Details

Autor(en) / Beteiligte

• MATHER, Kieren J
• LTEIF, Amale
• STEINBERG, Helmut O
• BARON, Alain D

Titel

Interactions Between Endothelin and Nitric Oxide in the Regulation of Vascular Tone in Obesity and Diabetes

Ist Teil von

• Diabetes (New York, N.Y.), 2004-08, Vol.53 (8), p.2060-2066

Ort / Verlag

Alexandria, VA: American Diabetes Association

Erscheinungsjahr

2004

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Interactions Between Endothelin and Nitric Oxide in the Regulation of Vascular Tone in Obesity and Diabetes Kieren J. Mather 1 , Amale Lteif 1 , Helmut O. Steinberg 1 and Alain D. Baron 1 2 1 Division of Endocrinology & Metabolism, Indiana University School of Medicine, Indianapolis, Indiana 2 Amylin Pharmaceuticals, San Diego, California Address correspondence and reprint requests to Kieren J. Mather, MD, FRCPC, 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 Abstract Endothelial dysfunction reflects an imbalance of vasodilators and vasoconstrictors. Endogenous endothelin activity seems to be increased in human obesity and type 2 diabetes, and cellular studies suggest that this factor may itself reduce bioavailable nitric oxide (NO). We studied 20 lean, 20 obese, and 14 type 2 diabetic individuals under three protocols, measuring leg vascular responses to intra-arterial infusions of N G -monomethyl- l -arginine ( l -NMMA; an inhibitor of NO synthase) alone or in combination with BQ123 (an antagonist of type A endothelin receptors) or phentolamine (used as a control vasodilator). NO synthase inhibition alone (study 1) produced an ∼40% increase in leg vascular resistance (LVR) in all three participant groups, which was not statistically different across groups (increase in LVR: lean, 135 ± 28; obese, 140 ± 32; type 2 diabetic, 184 ± 51 units; NS). By design, BQ123 at the infused rate of 3 μmol/min produced equivalent ∼35% reductions in LVR across groups. The subsequent addition of l -NMMA produced a greater increase in LVR among obese participants than lean or type 2 diabetic participants (study 2: lean, 182 ± 48; obese, 311 ± 66; type 2 diabetic, 186 ± 40; P = 0.07). Compared with study 1, the effect of l -NMMA was magnified by BQ123 in obese participants but not in lean or type 2 diabetic participants ( P = 0.005, study 1 vs. 2; P = 0.03 for group effect). Phentolamine (75 mg/min) produced vasodilation in obese participants comparable to that seen with BQ123 but failed to augment the l -NMMA response. Endothelin antagonism unmasks or augments NO synthesis capacity in obese but not type 2 diabetic participants. This suggests that impaired NO bioavailability as a result of endogenous endothelin may contribute to endothelial dysfunction in obesity, in addition to direct vasoconstrictor effects of endothelin. In contrast, endothelin antagonism alone is insufficient to restore impaired NO bioavailability in diabetes. ET, endothelin LBF, leg blood flow l-NMMA, NG-monomethyl-l-arginine LVR, leg vascular resistance NOS, nitric oxide synthase Footnotes Accepted May 4, 2004. Received January 26, 2004. DIABETES