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 ...

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.

Stauffer BL, Westby CM, Greiner JJ, Van Guilder GP, DeSouza CA. Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults. Am J Physiol Regul Integr Comp Physiol 298: R261-R265, 2010. First published November 25, 2009 doi:10.1152/ajpregu.00626.2009.-The prevalence of cardiovascular disease is lower in middle-aged and older women than men. Increased endothelin-1-mediated vasoconstriction has been linked to the etiology of a number of cardiovascular diseases, including atherosclerosis, heart failure, and hypertension. It is unknown whether a sex difference in endothelin-1-mediated vasoconstrictor tone exists in middle-aged and older adults. Therefore, we tested the hypothesis that middle-aged and older men would demonstrate greater ET-1-mediated vasoconstrictor tone than age-matched women. Forearm blood flow in response to intra-arterial infusions of endothelin (ET)-1, BQ-123 (a selective ET A receptor antagonist), and BQ-788 (a selective ETB receptor antagonist) was assessed by venous occlusion plethysmography in 21 women (age: 58 Ϯ 1 yr; body mass index: 26.0 Ϯ 1.0 kg/m 2 ) and 25 men (age: 57 Ϯ 2 yr; body mass index: 26.8 Ϯ 0.7 kg/m 2 ). In response to BQ-123, the increase in forearm blood flow from baseline was significantly higher in the men than the women (24 Ϯ 5% vs. 9 Ϯ 5%; P Ͻ 0.05). In contrast, the increase in forearm blood flow in response to BQ-123 coinfused with BQ-788 was greater in the women than the men, such that the maximum vasodilation to dual endothelin receptor blockade was similar between men and women (ϳ25%). There was no difference in the vasoconstrictor response to ET-1 between the sexes. These results indicate that middle-aged and older men are under greater ET A receptor-mediated vasoconstrictor tone than age-matched women. Since the ET A receptor is the predominant receptor subtype in the coronary vasculature, this sex difference in vasoconstrictor tone may be a mechanism contributing to the sex difference in the prevalence of coronary heart disease in middle-aged and older adults.endothelin-1; endothelin receptor antagonist; endothelium; vascular function; sex differences ENDOTHELIN-1 (ET-1) IS THE most abundant and important vasoconstrictor molecule released from the vasculature. Produced by the endothelium, ET-1 is predominantly released abluminally to activate ET A and ET B receptors located on the vascular smooth muscle causing smooth muscle contraction, cell proliferation, and hypertrophy (35). ET B receptors on the vascular endothelium produce vasodilation via a nitric oxide mechanism and are also a prominent clearance mechanism for circulating ET-1. ET A receptors are the predominant subtype [10 times greater number than ET B (37)] in the arterial system and the coronary arteries, in particular (30, 31, 34). Because of this disparity in receptor number, the contribution of the ET B receptor to coronary vasoregulation is limited (25). Importantly, ET-1 expression is elevated in atherosclerotic vessels (18,32), and ET-1-mediated vasoconstrict...

One hypothesized contributor to vision changes experienced by >75% of International Space Station astronauts is elevated intracranial pressure (ICP). While no definitive data yet exist, elevated ICP might be secondary to the microgravity‐induced cephalad fluid shift, resulting in venous congestion (overfilling and distension) and inhibition of cerebrospinal and lymphatic fluid drainage from the skull. The objective of this study was to measure internal jugular venous pressure (IJVP) during normo‐ and hypo‐gravity as an index of venous congestion. IJVP was measured noninvasively using compression sonography at rest during end‐expiration in 11 normal, healthy subjects (3 M, 8 F) during normal gravity (1G; supine) and weightlessness (0G; seated) produced by parabolic flight. IJVP also was measured in two subjects during parabolas approximating Lunar (1/6G) and Martian gravity (1/3G). Finally, IJVP was measured during increased intrathoracic pressure produced using controlled Valsalva maneuvers. IJVP was higher in 0G than 1G (23.9 ± 5.6 vs. 9.9 ± 5.1 mmHg, mean ± SD P < 0.001) in all subjects, and IJVP increased as gravity levels decreased in two subjects. Finally, IJVP was greater in 0G than 1G at all expiration pressures (P < 0.01). Taken together, these data suggest that IJVP is elevated during acute exposure to reduced gravity and may be elevated further by conditions that increase intrathoracic pressure, a strong modulator of central venous pressure and IJVP. However, whether elevated IJVP, and perhaps consequent venous congestion, observed during acute microgravity exposure contribute to vision changes during long‐duration spaceflight is yet to be determined.