. J. Marchais, A. P. Guerin, F. Metivier, and H. Adda
Arterial structure and function in end-stage renal disease
Nephrol. Dial. Transplant.,
October 1, 2002;
17(10):
1713 - 1724.
[Full Text]
[PDF]
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M. Guazzi, R. Brambilla, S. De Vita, and M. D. Guazzi
Diabetes Worsens Pulmonary Diffusion in Heart Failure, and Insulin Counteracts This Effect
Am. J. Respir. Crit. Care Med.,
October 1, 2002;
166(7):
978 - 982.
[Abstract]
[Full Text]
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M. Guazzi, I. Oreglia, and M. D. Guazzi
Insulin Improves Alveolar-Capillary Membrane Gas Conductance in Type 2 Diabetes
Diabetes Care,
October 1, 2002;
25(10):
1802 - 1806.
[Abstract]
[Full Text]
[PDF]
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S. P Marso
Review: The pathogenesis of type 2 diabetes and cardiovascular disease
The British Journal of Diabetes & Vascular Disease,
September 1, 2002;
2(5):
350 - 356.
[Abstract]
[PDF]
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A. J Krentz
Type 2 diabetes and atherosclerotic cardiovascular disease: do they share common antecedents?
The British Journal of Diabetes & Vascular Disease,
September 1, 2002;
2(5):
370 - 378.
[Abstract]
[PDF]
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J. E. Ramsay, W. R. Ferrell, L. Crawford, A. M. Wallace, I. A. Greer, and N. Sattar
Maternal Obesity Is Associated with Dysregulation of Metabolic, Vascular, and Inflammatory Pathways
J. Clin. Endocrinol. Metab.,
September 1, 2002;
87(9):
4231 - 4237.
[Abstract]
[Full Text]
[PDF]
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B. A. Kingwell, M. Formosa, M. Muhlmann, S. J. Bradley, and G. K. McConell
Nitric Oxide Synthase Inhibition Reduces Glucose Uptake During Exercise in Individuals With Type 2 Diabetes More Than in Control Subjects
Diabetes,
August 1, 2002;
51(8):
2572 - 2580.
[Abstract]
[Full Text]
[PDF]
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J. A. Beckman, M. A. Creager, and P. Libby
Diabetes and Atherosclerosis: Epidemiology, Pathophysiology, and Management
JAMA,
May 15, 2002;
287(19):
2570 - 2581.
[Abstract]
[Full Text]
[PDF]
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R. W. van Etten, E. J.P. de Koning, M. L. Honing, E. S. Stroes, C. A. Gaillard, and T. J. Rabelink
Intensive Lipid Lowering by Statin Therapy Does Not Improve Vasoreactivity in Patients With Type 2 Diabetes
Arterioscler Thromb Vasc Biol,
May 1, 2002;
22(5):
799 - 804.
[Abstract]
[Full Text]
[PDF]
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