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

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 ϳ40% 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 mol/min produced equivalent ϳ35% 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. Diabetes 53: 2060 -2066, 2004 V ascular tone is regulated through the actions of locally produced agents (1). Among the vasoconstrictors, the most potent agent is endothelin, which exerts its vasoconstrictor actions principally through type A endothelin (ET) A receptors (2). Of the vasodilators, nitric oxide (NO) seems to be the most important contributor to the acute regulation of vascular tone (1). Vascular tone in health reflects the balance of these opposing factors (3,4).Endothelial dysfunction in obesity and diabetes is evident clinically as a failure to vasodilate adequately after application of an endothelium-dependent vasodilator, but this may reflect not only impaired NO bioavailability (5-7) but also excess vasoconstrictor tone. Findings from both our laboratory (8) and others (9) suggest that endogenous ET-mediated vasoconstrictor tone is augmented in these insulin-resistant states. It is interesting that ET-1 and NO function in negative feedback loops for each other, each acting to limit the action of the other. These effects are exerted through actions a...

Neuroendocrine mechanisms in insulin resistance

“…Obese subjects also have an impaired sympathetic and blood flow response to insulin in skeletal muscle tissue (29) as well as a diminished capillary recruitment (83). Endothelial dysfunction in obesity is partly due to diminished NO-availability (84), which may explain the reduced vasodilatory response not only to insulin but also to stress. A transient impaired endothelial function has also been reported after acute stress in healthy subjects (85).…”

Sympathetic Vascular Tone in Human Obesity

“…potentiates the vasoconstrictor effect of inhibition of nitric oxide synthase in obese subjects but not in normal control or type 2 diabetics [Mather et al, 2004]. The tonic activation of ET A receptor inhibits basal synthesis of nitric oxide.…”

Blood pressure response to type A endothelin receptor antagonism in human obesity and diabetes mellitus

“…Obese and DM2 groups were otherwise matched for BMI, circulating free fatty acids, endothelin, insulin and lipids. 1,4 In lean subjects, SBP fell by 3.371.8 and 5.171.4 mm Hg at low and high doses (P ¼ 0.010 and P ¼ 0.004, respectively; Figure 1). A similar pattern was seen in obese subjects, (reductions of 1.1071.3 and 5.371.4 mm Hg, P ¼ 0.4 and P ¼ 0.002, respectively) and diabetic subjects, (reduction of 5.172.2 and 10.672.0 mm Hg, P ¼ 0.057 and P ¼ 0.001, respectively).…”

“…In previous reports from our laboratory, 1,4 we noted an effect of femoral arterial infusions of BQ123 on mean arterial pressure, and the observed leg blood flow data were adjusted for these changes and presented as leg vascular resistance. We have not previously presented the blood pressure data from these studies, and here we present these data in detail, including separate evaluations of systolic, diastolic and pulse pressure changes.…”

“…1,4 In brief, following an overnight fast, the femoral vein and artery were cannulated allowing measurement of leg blood flow by thermodilution and direct intra-arterial measurement of blood pressure. Baseline measurements were obtained following X30 min of rest after the insertion of the catheters.…”