Role of endogenous ET-1 in the regulation of myocardial blood flow in lean and obese humans.

Endothelin is an important determinant of peripheral vascular tone, and increased endogenous endothelin activity contributes to peripheral vascular dysfunction in human obesity. The contributions of endothelin to the regulation of coronary vascular tone in health in humans have not been well studied. We hypothesized that the contribution of endothelin to the regulation of myocardial perfusion would be augmented in human obesity. Using [NH(3)]ammonia positron emission tomography (PET), we measured myocardial perfusion under resting and adenosine-stimulated conditions on two separate days, with and without concurrent exposure to BQ123, an antagonist of type A endothelin receptors (1 micromol/min IV beginning 90 min before measurement). We studied 10 lean and 9 obese subjects without hypertension, hyperlipidemia, or diabetes mellitus. We observed a BQ123-induced increase in resting myocardial perfusion of approximately 40%, not different between lean and obese subjects (BQ123-induced increase in flow: lean 0.12 +/- 0.20, obese 0.32 +/- 0.51 ml/g/min, P = 0.02 BQ123 effect, P = 0.27 comparing response across groups). Although basal flow rates varied by region of the myocardium, the BQ123 effect was seen in all regions. BMI and cholesterol were significantly related to BQ123-induced increases in basal tone in multivariable analysis. There was no baseline difference in the adenosine-stimulated increase in blood flow between lean and obese subjects, and BQ123 failed to augment these responses in either group. These observations suggest that endothelin is an important contributor to the regulation of myocardial perfusion under resting conditions in healthy lean and obese humans, with increased contributions in proportion to increasing obesity.

Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans.

Endogenous endothelin action is augmented in human obesity and type 2 diabetes and contributes to endothelial dysfunction and impairs insulin-mediated vasodilation in humans. We hypothesized that insulin resistance-associated hyperinsulinemia could preferentially drive endothelin-mediated vasoconstriction. We applied hyperinsulinemic-euglycemic clamps with higher insulin dosing in obese subjects than lean subjects (30 vs. 10 mU.m(-2).min(-1), respectively), with the goal of matching insulin's nitric oxide (NO)-mediated vascular effects. We predicted that, under these circumstances, insulin-stimulated endothelin-1 (ET-1) action (assessed with the type A endothelin receptor antagonist BQ-123) would be augmented in proportion to hyperinsulinemia. NO bioactivity was assessed using the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine. Insulin-mediated vasodilation and insulin-stimulated NO bioavailability were well matched across groups by this approach. As expected, steady-state insulin levels were approximately threefold higher in obese than lean subjects (109.2 +/- 10.2 pmol/l vs. 518.4 +/- 84.0, P = 0.03). Despite this, the augmentation of insulin-mediated vasodilation by BQ-123 was not different between groups. ET-1 flux across the leg was not augmented by insulin alone but was increased with the addition of BQ-123 to insulin (P = 0.01 BQ-123 effect, P = not significant comparing groups). Endothelin antagonism augmented insulin-stimulated NO bioavailability and NOx flux, but not differently between groups and not proportional to hyperinsulinemia. These findings do not support the hypothesis that insulin resistance-associated hyperinsulinemia preferentially drives endothelin-mediated vasoconstriction.

Endothelin contributes differently to peripheral vascular tone and blood pressure in human obesity and diabetes.

Endothelin contributes to abnormalities in peripheral blood vessel function of subjects with obesity, with or without concurrent type 2 diabetes mellitus, but it is unknown if endothelin contributes specifically to obesity and diabetes-associated changes in blood pressure. We evaluated the effect of systemic endothelin antagonism on peripheral and central hemodynamics and peripheral vascular tone in lean, obese, and type 2 diabetic subjects without overt hypertension by cuff plethysmography. We measured the effects of acute systemic infusions of BQ123 (an antagonist of type A endothelin receptors) in seven lean (body mass index [BMI] 22.7 +/- 3.2 kg/m(2)), seven obese (BMI 35.8 +/- 4.6), and six diabetic subjects (BMI 38.2 +/- 5.0, glycosylated hemoglobin 8.1 +/- 2.2%). BQ123 was infused via antecubital vein sequentially at infusion rates from 0.1 to 1.0 mumol/min. Diastolic blood pressure was significantly lower than baseline across this dose range, but without a clear dose dependence and without differences in the dose response across groups. Obese and diabetic subjects exhibited progressive dilation of peripheral blood vessels (P

Diabetes and heart disease an evidence-driven guide to risk factors management in diabetes.

Type 2 diabetes is a worldwide epidemic. Cardiovascular diseases remain the major cause of death in patients with diabetes, partly because of the association of diabetes and the metabolic syndrome. In this review, we will discuss the evidence for treatment and prevention of cardiovascular diseases in patients with diabetes. Aggressive treatment of hypertension and dyslipidemia is at the cornerstone in the management of heart disease in those patients. Despite its known benefit on the prevention of the microvascular complications of diabetes, intensive glycemic control may or may not have a significant effect on reducing macrovascular diseases. Finally, lifestyle changes and other cardiovascular therapies aimed at preventing heart disease may also prevent or delay the development of diabetes.