Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus

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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				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]