Abstract-Increased endothelin-1-mediated vasoconstrictor tone has been linked to the etiology of a number of pathologies associated with human aging, including hypertension, congestive heart failure, and coronary artery disease. However, it is currently unclear whether aging, per se, is associated with enhanced endothelin-1 system activity. We hypothesized that endothelin-1 vasoconstrictor activity is greater in healthy older compared with young men and that regular aerobic exercise is an effective intervention for reducing endothelin-1 vasoconstrictor tone in older previously sedentary men. Forearm blood flow (plethysmography) responses to intra-arterial infusion of endothelin-1 (5 pmol/min; for 20 minutes) and selective (BQ-123; 100 nmol/min; for 60 minutes) and nonselective (BQ-123ϩBQ-788; 100 nmol/min; for 60 minutes) endothelin-1 receptor blockade were determined in 28 healthy, sedentary men: 13 younger (age: 27Ϯ1 years) and 15 older (age: 62Ϯ2 years). The vasoconstrictor response to endothelin-1 was significantly blunted (Ϸ65%) in the older versus younger men. In response to BQ-123, resting forearm blood flow increased (Ϸ20%; PϽ0.05) in the older but not in the younger men. Key Words: elderly Ⅲ exercise Ⅲ endothelin Ⅲ blood flow regulation M any of the cardiovascular complications associated with aging (eg, hypertension, arterial spasm, and myocardial infarction) are attributable, at least in part, to endothelial dysfunction, particularly vasomotor dysregulation. 1-3 Impaired vasomotor function occurs early in the atherosclerotic process, contributes to disease development and progression, and can trigger acute cardiovascular events. 4 -6 In addition to the synthesis and release of relaxing factors, such as NO, the vascular endothelium also produces contracting factors, the most potent of which is endothelin (ET)-1. Produced by the proteolytic cleavage of big ET-1 by ET converting enzyme, endothelial ET-1 is predominantly (Ͼ80%) released abluminally toward the vascular smooth muscle. 7 Binding of ET-1 to ET A and ET B receptors on vascular smooth muscle cells activates the phospholipase C-inositol triphosphate pathway resulting in an increase in intracellular calcium causing phosphorylation of myosin kinase and, in turn, long-lasting smooth muscle cell contraction. 7,8 Importantly, increased ET-1-mediated vasoconstriction has been linked to the etiology of a number of cardiovascular pathologies, including hypertension, vasospasm, coronary artery disease, and chronic heart failure. 8 -10 There is strong evidence in animal models that aging is associated with elevated ET-1 system activation. 11,12 However, data regarding the influence of aging on ET-1 system activity in adult humans are limited. Kumazaki et al 13 reported that cultured endothelial cells from the aorta of adults over the age of 50 years produce and release more ET-1 compared with cells from younger adults. Some studies have reported age-related increases in circulating levels of ET-1 14,15 ; however, the pathophysiological significance of ...
Objective: Both obesity and the metabolic syndrome (MetS) have been independently linked with increased oxidative and inflammatory stress. This study tested the hypothesis that obesity with MetS is associated with greater oxidative and inflammatory burden compared with obesity alone. Research Methods and Procedures: Forty‐eight normal‐weight and 40 obese (20 without MetS; 20 with MetS) adults were studied. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria. Plasma concentrations of oxidized low‐density lipoprotein, C‐reactive protein, tumor necrosis factor‐α, interleukin (IL)‐6, and IL‐18 were determined by enzyme immunoassay. Results: Plasma biomarkers of oxidative stress and inflammation were lowest in normal‐weight controls. Of note, obese MetS adults demonstrated significantly higher plasma concentrations of oxidized low‐density lipoprotein (62.3 ± 3.2 vs. 54.0 ± 4.0 U/L; p < 0.05), C‐reactive protein (3.0 ± 0.6 vs. 1.5 ± 0.3 mg/L; p < 0.01), tumor necrosis factor‐α (2.1 ± 0.1 vs. 1.6 ± 0.1 pg/mL; p < 0.05), IL‐6 (2.8 ± 0.4 vs. 1.4 ± 0.2 pg/mL; p < 0.01), and IL‐18 (253 ± 16 vs. 199 ± 16 pg/mL; p < 0.01), compared with obese adults without MetS. Discussion: These results suggest that MetS heightens oxidative stress and inflammatory burden in obese adults. Increased oxidative and inflammatory stress may contribute to the greater risk of coronary heart disease and cerebrovascular disease in obese adults with MetS.
Endothelin (ET)-1-mediated vasoconstrictor tone contributes to the development and progression of several adiposity-related conditions, including hypertension and atherosclerotic vascular disease. The aims of the present study were to determine 1) whether endogenous ET-1 vasoconstrictor activity is elevated in overweight and obese adults, and, if so, 2) whether increased ET-1-mediated vasoconstriction contributes to the adiposity-related impairment in endothelium-dependent vasodilation. Seventy-nine adults were studied: 34 normal weight [body mass index (BMI) < 25 kg/m(2)], 22 overweight (BMI ≥ 25 and < 30 kg/m(2)), and 23 obese (BMI ≥ 30 kg/m(2)). Forearm blood flow (FBF) responses to intra-arterial infusion of ET-1 (5 pmol/min for 20 min) and selective ET-1 receptor blockade (BQ-123, 100 nmol/min for 60 min) were determined. In a subset of the study population, FBF responses to ACh (4.0, 8.0, and 16.0 μg·100 ml tissue(-1)·min(-1)) were measured in the absence and presence of selective ET-1 receptor blockade. The vasoconstrictor response to ET-1 was significantly blunted in overweight and obese adults (∼ 70%) compared with normal weight adults. Selective ET-1 receptor blockade elicited a significant vasodilator response (∼ 20%) in overweight and obese adults but did not alter FBF in normal weight adults. Coinfusion of BQ-123 did not affect FBF responses to ACh in normal weight adults but resulted in an ∼ 20% increase (P < 0.05) in ACh-induced vasodilation in overweight and obese adults. These results demonstrate that overweight and obesity are associated with enhanced ET-1-mediated vasoconstriction that contributes to endothelial vasodilator dysfunction and may play a role in the increased prevalence of hypertension with increased adiposity.
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