Endothelin-1 vasoconstriction and the age-related decline in endothelium-dependent vasodilatation in men

2011 ◽  
Vol 120 (11) ◽  
pp. 485-491 ◽  
Author(s):  
Christian M. Westby ◽  
Brian R. Weil ◽  
Jared J. Greiner ◽  
Brian L. Stauffer ◽  
Christopher A. Desouza
Keyword(s):  
Young Men ◽  
Older Men ◽  
Endothelin 1 ◽  
Age Related ◽  
Eta Receptor ◽  
Vasomotor Regulation ◽  
Artery Disease ◽  
Potent Vasoconstrictor ◽  
Vasoconstrictor Peptide

ET (endothelin)-1, a potent vasoconstrictor peptide released by the endothelium, plays an important role in vasomotor regulation and has been linked to diminished endothelial vasodilator capacity in several pathologies associated with human aging, including hypertension, Type 2 diabetes and coronary artery disease. However, it is currently unknown whether the decline in endothelial vasodilatation with advancing age is due to elevated ET-1 vasconstrictor activity. Accordingly, we tested the hypothesis that the age-related impairment in ACh (acetylcholine)-mediated endothelium-dependent vasodilatation is due, at least in part, to increased ET-1-mediated vasoconstrictor tone. FBF (forearm blood flow) responses to ACh, SNP (sodium nitroprusside) and BQ-123 (ETA receptor blocker) were determined in 14 young (age, 25±1 years) and 14 older (age, 61±2 years) healthy non-obese men. Additionally, FBF responses to ACh were determined in the presence of ETA blockade. Vasodilatation to ACh was lower (approx. 25%; P<0.05) in the older men (from 4.9±0.2 to 13.9±0.9 ml·100 ml−1 of tissue·min−1) compared with the young men (4.6±0.3 to 17.2±1.0 ml·100 ml−1 of tissue·min−1). There were no differences in FBF responses to SNP between the young (4.8±0.3 to 18.5±0.3 ml·100 ml−1 of tissue·min−1) and older (5.1±0.3 to 17.3±0.8 ml·100 ml−1 of tissue·min−1) men. In the young men, resting FBF was not significantly altered by BQ-123, whereas, in the older men, FBF increased approx. 25% in response to BQ-123 infusion (P<0.05). Co-infusion of ACh with BQ-123 resulted in an approx. 20% increase in the ACh-induced vasodilatation in older men compared with saline. In contrast, FBF responses to ACh were not significantly altered by ETA blockade in the young men. In conclusion, these results demonstrate that ET-1 vasoconstrictor activity contributes, at least in part, to diminished endothelium-dependent vasodilatation in older men.

scholarly journals Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status

2009 ◽  
Vol 296 (5) ◽  
pp. E1042-E1048 ◽  
Author(s):  
John Andree Babraj ◽  
Kristy Mustard ◽  
Calum Sutherland ◽  
Mhari C. Towler ◽  
Shaui Chen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Young Men ◽  
Older Men ◽  
Age Related ◽  
Skeletal Muscle Glucose Uptake ◽  
Ampk Activity ◽  
Young Subjects ◽  
Extracellular Regulated Kinase ◽  
Amp Activated Protein Kinase

We demonstrated previously that, in healthy young men, 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) stimulates human muscle 2-deoxyglucose (2DG) uptake without detectable activation of muscle AMP-activated protein kinase (AMPK) but with extracellular-regulated kinase 1/2 (ERK1/2) activation. We tested whether AICAR stimulates muscle 2DG uptake in healthy older patients with or without type 2 diabetes (T2D). Six healthy young subjects (23 ± 3 yr, BMI 25 ± 2 kg/m−2; means ± SE), eight older subjects (59 ± 4 yr, BMI 28 ± 2 kg/m−2), and eight subjects with T2D (62 ± 4 yr, BMI 27 ± 2 kg/m−2) received a 6-h 2DG infusion (prime 10 mg/kg, 6 mg·kg−1·h−1) and AICAR (10 or 20 mg·kg−1·h−1) from 3 to 6 h. Quadriceps biopsies were taken at 0, 3, and 6 h. We determined 1) 2DG uptake, 2) total AMPKα activity, AMPK, acetyl-CoA carboxylase (ACC), and AS160 phosphorylation, and 3) ERK1/2 phosphorylation. Ten milligrams per kilogram per hour AICAR increased 2DG uptake by 2.9 ± 0.7-fold in young men ( P < 0.001), 1.8 ± 0.2-fold in older men ( P < 0.01), and 1.6 ± 0.1-fold in men with T2D; 20 mg·kg−1·h−1 AICAR increases were 2.5 ± 0.1-fold (older men, P < 0.001) and 2.2 ± 0.2-fold (men with T2D, P < 0.001). At 3-h AMPK activity and AMPK, ACC and AS160 phosphorylation were unchanged, but ERK1/2 phosphorylation increased at both AICAR doses. The fold changes of ERK1/2 phosphorylation and 2DG uptake closely correlated ( R2 = 0.55, P = 0.003). AICAR stimulates muscle 2DG uptake in T2D to the same extent as in healthy age-matched controls, but there is an age-related reduction.

Does endoplasmic reticulum stress mediate endothelin-1-induced renal inflammation?

2013 ◽  
Vol 305 (2) ◽  
pp. R107-R109 ◽  
Author(s):  
Carmen De Miguel ◽  
Jennifer S. Pollock
Keyword(s):  
Endoplasmic Reticulum ◽  
Thick Ascending Limb ◽  
Afferent Arteriole ◽  
Renal Vasculature ◽  
Renal Inflammation ◽  
Endothelin 1 ◽  
Collecting Ducts ◽  
Potent Vasoconstrictor ◽  
Eventual Death ◽  
Vasoconstrictor Peptide

Endothelin-1 (ET-1) is the most potent vasoconstrictor peptide known. It exerts its actions through two pharmacologically different receptors: ETA and ETB receptors. In the renal vasculature, there is a majority of ETB receptors in the efferent arteriole, whereas a greater amount of ETA receptors are located in the afferent arteriole. The nephron is rich in ETB receptors, especially in the thick ascending limb and collecting ducts, while containing a smaller amount of ETA receptors. High levels of circulating or renal ET-1 have been described in cardiovascular diseases such as hypertension or diabetes, diseases also associated to renal inflammation. Despite extensive evidence associating high levels of ET-1 to increased renal inflammation, the molecular mechanism(s) by which ET-1 leads to renal immune infiltration and/or immune activation remains unknown. In this minireview, we propose that the ET-1/ETA pathway mediates an increase in renal endoplasmic reticulum (ER) stress, initially a survival mechanism that if prolonged, leads to the eventual death of the cell via apoptosis.

scholarly journals CONVERGENT AGING LOCI: PATHWAYS THAT TRANSCEND INDIVIDUAL DISEASES

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S221-S221
Author(s):  
Luke C Pilling ◽  
Luigi Ferrucci ◽  
David Melzer
Keyword(s):  
Disease Risk ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Telomere Shortening ◽  
Chronic Disease Risk ◽  
Trade Offs ◽  
Age Related ◽  
Genome Wide ◽  
Artery Disease

Abstract Thousands of loci across the genome have been identified for specific diseases in genome-wide association studies (GWAS), yet very few are associated with lifespan itself. We hypothesized that specific biological pathways transcend individual diseases and affect health and lifespan more broadly. Using the published results for the most recent GWAS for 10 key age-related diseases (including coronary artery disease, type-2 diabetes, and several cancers) we identified 22 loci with a strong genetic association with at least three of the diseases. These multi-trait aging loci include known genes affecting multiple diverse health end points, such as CDKN2A/B (9p21.3) and APOE. There are also novel multi-trait genes including SH2B3 and CASC8, likely involved in hallmark pathways of aging biology, including telomere shortening and inflammation. Several of these loci involve trade-offs between chronic disease risk and cancer.

scholarly journals Differences in the Apparent Metabolic Clearance Rate of Testosterone in Young and Older Men with Gonadotropin Suppression Receiving Graded Doses of Testosterone

2006 ◽  
Vol 91 (11) ◽  
pp. 4669-4675 ◽  
Author(s):  
Andrea D. Coviello ◽  
Kishore Lakshman ◽  
Norman A. Mazer ◽  
Shalender Bhasin
Keyword(s):  
Lean Body Mass ◽  
Body Mass ◽  
Young Men ◽  
Serum Testosterone ◽  
Older Men ◽  
Total Testosterone ◽  
Metabolic Clearance ◽  
Clearance Rates ◽  
Testosterone Levels ◽  
Age Related

Abstract Background: Recently we found that testosterone levels are higher in older men than young men receiving exogenous testosterone. We hypothesized that older men have lower apparent testosterone metabolic clearance rates (aMCR-T) that contribute to higher testosterone levels. Objective: The objective of the study was to compare aMCR-T in older and young men and identify predictors of aMCR-T. Methods: Sixty-one younger (19–35 yr) and 60 older (59–75 yr) men were given a monthly GnRH agonist and weekly testosterone enanthate (TE) (25, 50, 125, 300, or 600 mg) for 5 months. Estimated aMCR-T was calculated from the amount of TE delivered weekly and trough serum testosterone concentrations, corrected for real-time absorption kinetics from the im testosterone depot. Results: Older men had lower total (316 ± 13 vs. 585 ± 26 ng/dl, P &lt; 0.00001) and free testosterone (4 ± 0.1 vs. 6 ± 0.3 ng/dl, P &lt; 0.00001) and higher SHBG (52 ± 3 vs. 33 ± 2 nmol/liter, P &lt; 0.00001) than younger men at baseline. Total and free testosterones increased with TE dose and were higher in older men than young men in the 125-, 300-, and 600-mg dose groups. aMCR-T was lower in older men than young men (1390 ± 69 vs. 1821 ± 102 liter/d, P = 0.006). aMCR-T correlated negatively with age (P = 0.0007), SHBG (P = 0.046), and total testosterone during treatment (P = 0.02) and percent body fat at baseline (P = 0.01) and during treatment (P = 0.004). aMCR-T correlated positively with lean body mass at baseline (P = 0.03) and during treatment (P = 0.01). In multiple regression models, significant predictors of aMCR-T included lean body mass (P = 0.008), percent fat mass (P = 0.009), and SHBG (P = 0.001). Conclusions: Higher testosterone levels in older men receiving TE were associated with an age-related decrease in apparent testosterone metabolic clearance rates. Body composition and SHBG were significant predictors of aMCR-T.

Interaction among ET-1, endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins

1994 ◽  
Vol 267 (1) ◽  
pp. H139-H147 ◽  
Author(s):  
T. M. Zellers ◽  
J. McCormick ◽  
Y. Wu
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Potent Vasoconstrictor ◽  
Eta Receptor Antagonist ◽  
Arteries And Veins

Endothelin-1 causes vasodilation of the intact porcine pulmonary vascular bed. To determine the cause of this vasodilation, we investigated the interactions of endothelin-1 (ET-1), endothelium-derived nitric oxide (EDNO), and prostacyclin in isolated small porcine pulmonary arteries and veins under in vitro conditions. ET-1 caused concentration-dependent contractions in arteries and veins, augmented by the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine, in pulmonary veins. BQ-123 (ETA-receptor antagonist) depressed the ET-1-induced contractions. Sarafotoxin S6C, an ETB-receptor agonist, caused contractions of pulmonary veins only. Endothelium-dependent relaxations to bradykinin and ET-1 were greater in pulmonary veins compared with arteries, inhibited by N omega-nitro-L-arginine, and reversed by L-arginine. BQ-123 augmented ET-1-induced arterial relaxation. ET-3 and sarafotoxin S6C, ETB-receptor agonists, caused comparable endothelium-dependent relaxations in arteries and veins. ET-1 caused a fourfold greater increase in prostacyclin release in pulmonary veins compared with arteries. We conclude that ET-1 is a potent vasoconstrictor of porcine pulmonary vessels and stimulates the release of EDNO and prostacyclin, which oppose the contractions to the peptide. The release of these endothelium-derived vasodilators appears greater in pulmonary veins.

Age-related resistance to skeletal muscle fatigue is preserved during ischemia

2007 ◽  
Vol 103 (5) ◽  
pp. 1628-1635 ◽  
Author(s):  
Linda H. Chung ◽  
Damien M. Callahan ◽  
Jane A. Kent-Braun
Keyword(s):  
Skeletal Muscle ◽  
Fatigue Resistance ◽  
Oxidative Metabolism ◽  
Ischemia Reperfusion ◽  
Age Groups ◽  
Young Men ◽  
The Elderly ◽  
Older Men ◽  
Contractile Properties ◽  
Age Related

During voluntary contractions, the skeletal muscle of healthy older adults often fatigues less than that of young adults, a result that has been explained by relatively greater reliance on muscle oxidative metabolism in the elderly. Our aim was to investigate whether this age-related fatigue resistance was eliminated when oxidative metabolism was minimized via ischemia induced by cuff (220 mmHg). We hypothesized that 1) older men ( n = 12) would fatigue less than young men ( n = 12) during free-flow (FF) contractions; 2) both groups would fatigue similarly during ischemia; and 3) reperfusion would reestablish the fatigue resistance of the old. Subjects performed 6 min of intermittent, maximal voluntary isometric contractions of the ankle dorsiflexors under FF and ischemia-reperfusion (IR) conditions. Ischemia was maintained for the first 3 min of contractions, followed by rapid cuff deflation and reperfusion for 3 additional minutes of contractions. Central activation, peripheral activation, and muscle contractile properties were measured at 3 and 6 min of contractions. Older men fatigued less than young men during FF ( P ≤ 0.02), ischemia ( P < 0.001), and reperfusion ( P < 0.001). During FF, activation and contractile properties changed similarly across age groups. At the end of ischemia, central ( P = 0.02) and peripheral ( P ≤ 0.03) activation declined more in the young, with no effect of age on the changes in contractile properties. Thus age-related fatigue resistance was evident during FF and IR, indicating that differences in blood flow and oxidative metabolism do not explain the fatigue resistance of old age.

scholarly journals “Endothelial Protector Drugs” and Diabetes: Is there a Role for these Drugs?

2015 ◽  
pp. 1-3 ◽  
Author(s):  
Marco Bertini
Keyword(s):  
Endothelial Dysfunction ◽  
Diabetic Animal ◽  
Diabetic Patients ◽  
Diabetic Vasculopathy ◽  
Potent Vasoconstrictor ◽  
Vasoconstrictor Peptide ◽  
Circulating Levels ◽  
Local Levels

Diabetic vasculopathy, including macro and micro vascular disorders, is the leading cause of morbidity and mortality in patients with type 1 (T1) and type 2 (T2) diabetes mellitus (DM) [1]. A lot of researches pointed out that endothelial dysfunction, characterized by an imbalance between Endothelium-Derived Relaxing Factors (EDRFs) and endothelium-derived contracting factors (EDCFs) play a central role on the development and progression of diabetic vasculopathy [2-5]. Endothelial dysfunction and inflammation, as indicated by abnormal flow-dependent vasodilatation and by increased circulating levels of adhesion molecules (ICAM-1 and E-selectin) are known to occur in T2DM and seems to be an important predictor in systemic atherogenesis [6]. Both hyperglycemia and insulin administration increasing circulating levels of endothelin-1 (ET-1), an endothelial cell (EC)-derived potent vasoconstrictor peptide with mitogenic, pro-oxidative and pro-inflammatory properties that have shown to be extremely relevant to the pathophysiology of diabetic vasculopathy [7-10]. Circulating and local levels of ET-1 are increased in diabetic animal models and diabetic patients [1,11,12].

Age-Related Differences in Muscle Power during Single-Step Balance Recovery

2006 ◽  
Vol 22 (3) ◽  
pp. 186-193 ◽  
Author(s):  
Michael L. Madigan
Keyword(s):  
Muscle Function ◽  
Peak Power ◽  
Muscle Power ◽  
Young Men ◽  
Older Men ◽  
Single Step ◽  
Joint Torque ◽  
Balance Recovery ◽  
Age Related ◽  
The Right

The purpose of this study was to investigate agerelated differences in muscle power during a surrogate task of trip recovery. Participants included 10 healthy young men (19–23 years old) and 10 healthy older men (65–83). The task involved releasing participants from a forward-leaning posture. After release, participants attempted to recover their balance using a single step of the right foot. Muscle power at the hip, knee, and ankle of the stepping limb were determined from the product of joint angular velocity and joint torque. Muscle powers during balance recovery followed a relatively consistent pattern in both young and older men, and showed effects of both lean and age. Interestingly, the effects of age did not always involve smaller peak power values in the older men as expected from the well-documented loss of muscle power with aging. Older men exhibited smaller peak muscle power at the knee and larger peak muscle power at the ankle and hip compared to young men. The increases in muscle power at the ankle and hip may result from a neuromuscular adaptation aimed at improving balance recovery ability by compensating for the age-related loss of muscle function.

Velocity dependence of eccentric strength in young and old men: the need for speed!

2015 ◽  
Vol 40 (7) ◽  
pp. 703-710 ◽  
Author(s):  
Geoffrey A. Power ◽  
Demetri P. Makrakos ◽  
Daniel E. Stevens ◽  
Charles L. Rice ◽  
Anthony A. Vandervoort
Keyword(s):  
Large Range ◽  
Young Men ◽  
Older Men ◽  
Isometric Strength ◽  
Voluntary Activation ◽  
Velocity Dependence ◽  
Younger Adults ◽  
Age Related ◽  
Angular Velocities ◽  
Old Men

Older adults better maintain eccentric strength relative to isometric strength, as indicated by a higher ratio of eccentric:isometric torque as compared with younger adults. The effect of increasing angular velocities (>200°/s) on the age-related maintenance of eccentric strength has not been tested and thus it is unknown whether the eccentric:isometric ratio is velocity dependent in old age. The purpose of this study was to investigate eccentric strength of the ankle dorsiflexors over a large range of lengthening angular velocities in young and older men. Isometric neuromuscular properties were assessed on a HUMAC NORM dynamometer. Nine young (∼24 years) and 9 older (∼76 years) healthy men performed maximal voluntary eccentric contractions at angular velocities of 15–360°/s. Despite near full voluntary activation (>95%), the older men were ∼30% weaker than the young men for isometric strength (P < 0.05). Across all lengthening velocities, older men had a greater eccentric:isometric ratio than young men (P < 0.05). Additionally, there was a velocity dependence of strength in both young and older men: eccentric strength increased as velocity increased up to 120°/s (P < 0.05) and plateaued thereafter. In young and older men, eccentric strength at 15°/s was ∼20% and ∼40% greater than isometric strength (P < 0.05), while at 360°/s eccentric strength was ∼50% and ∼90% greater, respectively (P < 0.05). These findings indicate that with increasing angular velocity, both young and older men have considerable increases in the eccentric:isometric ratio of torque production.

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