Endothelin Contributes to Basal Vascular Tone and Endothelial Dysfunction in Human Obesity and Type 2 Diabetes

Endothelin Contributes to Basal Vascular Tone and Endothelial Dysfunction in Human Obesity and Type 2 Diabetes Kieren J. Mather 1 , Bahram Mirzamohammadi 1 , Amale Lteif 1 , Helmut O. Steinberg 1 and Alain D. Baron 1 2 1 Division of Endocrinology & Metabolism, Indiana University-Purdue University Indianapolis School of Medicine, Indianapolis, Indiana 2 Amylin Pharmaceuticals, Indianapolis, Indiana Abstract Endothelium-dependent vasodilation is impaired in clinical states of insulin resistance such as obesity and type 2 diabetes. Individuals who have hyperinsulinemic insulin resistance have relatively elevated circulating levels of endothelin (ET)-1, suggesting that ET-1 may be important in the endothelial dysfunction and alterations of vascular tone in these conditions. In 8 lean subjects, 12 nondiabetic obese subjects, and 8 subjects with type 2 diabetes, we measured basal and methacholine-stimulated rates of leg blood flow (LBF) and total serum nitrates (NOx) before and after the intrafemoral arterial administration of BQ123, a specific blocker of ET A receptors. BQ123 produced significant vasodilation in the obese and type 2 diabetic subjects (leg vascular resistance = mean arterial pressure/LBF fell by 34 and 36%; P < 0.005) but not in the lean subjects (13%; P = NS, P = 0.018 comparing all groups). ET A blockade did not change basal NOx flux (NOx*LBF). This suggests increased basal ET-1 constrictor tone among obese and type 2 diabetic subjects. BQ123 corrected the baseline defect in endothelium-dependent vasodilation seen in obese and type 2 diabetic subjects, suggesting an important contribution of ET-1 to endothelial dysfunction in these subjects. In contrast to basal conditions, stimulated NOx flux was augmented by BQ123 in obese and type 2 diabetic subjects but not in L subjects ( P = 0.04), suggesting a combined effect of ET A blockade to reduce constrictor tone and augment dilator tone. Endothelin seems to contribute to endothelial dysfunction and the regulation of vascular tone in human obesity and type 2 diabetes. Footnotes Address correspondence and reprint requests to Kieren Mather, MD, Division of Endocrinology & Metabolism, Department of Medicine, Indiana University School of Medicine, CL459, 541 North Clinical Dr., Indianapolis, IN 46202. E-mail: kmather{at}iupui.edu . Received for publication 27 November 2001 and accepted in revised form 26 August 2002. ET, endothelin; HOMA-IR, homeostasis model assessment-insulin resistance; LBF, leg bl