Additive Effect of Coexistent Type 2 Diabetes and Arterial Hypertension on Endothelial Dysfunction in Resistance Arteries of Human Forearm Vasculature

Abstract

Population studies suggest that vascular complications accumulate when arterial hyper tension supervenes on diabetes mellitus. Although it has been demonstrated that endothelial function is impaired in patients with either diabetes mellitus or arterial hypertension it is unknown whether or not both diseases exert additive effects on endothelial dysfunction. The authors therefore investigated endothelium-dependent and endothelium-independent vasodilation in the forearm vasculature of 44 individuals: in 10 type 2 diabetic patients (DM), in 12 patients with arterial hypertension (HT), in 10 patients with both DM and HT (DM+HT), and in 12 healthy control subjects (C). Forearm blood flow (FBF) was measured by venous occlusion plethysmography at rest and following intraarterial infusion of acetylcholine (ACh) and the NO-donor sodium nitroprusside (SNP) at increasing doses. FBF at rest was significantly lower in diabetic patients: 2.2 ±0.1 (DM) and 2.6 ±0.2 (DM+HT) versus 3.1 ±0.1 (HT) and 3.4 ±0.2 (C) mL/min per 100 mL of tissue. ACh and SNP both increased FBF dose-dependently in each group. The maximum response to ACh was progressively decreased in DM and HT: 13.7 (C) > 8.1 (DM) > 7.6 (HT) > and 5.7 (DM+HT) mL/min per 100 mL of (continued on next page) tissue. Reduction of the endothelium-dependent flow reserve assessed as percent increase in maximum FBF was also impaired following the same rank order: 349 (C) > 268 (DM) > 160 (HT) > 126 (DM+HT) %. The flow response to the NO-donor SNP amounted to: 327 (C), 306 (DM), 200 (HT), and 194% (DM+HT). In DM+HT the reduction of endothelium-dependent flow response was more pronounced compared with the endothelium-independent flow response. The present data provide evidence that type 2 diabetes and arterial hypertension impair endothelium-dependent dilation of resistance arteries in an additive manner suggesting that this progressive endothelial dysfunction might contribute to the increased incidence of cardiovascular complications when both diseases are coexistent.

Get full access to this article

View all access options for this article.

References

Vanhoutte PM : Endothelial dysfunction and atherosclerosis . Eur Heart J 18 (suppl E):E19-29, 1997.

Cooke JP , Dzau VJ : Derangements of the nitric oxide synthase pathway, L-arginine, and cardiovascular diseases. Circulation 96:379-382, 1997.

Orchard TJ , Strandness E. Jr: Assessment of peripheral vascular disease in diabetes. Circulation 88:819-828, 1993.

Christlieb AR : Diabetes and hypertensive vascular disease . Mechanisms and treatment. Am J Cardiol 32:592-606, 1973.

Deckert T. , Poulsen JE , Larsen, M. : Prognosis of diabetics with diabetes onset before the age of thirty-one . II: Factors influencing the prognosis. Diabetologia 14:371-377, 1978.

Lorenz M. , Gagliero E. : Perspectives in diabetes. Pathobiology of endothelial and other vascular cells in diabetes mellitus. Call for data. Diabetes 40:653-659,1991.

Stehouwer Cda , Schaper NC : The pathogenesis of vascular complications of diabetes mellitus: One voice or many? Eur J Clin Invest 26:535-543, 1996.

Hsueh WA , Anderson PW : Hypertension, the endothelial cell, and the vascular complications of diabetes mellitus. Hypertension 20:253-263, 1992.

Sowers JR , Epstein M. : Diabetes mellitus and associated hypertension, vascular disease, and nephropathy . An update. Hypertension 26:869-879, 1995.

10.

Chobanian AV : The 1988 report of the joint national committee on detection, evaluation, and treatment of high blood pressure. Arch Intern Med 148:1023-1038, 1988.

11.

Ziegler D. : Diabetische Neuropathie. München, Wien, Baltimore: Urban & Schwarzenberg, 1993.

12.

Kelm M. , Preik M. , Hafner DJ , et al: Evidence for a multifactorial process involved in the impaired flow response to nitric oxide in hypertensive patients with endothelial dysfunction . Hypertension 27:346-353, 1996.

13.

Preik M. , Kelm M. , Feelisch M. , et al: Impaired effectiveness of nitric oxide donors in resistance arteries of patients with arterial hypertension. J Hypertension 14:903-908, 1996.

14.

Benjamin N. , Calver A. , Collier J. , et al: Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension 25:918-923, 1995.

15.

Alexander RW : Hypertension and the pathogenesis of atherosclerosis: Oxidative stress and the mediation of arterial inflammatory response: A new perspective. Hypertension 25:155-161, 1995.

16.

Panza JA , Quyyumi AA , Brush JE , et al: Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323 :22-26, 1990.

17.

Linder L. , Kiowski W. , Bühler FR , et al: Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation 81:1762-1767, 1990 .

18.

Lüscher T. : The endothelium: Target and promoter of hypertension? Hypertension 15:482-486, 1990.

19.

Taddei S. , Virdis A. , Mattei P. , et al: Endothelium-dependent forearm vasodilation is reduced in normotensive subjects with familial history of hypertension. J Cardiovasc Pharmacol 20(suppl 12):193-195, 1992.

20.

Benjamin N. , Vane JR : Nitric oxide and hypertension. Circulation 94:1197-1198, 1996.

21.

Halkin A. , Eriksson LE , Nilson GE : Vascular responsiveness and cation exchange in insulin-dependent diabetes . Clin Sci 81:223-232, 1991.

22.

Rongen GA , Ginneken E. , Thien T. , et al: Preserved vasodilator response to adenosine in insulin-dependent diabetes mellitus. Eur J Clin Invest 26:192-198, 1996.

23.

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 90:2548-2554, 1992 .

24.

Johnstone MT , Creager SJ , Scales KM , et al: Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 88:2510-2516, 1993.

25.

McVeigh GE , Brennan GM , Johnston GD , et al: Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35:771-776, 1992.

26.

Ting HH , Timini FK , Boles KS , et al: Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin dependent diabetes mellitus. J Clin Invest 97:22-28, 1996.

27.

Gerhard M. , Roddy MA , Creager SJ , et al: Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension 27:849-853, 1996.

28.

Kelm M. , Yoshida K. : Metabolic fate of nitric oxide and related N-oxides. In: Methods in Nitric Oxide Research, ed. by Feelisch M , Stamler JS. Sussex : John Wiley & Sons Ltd, 1996 , pp 47-58.

29.

Rösen P. , Ballhausen T. , Bloch W. , et al: Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: Influence of tocopherol as antioxidant. Diabetologia 38:1157-1168, 1995.

30.

Mäkimattila S. , Virkamäki A. , Groop PH , et al: Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. Circulation 94:1276-1282, 1996.

31.

Natali A. , Buzzigoli G. , Taddei et al: Effects of insulin on hemodynamics and metabolism in human forearm . Diabetes 39:490-500, 1990.

32.

Houben Ajhm , Schaper NC , de Haan Cha , et al: The effects of 7-hour local hyperglycaemia on forearm macro- and microcirculatory blood flow and vascular reactivity in healthy man. Diabetologia 37:750-756, 1994.

33.

Tack Cjj , Schefman Aep , Willems JL , et al: Direct vasodilator effects of physiological hyperinsulinaemia in human skeletal muscle. Eur J Clin Invest 26:772-778, 1996.

34.

Scherrer U. , Randin D. , Vollenweider L. , et al: Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest 94:2511-2515, 1994.

35.

Rodrigues-Manas L. , Arribas S. , Giron C. , et al: Interference of glycosylated human hemoglobin with endothelium-dependent responses. Circulation 88 :2111-2116, 1993.