(Circulation. 2000;102:1351.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Regular Aerobic Exercise Prevents and Restores Age-Related Declines in Endothelium-Dependent Vasodilation in Healthy Men
From the Human Cardiovascular Research Laboratory, Center for Physical Activity, Disease Prevention, and Aging, Department of Kinesiology and Applied Physiology, University of Colorado, Boulder (C.A.D., L.F.S., C.M.C., F.A.D., K.D.M., H.T., D.R.S.); and the Department of Medicine, Divisions of Cardiology and Geriatric Medicine, University of Colorado, Health Sciences Center, Denver (D.R.S.).
Correspondence to Christopher DeSouza, PhD, Department of Kinesiology and Applied Physiology, University of Colorado, Campus Box 354, Boulder, CO 80309. E-mail desouzac{at}stripe.colorado.edu
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Abstract |
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Background—In sedentary humans endothelium-dependent vasodilation is impaired with advancing age contributing to their increased cardiovascular risk, whereas endurance-trained adults demonstrate lower age-related risk. We determined the influence of regular aerobic exercise on the age-related decline in endothelium-dependent vasodilation.
Methods and Results—In a cross-sectional study, 68 healthy men 22
to 35 or 50 to 76 years of age who were either sedentary or endurance
exercise–trained were studied. Forearm blood flow (FBF) responses to
intra-arterial infusions of acetylcholine and sodium
nitroprusside were measured by strain-gauge plethysmography. Among the
sedentary men, the maximum FBF response to acetylcholine was 25% lower
in the middle aged and older compared with the young group
(P<0.01). In contrast, there was no age-related
difference in the vasodilatory response to acetylcholine among the
endurance-trained men. FBF at the highest acetylcholine dose was almost
identical in the middle aged and older (17.3±1.3 mL/100 mL tissue per
minute) and young (17.7±1.4 mL/100 mL tissue per minute)
endurance-trained groups. There were no differences in the FBF
responses to sodium nitroprusside among the sedentary and endurance-
trained groups. In an exercise intervention study, 13 previously
sedentary middle aged and older healthy men completed a 3-month,
home-based aerobic exercise intervention (primarily walking). After the
exercise intervention, acetylcholine-mediated vasodilation increased
30% (P<0.01) to levels similar to those in young
adults and middle aged and older endurance-trained men.
Conclusions—Our results indicate that regular aerobic exercise can prevent the age-associated loss in endothelium-dependent vasodilation and restore levels in previously sedentary middle aged and older healthy men. This may represent an important mechanism by which regular aerobic exercise lowers the risk of cardiovascular disease in this population.
Key Words: exercise • endothelium • vasodilation • nitric oxide • blood flow
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Introduction |
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The vascular endothelium plays an important role in the regulation of vascular tone and the maintenance of cardiovascular homeostasis.1 2 Importantly, endothelial dysfunction, particularly impaired endothelium-dependent vasodilation, has been linked to the pathogenesis of atherosclerotic vascular disease and acute cardiovascular events.3 Indeed, reduced endothelial vasodilatory function occurs early in atherogenesis before histological and angiographic evidence of atherosclerosis.4 5 6 In addition, impaired endothelium-dependent vasodilation is a common characteristic of several atherosclerosis risk factors including diabetes,7 hypertension,8 dyslipidemia,9 and aging.10 11
In humans, advancing age is associated with a progressive impairment in endothelium-dependent vasodilation.10 11 Age-related reductions in endothelium-dependent vasodilation have been observed in both the brachial10 11 and coronary arteries.12 The progressive loss in endothelial vasodilatory function is thought to contribute to the increased risk of atherosclerosis and thrombosis with adult aging.10 13
Regular aerobic exercise is associated with a reduced risk of atherosclerotic vascular disease and acute cardiovascular events, particularly in middle-aged and older adults.14 15 In addition to favorably modifying traditional risk factors such as blood pressure, a novel mechanism by which regular exercise may confer this protection is through improved vascular endothelial function.16 Indeed, recent evidence suggests that regular aerobic exercise is an effective intervention strategy for improving endothelium-dependent vasodilation in disease states such as chronic heart failure and hypertension.17 18 However, whether regular exercise can prevent the age-related loss in endothelial vasodilator function and/or restore lost function in previously sedentary middle aged and older adults is unknown.
Accordingly, the aims of the present investigation were to determine (1) whether the decline in endothelium-dependent vasodilation observed with sedentary aging is absent in men who regularly perform aerobic-endurance exercise and (2) if a program of aerobic exercise training improves endothelium-dependent vasodilation in previously sedentary middle aged and older men. We hypothesized that the normal decline in endothelium-dependent vasodilation with age would not occur in habitually endurance-trained men and that regular aerobic exercise would restore the age-associated loss of endothelium-dependent vasodilation in previously sedentary middle aged and older men.
To systematically address these aims, we used 2 experimental approaches. First, we used a cross-sectional model to examine the influence of habitual aerobic exercise on the age-associated reduction in endothelium-dependent vasodilation. We then performed an intervention study to determine the effects of aerobic exercise training on endothelium-dependent vasodilation in sedentary middle aged and older men.
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Methods |
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Subjects
Cross-Sectional Study
We studied 68 healthy men 22 to 35 or 50 to 76 years of age: 12 young and 24 middle aged and older sedentary men and 12 young and 20 middle aged and older endurance-trained (runners) men. The endurance-trained subjects were matched for age-adjusted running performance as described previously by our laboratory19 and had been running for 7±2 and 20±2 years, respectively. The endurance-trained men were recruited from various running clubs throughout the Boulder area and from participants in the Bolder Boulder, the second largest 10-km road race in the United States. The sedentary subjects were recruited through various forms of advertisement and had not participated in a regular aerobic exercise program for
2 years before the start of the study. All subjects were
free of overt disease as assessed by medical history and fasting blood
chemistries. Subjects were excluded from the study if they
presented a history or evidence of hepatic, renal, or
hematological disease; peripheral vascular disease; stroke;
diabetes (fasting plasma glucose >7.0 mmol/L)20 ;
dyslipoproteinemia (cholesterol 6.2 mmol/L,
triglycerides 4.5 mmol/L)21 ;
hypertension (blood pressure 140/90 mm Hg)22 ; or
body mass index (BMI) >35 kg/m2. The middle aged
and older sedentary and endurance-trained men were further evaluated
for clinical evidence of cardiovascular disease with a
focused physical examination and resting and maximal exercise ECGs and
blood pressure. No subjects were taking medication, and all subjects
were nonsmokers. Before participation, all of the subjects had the
research study and its potential risks and benefits explained fully
before providing written informed consent according to the guidelines
of the University of Colorado at Boulder.
Intervention Study
Thirteen of the 24 middle aged and older sedentary men who
participated in the cross-sectional study went on to complete a 3-month
aerobic exercise training program. All baseline measures were
subsequently repeated in these subjects after the exercise
intervention.
Measurements
Endurance-trained subjects and subjects who completed the
3-month exercise intervention were studied 20 to 24 hours after their
last exercise training session to avoid the immediate (acute) effects
of exercise while still representing their normal
physiological state (ie, habitually
exercising).
Body Composition
Body mass was measured to the nearest 0.1 kg with a medical beam
balance (Detecto). Percentage of body fat was determined by dual-energy
x-ray absorptiometry (DXA, model DPX-IQ, Lunar Radiation
Corp).23 BMI was calculated as weight (kilograms) divided
by height (meters) squared. Minimal waist circumference was measured
according to previously published guidelines.24
Treadmill Exercise Test
For assessment of aerobic fitness, subjects performed
incremental treadmill exercise with a modified Balke protocol as
previously described.19 Maximal oxygen consumption
(
O2max) was measured with
on-line, computer-assisted, open-circuit spirometry. In addition, heart
rate and rating of perceived exertion (RPE)25 were
measured throughout exercise, and total exercise time to exhaustion was
recorded.
Metabolic Measurements
Fasting plasma lipid and lipoprotein, glucose, and insulin
concentrations were determined with conventional methods by the
clinical laboratory affiliated with the General Clinical Research
Center as previously described.26
Plasma Homocysteine
Fasting plasma concentrations of homocysteine were measured in
duplicate with a commercially available enzyme immunoassay
(Bio-Rad).27
Arterial Catheterization
Under strict aseptic conditions, a 5-cm, 20-gauge catheter was
inserted into the brachial artery of the nondominant arm under local
anesthesia (2% lidocaine). The catheter was connected to a
pressure transducer and continuously flushed at 3 mL/h with heparinized
saline (2 U/mL). Heart rate and arterial pressure were
continuously measured throughout. Mean arterial pressure
(MAP) was calculated as one-third pulse pressure plus
diastolic pressure.
Forearm Blood Flow
Forearm blood flow (FBF) was measured in both the experimental
(nondominant) and contralateral (dominant) forearm with strain-gauge
venous occlusion plethysmography (D.E. Hokanson), with both forearms
positioned above heart level.28 One minute before the
measurement of FBF, circulation to the hand was arrested by inflation
of wrist cuffs to suprasystolic levels. Thereafter, a cuff
placed around each upper arm was inflated to 50 mm Hg to occlude
venous outflow. Flow was recorded 4 times each minute at rest and
throughout each drug infusion protocol. Flows during the last minute of
rest and each drug dose were measured and the mean value reported. All
FBF values are presented in milliliters per 100 milliliters of
forearm volume per minute. Forearm volume was determined by the water
displacement method.
Intra-Arterial Infusion Protocol
All studies were performed between 7 and 10 AM after
a 12-hour overnight fast in a temperature-controlled room. Drug
infusion rates were normalized per 100 mL tissue and infused at 5
mL/min by a syringe pump. After the measurement of resting blood flow
for 5 minutes, endothelium-dependent and
endothelium-independent vasodilation was assessed by
the FBF responses to incremental doses of acetylcholine (IOLAB
Pharmaceuticals) and sodium nitroprusside (Elkins-Sinn), respectively.
Acetylcholine was infused at rates of 1.0, 2.0, 4.0, 8.0, and 16.0
µg/100 mL forearm tissue per minute and sodium nitroprusside at 0.25,
1.0, 2.0, and 4.0 µg/100 mL forearm tissue per minute. Each dose was
infused for 5 minutes, and sufficient time (20 minutes) was provided
to allow FBF to return to resting levels between drug infusions. To
avoid an order effect, the sequence of administration of acetylcholine
and sodium nitroprusside was randomized.
Exercise Intervention
To initiate the 3-month aerobic exercise training program,
the subjects underwent a supervised orientation, after which they
exercised on their own. For the first 2 to 3 weeks of the exercise
program subjects walked for 30 minutes per day, 3 to 4 days per week,
at an intensity of 60% of their individually determined maximal
heart rate. As their tolerance for exercise improved, subjects were
asked to increase the duration of exercise to 40 to 45 minutes per day
and the intensity of their exercise to 70% to 75% of their maximal
heart rate for 5 to 6 days per week. Compliance was documented with the
use of heart rate monitors and personal activity logs. The subjects
were asked to record their prescribed exercise activity as well as
any other additional physical activity on a daily basis. Both the heart
rate monitors and physical activity logs were returned to the
laboratory every 2 weeks and analyzed.
Statistical Analysis
Data for the cross-sectional study were analyzed
by multifactor ANOVA (age times training status). When indicated by a
significant F value, specific mean comparisons were
performed to identify significant group differences. Because MAP did
not change throughout the infusion protocol, forearm vascular
conductance (FVC) was calculated as FBF divided by MAP and expressed as
arbitrary units (AU)x102. Group differences in
the FBF and FVC responses to acetylcholine and sodium nitroprusside
were determined by repeated-measures ANOVA. Relations between
variables of interest were assessed by means of Pearson’s
correlation coefficient and linear regression analysis. Changes
in the dependent variables resulting from the exercise intervention
were assessed by repeated-measures ANOVA. All data are expressed as
mean±SEM. Statistical significance was set at P<0.05.
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Results |
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Cross-Sectional Study
Table 1
presents selected
subject characteristics. Body mass, BMI, and waist circumference were
higher (P<0.01) in the sedentary men compared with their
age-matched, endurance-trained counterparts.
O2max was higher in
the endurance-trained men than in the sedentary men at both ages
(P<0.01). There were no differences in resting MAP, FBF, or
FVC among the 4 groups. Although all metabolic factors were
well within clinically normal levels, in general, the middle aged and
older sedentary men demonstrated the highest plasma
triglyceride, homocysteine, glucose, and insulin
concentrations of all groups (P<0.05).
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Figure 1 shows the FBF and FVC
responses to acetylcholine in the sedentary and endurance-trained
groups. As expected, the FBF and FVC responses to acetylcholine were
attenuated with age in the sedentary men (P<0.01). At the
highest acetylcholine dose (16 µg/100 mL tissue per minute), FBF was
25% lower in the middle aged and older (12.1±0.9 mL/100 mL tissue per
minute) compared with young (16.1±1.7 mL/100 mL tissue per minute)
sedentary men. In contrast, the endurance-trained men did not
demonstrate an age-associated decline in
endothelium-dependent vasodilation; FBF at the highest
dose of acetylcholine was almost identical in the middle aged and older
(17.3±1.3 mL/100 mL tissue per minute) and young (17.7±1.4 mL/100 mL
tissue per minute) groups. As such, the FBF and FVC responses to
acetylcholine in the middle aged and older endurance-trained subjects
were markedly greater (P<0.01) than those in the middle
aged and older sedentary men. The vasodilatory responses to
acetylcholine were similar between the young sedentary and
endurance-trained men. There were no significant differences among the
groups in the forearm vasodilatory responses to sodium nitroprusside
(Figure 2).
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In the overall study population, FBF at the highest dose of
acetylcholine was related to waist circumference (r=-0.32;
P<0.01) and
O2max
(r=0.25; P<0.05). No other significant relations
were observed.
Exercise Intervention Study
All 13 middle aged and older men (age 56±2 years) completed
the 3-month exercise intervention study. Subjects exercised an average
of 5.5±0.3 days per week for 42±1 minutes per day at 72±1% of
maximal heart rate. There were no significant changes in body mass,
adiposity, heart rate at rest, arterial blood pressure, or
plasma cholesterol, glucose, or insulin concentrations
(Table 2). Aerobic exercise training
increased exercise time by 20% (P<0.01), and decreased
heart rate and RPE at the same absolute submaximal level of exercise
(70% of baseline maximal oxygen consumption; P<0.05);
O2max was not
significantly changed. There were no significant changes in resting FBF
or FVC after exercise training.
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Aerobic exercise training significantly increased the FBF and FVC
responses to acetylcholine (Figure 3).
FBF at the highest dose of acetylcholine was 30% higher after
(15.9±1.5 mL/100 mL tissue per minute) versus before (12.3±1.3 mL/100
mL tissue per minute) exercise training (P<0.01). The FBF
responses to acetylcholine after exercise training were not
significantly different from those observed in the young adults and
middle aged and older endurance-trained men. There were no differences
in the vasodilatory responses to sodium nitroprusside after exercise
training (Figure 3). There were no significant correlates of the
improvement in endothelium-dependent vasodilation.
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Discussion |
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The primary new findings of the present study are that (1) endurance-trained men do not demonstrate an age-related decline in endothelium-dependent vasodilation; (2) middle aged and older men who regularly perform aerobic exercise exhibit greater acetylcholine-mediated vasodilation compared with their sedentary peers; and (3) regular aerobic exercise can restore the loss of endothelium-dependent vasodilation in previously sedentary middle aged and older men. To the best of our knowledge, this is the first study to demonstrate that regular aerobic exercise not only can prevent the age-associated loss in endothelium-dependent vasodilation but can restore the function lost as a result of sedentary aging.
In men, endothelium-dependent vasodilation has been shown to decline progressively with advancing age,8 10 starting as early as 20 years of age. The results of our cross-sectional study are in line with these previous findings. Specifically, we observed a 25% age-related reduction in acetylcholine-mediated vasodilation in sedentary men, whereas endothelium-independent vasodilation was unaltered. The key finding of our cross-sectional study, however, was that in stark contrast to their sedentary peers, endothelium-dependent vasodilation was remarkably well preserved with age in men who regularly performed aerobic endurance exercise. In fact, the FBF responses to each dose of acetylcholine were almost identical between the young and middle aged and older endurance-trained men. As such, the middle aged and older endurance-trained men demonstrated significantly greater acetylcholine-mediated vasodilation compared with sedentary men of similar age.
In the present study, we observed no significant differences in the forearm vascular responses to acetylcholine between the young trained and sedentary men. This finding is at odds with those of Kingwell et al,29 who reported enhanced vascular reactivity to acetylcholine in young endurance-trained athletes compared with age-matched sedentary control subjects. This discrepancy is likely due to the differences in plasma cholesterol concentrations among subjects in each study. Elevations in plasma cholesterol levels, at any age, are associated with impaired endothelium-dependent vasodilation.30 31 In the study by Kingwell and coworkers,29 plasma cholesterol levels were lower in the endurance-trained athletes compared with the sedentary control subjects and correlated with the enhanced vascular responsiveness to acetylcholine. In contrast, there were no differences in plasma cholesterol concentrations between the young sedentary and endurance-trained men in the present study. Thus, regular aerobic exercise, independent of changes in total cholesterol, does not appear to improve acetylcholine-mediated brachial vasodilation in young healthy adult males. It is important to recognize the context of this finding (ie, young healthy adults) and that regular aerobic exercise may be beneficial in young adults who have depressed endothelial vasodilatory function such as young patients with essential hypertension.
Collectively, the results of our cross-sectional study suggest
that impaired endothelium-dependent vasodilation may
not be an inevitable (intrinsic) consequence of biological aging.
Rather, this dysfunction may be due, at least in part, to age-related
reductions in physical activity/aerobic fitness and associated
increases in body fatness. In the present study,
O2max (a measure of habitual
physical activity/aerobic fitness) and waist circumference were the
only physiological correlates of the maximal
vasodilation to acetylcholine.
Our cross-sectional findings of greater
endothelial vasodilatory capacity in trained compared
with sedentary older men suggested that regular aerobic exercise may be
an effective lifestyle intervention strategy for improving
endothelial vasodilatory function in middle aged and
older sedentary men. The results of our exercise intervention study
support this postulate. Specifically, 3 months of regular aerobic
exercise (primarily walking) resulted in a 30% increase in
endothelium-dependent vasodilation in previously
sedentary middle aged and older men. Moreover, this improvement
occurred without concomitant changes in body mass, adiposity,
arterial blood pressure, total cholesterol, or
O2max, suggesting a primary
effect of aerobic exercise on endothelial cell
function. Interestingly, the magnitude of the exercise-induced increase
in endothelium-dependent vasodilation was proportional
to the age-related decline in vasodilation observed in the sedentary
men in our cross-sectional study. Indeed, after exercise training, the
FBF responses to acetylcholine were similar to those of the middle aged
and older endurance-trained men, demonstrating, for the first time,
that regular aerobic exercise can restore the loss in
endothelium-dependent vasodilation in healthy middle
aged and older men. It is important to note that the improvements in
endothelium-dependent vasodilation were attained with
home-based aerobic exercise training and with a mode (walking) and
intensity (moderate) of exercise that can be safely performed by most
if not all sedentary healthy older men.
The mechanisms by which regular aerobic exercise may prevent and/or reverse the age-associated decline in endothelium-dependent vasodilation are not clear. One potential mechanism for the exercise-induced increase in endothelium-dependent vasodilation is increased nitric oxide (NO) production and/or release. Sessa et al32 demonstrated enhanced endothelial NO synthase (eNOS) gene expression and NO production in dogs after 10 days of exercise training. Exercise-induced increases in eNOS gene expression may account, at least in part, for the adaptation in vasodilatory function observed in the forearm in response to exercise involving primarily the legs. It is plausible that mechanical alteration/deformation of the endothelium during exercise as a result of increased systemic arterial pressure and pulsatile flow contributes to eNOS upregulation.33 The prominent leftward shift in the dose-response curve to acetylcholine that we observed after compared with before exercise training suggests that regular exercise may improve endothelial cell muscarinic receptor sensitivity, number, and/or the intracellular signal transduction pathway that links receptor activation to NO synthesis and release.17 34 Cheng et al34 have demonstrated an upregulation of endothelial muscarinic receptors after acute exercise in rats. Other potential mechanisms that may contribute to the favorable effect of exercise on endothelial vasodilatory function include increased prostaglandin release, reduced free radical–mediated NO degradation, and lower sympathetic vasoconstrictor tone.16 17
Considering that many of the cardiovascular complications associated with sedentary aging such as hypertension, coronary artery disease, and thrombosis are pathogenetically linked to endothelial dysfunction,5 8 our findings may have important implications regarding both primary and secondary prevention of cardiovascular disease. From a primary prevention perspective, our results suggest that habitual aerobic exercise may prevent the age-related reduction in endothelium-dependent vasodilation observed in sedentary adults. Preserved endothelium-mediated vasodilation may contribute to the lower incidence of cardiovascular events observed in middle aged and older men who exercise regularly.14 15 With regard to secondary prevention, the present findings indicate that regular aerobic exercise is an effective lifestyle intervention for reversing the loss in endothelium-dependent vasodilation in middle aged and older sedentary men. Improved endothelial function, if sustained, should reduce the risk of cardiovascular disease and related thrombotic events in this population.
Conclusions
The results of the present study provide experimental support
for the hypothesis that regular aerobic exercise can prevent the
age-related decline in endothelium-dependent
vasodilation and restore the loss in vasodilatory function in
previously sedentary middle aged and older men. Given the clinical
importance of endothelial function to
cardiovascular health, regular aerobic exercise
represents an important therapeutic strategy for counteracting
the deleterious effects of sedentary aging on
endothelial function.
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Acknowledgments |
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This study was supported by National Institutes of Health awards HL-03840 (Dr DeSouza), AG00847 (Dr Tanaka), and AG13038, AG03765, and AG16071 (Dr Seals); by the General Clinical Research Center (5-01-RR-00051); and by American Heart Association awards CWFW-02-98 (Dr Shapiro) and 9960234Z (Dr Tanaka). We would like to thank all of the subjects who participated in the study as well as Yoli Casas, Jayne Semmler, Jill Tanaka, and Teresa Wilson for technical assistance.
Received February 29, 2000; revision received April 14, 2000; accepted April 19, 2000.
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 D. W. Trott, F. Gunduz, M. H. Laughlin, and C. R. Woodman Exercise training reverses age-related decrements in endothelium-dependent dilation in skeletal muscle feed arteries J Appl Physiol, June 1, 2009; 106(6): 1925 - 1934. [Abstract] [Full Text] [PDF]
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M. J. Joyner Keeping the juices flowing with age: vitamin C and exercise hyperaemia J. Physiol., June 1, 2009; 587(11): 2423 - 2423. [Full Text] [PDF]
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H. Komine, J. Sugawara, K. Hayashi, M. Yoshizawa, and T. Yokoi Regular endurance exercise in young men increases arterial baroreflex sensitivity through neural alteration of baroreflex arc J Appl Physiol, May 1, 2009; 106(5): 1499 - 1505. [Abstract] [Full Text] [PDF]
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B. S. Kirby, W. F. Voyles, C. B. Simpson, R. E. Carlson, W. G. Schrage, and F. A. Dinenno Endothelium-dependent vasodilatation and exercise hyperaemia in ageing humans: impact of acute ascorbic acid administration J. Physiol., May 1, 2009; 587(9): 1989 - 2003. [Abstract] [Full Text] [PDF]
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C.-H. Shao, X. H. T. Wehrens, T. A. Wyatt, S. Parbhu, G. J. Rozanski, K. P. Patel, and K. R. Bidasee Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation J Appl Physiol, April 1, 2009; 106(4): 1280 - 1292. [Abstract] [Full Text] [PDF]
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 G. L. Pierce, L. A. Lesniewski, B. R. Lawson, S. D. Beske, and D. R. Seals Nuclear Factor-{kappa}B Activation Contributes to Vascular Endothelial Dysfunction via Oxidative Stress in Overweight/Obese Middle-Aged and Older Humans Circulation, March 10, 2009; 119(9): 1284 - 1292. [Abstract] [Full Text] [PDF]
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 P. E. Gates, W. D. Strain, and A. C. Shore Human endothelial function and microvascular ageing Exp Physiol, March 1, 2009; 94(3): 311 - 316. [Abstract] [Full Text] [PDF]
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 L. A. Lesniewski, M. L. Connell, J. R. Durrant, B. J. Folian, M. C. Anderson, A. J. Donato, and D. R. Seals B6D2F1 Mice Are a Suitable Model of Oxidative Stress-Mediated Impaired Endothelium-Dependent Dilation With Aging J Gerontol A Biol Sci Med Sci, February 10, 2009; (2009) gln049v1. [Abstract] [Full Text] [PDF]
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S. K. Nishiyama, D. W. Wray, and R. S. Richardson Aging affects vascular structure and function in a limb-specific manner J Appl Physiol, November 1, 2008; 105(5): 1661 - 1670. [Abstract] [Full Text] [PDF]
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D. R. Seals, C. A. DeSouza, A. J. Donato, and H. Tanaka Habitual exercise and arterial aging J Appl Physiol, October 1, 2008; 105(4): 1323 - 1332. [Abstract] [Full Text] [PDF]
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A. J. Donato, I. Eskurza, K. L. Jablonski, L. B. Gano, G. L. Pierce, and D. R. Seals Cytochrome P-450 2C9 signaling does not contribute to age-associated vascular endothelial dysfunction in humans J Appl Physiol, October 1, 2008; 105(4): 1359 - 1363. [Abstract] [Full Text] [PDF]
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D. H. J. Thijssen, M. M. van Bemmel, L. M. Bullens, E. A. Dawson, N. D. Hopkins, T. M. Tinken, M. A. Black, M. T. E. Hopman, N. T. Cable, and D. J. Green The impact of baseline diameter on flow-mediated dilation differs in young and older humans Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1594 - H1598. [Abstract] [Full Text] [PDF]
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D. H. J. Thijssen and M. T. E. Hopman Counterpoint: Exercise training does not induce vascular adaptations beyond the active muscle beds J Appl Physiol, September 1, 2008; 105(3): 1004 - 1006. [Full Text] [PDF]
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D. J. Green, A. J. Maiorana, and N. T. Cable Point:Counterpoint: Exercise training does/does not induce vascular adaptations beyond the active muscle beds J Appl Physiol, September 1, 2008; 105(3): 1002 - 1004. [Full Text] [PDF]
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P. N. Ainslie, J. D. Cotter, K. P. George, S. Lucas, C. Murrell, R. Shave, K. N. Thomas, M. J. A. Williams, and G. Atkinson Elevation in cerebral blood flow velocity with aerobic fitness throughout healthy human ageing J. Physiol., August 15, 2008; 586(16): 4005 - 4010. [Abstract] [Full Text] [PDF]
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J. N. Barnes and H. Tanaka Commentary on Viewpoint: Exercise and cardiovascular risk reduction: Time to update the rationale for exercise? J Appl Physiol, August 1, 2008; 105(2): 777 - 777. [Full Text] [PDF]
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M. Dhindsa, S. M. Sommerlad, A. E. DeVan, J. N. Barnes, J. Sugawara, O. Ley, and H. Tanaka Interrelationships among noninvasive measures of postischemic macro- and microvascular reactivity J Appl Physiol, August 1, 2008; 105(2): 427 - 432. [Abstract] [Full Text] [PDF]
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M. A. Black, D. J. Green, and N. T. Cable Exercise prevents age-related decline in nitric-oxide-mediated vasodilator function in cutaneous microvessels J. Physiol., July 15, 2008; 586(14): 3511 - 3524. [Abstract] [Full Text] [PDF]
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 M. Rakobowchuk, S. Tanguay, K. A. Burgomaster, K. R. Howarth, M. J. Gibala, and M. J. MacDonald Sprint interval and traditional endurance training induce similar improvements in peripheral arterial stiffness and flow-mediated dilation in healthy humans Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R236 - R242. [Abstract] [Full Text] [PDF]
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 G. L. Pierce, S. D. Beske, B. R. Lawson, K. L. Southall, F. J. Benay, A. J. Donato, and D. R. Seals Weight Loss Alone Improves Conduit and Resistance Artery Endothelial Function in Young and Older Overweight/Obese Adults Hypertension, July 1, 2008; 52(1): 72 - 79. [Abstract] [Full Text] [PDF]
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 J. Padilla, R. A Harris, L. D Rink, and J. P Wallace Characterization of the brachial artery shear stress following walking exercise Vascular Medicine, May 1, 2008; 13(2): 105 - 111. [Abstract] [PDF]
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G. P. Van Guilder, B. L. Stauffer, J. J. Greiner, and C. A. DeSouza Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1685 - H1692. [Abstract] [Full Text] [PDF]
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M. H. Laughlin, S. C. Newcomer, and S. B. Bender Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype J Appl Physiol, March 1, 2008; 104(3): 588 - 600. [Abstract] [Full Text] [PDF]
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M. D. Delp, B. J. Behnke, S. A. Spier, G. Wu, and J. M. Muller-Delp Ageing diminishes endothelium-dependent vasodilatation and tetrahydrobiopterin content in rat skeletal muscle arterioles J. Physiol., February 15, 2008; 586(4): 1161 - 1168. [Abstract] [Full Text] [PDF]
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G. P. Van Guilder, G. L. Hoetzer, J. J. Greiner, B. L. Stauffer, and C. A. DeSouza Metabolic syndrome and endothelial fibrinolytic capacity in obese adults Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R39 - R44. [Abstract] [Full Text] [PDF]
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 N. M. Hamburg, C. J. McMackin, A. L. Huang, S. M. Shenouda, M. E. Widlansky, E. Schulz, N. Gokce, N. B. Ruderman, J. F. Keaney Jr, and J. A. Vita Physical Inactivity Rapidly Induces Insulin Resistance and Microvascular Dysfunction in Healthy Volunteers Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2650 - 2656. [Abstract] [Full Text] [PDF]
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 B. Frye, S. Scheinthal, T. Kemarskaya, and R. Pruchno Tai Chi and Low Impact Exercise: Effects on the Physical Functioning and Psychological Well-Being of Older People Journal of Applied Gerontology, November 1, 2007; 26(5): 433 - 453. [Abstract] [PDF]
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C. R. Woodman, D. W. Trott, and M. H. Laughlin Short-term increases in intraluminal pressure reverse age-related decrements in endothelium-dependent dilation in soleus muscle feed arteries J Appl Physiol, October 1, 2007; 103(4): 1172 - 1179. [Abstract] [Full Text] [PDF]
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J. Sugawara, H. Komine, K. Hayashi, M. Yoshizawa, T. Otsuki, N. Shimojo, T. Miyauchi, T. Yokoi, S. Maeda, and H. Tanaka Systemic {alpha}-adrenergic and nitric oxide inhibition on basal limb blood flow: effects of endurance training in middle-aged and older adults Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1466 - H1472. [Abstract] [Full Text] [PDF]
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G. P. Van Guilder, C. M. Westby, J. J. Greiner, B. L. Stauffer, and C. A. DeSouza Endothelin-1 Vasoconstrictor Tone Increases With Age in Healthy Men But Can Be Reduced by Regular Aerobic Exercise Hypertension, August 1, 2007; 50(2): 403 - 409. [Abstract] [Full Text] [PDF]
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K. D. Monahan Effect of aging on baroreflex function in humans Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R3 - R12. [Abstract] [Full Text] [PDF]
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 S. Fujita, B. B. Rasmussen, J. G. Cadenas, M. J. Drummond, E. L. Glynn, F. R. Sattler, and E. Volpi Aerobic Exercise Overcomes the Age-Related Insulin Resistance of Muscle Protein Metabolism by Improving Endothelial Function and Akt/Mammalian Target of Rapamycin Signaling Diabetes, June 1, 2007; 56(6): 1615 - 1622. [Abstract] [Full Text] [PDF]
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S. A. Spier, M. D. Delp, J. N. Stallone, J. M. Dominguez II, and J. M. Muller-Delp Exercise training enhances flow-induced vasodilation in skeletal muscle resistance arteries of aged rats: role of PGI2 and nitric oxide Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3119 - H3127. [Abstract] [Full Text] [PDF]
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A. J. Donato, L. A. Lesniewski, and M. D. Delp Ageing and exercise training alter adrenergic vasomotor responses of rat skeletal muscle arterioles J. Physiol., February 15, 2007; 579(1): 115 - 125. [Abstract] [Full Text] [PDF]
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W. G. Schrage, J. H. Eisenach, and M. J. Joyner Ageing reduces nitric-oxide- and prostaglandin-mediated vasodilatation in exercising humans J. Physiol., February 15, 2007; 579(1): 227 - 236. [Abstract] [Full Text] [PDF]
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 B. J. Schank, L. S. Acree, J. Longfors, and A. W. Gardner Differences in Vascular Reactivity Between Men and Women Angiology, January 1, 2007; 57(6): 702 - 708. [Abstract] [PDF]
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D. H. J. Thijssen, P. de Groot, M. Kooijman, P. Smits, and M. T. E. Hopman Sympathetic nervous system contributes to the age-related impairment of flow-mediated dilation of the superficial femoral artery Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H3122 - H3129. [Abstract] [Full Text] [PDF]
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 P E Gates and D R Seals Decline in large elastic artery compliance with age: a therapeutic target for habitual exercise Br. J. Sports Med., November 1, 2006; 40(11): 897 - 899. [Full Text] [PDF]
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 S. E. Petersen, F. Wiesmann, L. E. Hudsmith, M. D. Robson, J. M. Francis, J. B. Selvanayagam, S. Neubauer, and K. M. Channon Functional and Structural Vascular Remodeling in Elite Rowers Assessed by Cardiovascular Magnetic Resonance J. Am. Coll. Cardiol., August 15, 2006; 48(4): 790 - 797. [Abstract] [Full Text] [PDF]
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J. N. Cook, A. E. DeVan, J. L. Schleifer, M. M. Anton, M. Y. Cortez-Cooper, and H. Tanaka Arterial compliance of rowers: implications for combined aerobic and strength training on arterial elasticity Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1596 - H1600. [Abstract] [Full Text] [PDF]
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I. Eskurza, Z. D. Kahn, and D. R. Seals Xanthine oxidase does not contribute to impaired peripheral conduit artery endothelium-dependent dilatation with ageing J. Physiol., March 15, 2006; 571(3): 661 - 668. [Abstract] [Full Text] [PDF]
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D. W. Wray, A. Uberoi, L. Lawrenson, and R. S. Richardson Evidence of preserved endothelial function and vascular plasticity with age Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1271 - H1277. [Abstract] [Full Text] [PDF]
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A. J. Donato, A. Uberoi, D. W. Wray, S. Nishiyama, L. Lawrenson, and R. S. Richardson Differential effects of aging on limb blood flow in humans Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H272 - H278. [Abstract] [Full Text] [PDF]
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 G. P. Van Guilder, G. L. Hoetzer, D. T. Smith, H. M. Irmiger, J. J. Greiner, B. L. Stauffer, and C. A. DeSouza Endothelial t-PA release is impaired in overweight and obese adults but can be improved with regular aerobic exercise Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E807 - E813. [Abstract] [Full Text] [PDF]
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I. Eskurza, L. A Myerburgh, Z. D Kahn, and D. R Seals Tetrahydrobiopterin augments endothelium-dependent dilatation in sedentary but not in habitually exercising older adults J. Physiol., November 1, 2005; 568(3): 1057 - 1065. [Abstract] [Full Text] [PDF]
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 M. A. Sackner, E. Gummels, and J. A. Adams Effect of Moderate-Intensity Exercise, Whole-Body Periodic Acceleration, and Passive Cycling on Nitric Oxide Release Into Circulation Chest, October 1, 2005; 128(4): 2794 - 2803. [Abstract] [Full Text] [PDF]
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M. W. P. Bleeker, P. C. E. De Groot, G. A. Rongen, J. Rittweger, D. Felsenberg, P. Smits, and M. T. E. Hopman Vascular adaptation to deconditioning and the effect of an exercise countermeasure: results of the Berlin Bed Rest study J Appl Physiol, October 1, 2005; 99(4): 1293 - 1300. [Abstract] [Full Text] [PDF]
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D. W. Wray, A. Uberoi, L. Lawrenson, and R. S. Richardson Heterogeneous limb vascular responsiveness to shear stimuli during dynamic exercise in humans J Appl Physiol, July 1, 2005; 99(1): 81 - 86. [Abstract] [Full Text] [PDF]
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S. C. Newcomer, U. A. Leuenberger, C. S. Hogeman, and D. N. Proctor Heterogeneous vasodilator responses of human limbs: influence of age and habitual endurance training Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H308 - H315. [Abstract] [Full Text] [PDF]
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 A. J. Donato, L. A. Lesniewski, and M. D. Delp The effects of aging and exercise training on endothelin-1 vasoconstrictor responses in rat skeletal muscle arterioles Cardiovasc Res, May 1, 2005; 66(2): 393 - 401. [Abstract] [Full Text] [PDF]
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M. W. P. Bleeker, P. C. E. De Groot, F. Poelkens, G. A. Rongen, P. Smits, and M. T. E. Hopman Vascular adaptation to 4 wk of deconditioning by unilateral lower limb suspension Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1747 - H1755. [Abstract] [Full Text] [PDF]
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C. R. Woodman, E. M. Price, and M. H. Laughlin Shear stress induces eNOS mRNA expression and improves endothelium-dependent dilation in senescent soleus muscle feed arteries J Appl Physiol, March 1, 2005; 98(3): 940 - 946. [Abstract] [Full Text] [PDF]
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D. J. Green, W. Bilsborough, L. H. Naylor, C. Reed, J. Wright, G. O'Driscoll, and J. H. Walsh Comparison of forearm blood flow responses to incremental handgrip and cycle ergometer exercise: relative contribution of nitric oxide J. Physiol., January 15, 2005; 562(2): 617 - 628. [Abstract] [Full Text] [PDF]
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D. J Green, A. Maiorana, G. O'Driscoll, and R. Taylor Effect of exercise training on endothelium-derived nitric oxide function in humans J. Physiol., November 15, 2004; 561(1): 1 - 25. [Abstract] [Full Text] [PDF]
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R. J. Spina, T. E. Meyer, L. R. Peterson, D. T. Villareal, M. R. Rinder, and A. A. Ehsani Absence of left ventricular and arterial adaptations to exercise in octogenarians J Appl Physiol, November 1, 2004; 97(5): 1654 - 1659. [Abstract] [Full Text] [PDF]
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P. E. Gates, H. Tanaka, W. R. Hiatt, and D. R. Seals Dietary Sodium Restriction Rapidly Improves Large Elastic Artery Compliance in Older Adults With Systolic Hypertension Hypertension, July 1, 2004; 44(1): 35 - 41. [Abstract] [Full Text] [PDF]
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K. P. Davy and J. E. Hall Obesity and hypertension: two epidemics or one? Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2004; 286(5): R803 - R813. [Abstract] [Full Text] [PDF]
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S. A. Spier, M. D. Delp, C. J. Meininger, A. J. Donato, M. W. Ramsey, and J. M. Muller-Delp Effects of ageing and exercise training on endothelium-dependent vasodilatation and structure of rat skeletal muscle arterioles J. Physiol., May 1, 2004; 556(3): 947 - 958. [Abstract] [Full Text] [PDF]
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S. C. Newcomer, U. A. Leuenberger, C. S. Hogeman, B. D. Handly, and D. N. Proctor Different vasodilator responses of human arms and legs J. Physiol., May 1, 2004; 556(3): 1001 - 1011. [Abstract] [Full Text] [PDF]
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I. Eskurza, K. D. Monahan, J. A. Robinson, and D. R. Seals Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing J. Physiol., April 1, 2004; 556(1): 315 - 324. [Abstract] [Full Text] [PDF]
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L. Lawrenson, J. Hoff, and R. S. Richardson Aging attenuates vascular and metabolic plasticity but does not limit improvement in muscle VO2 max Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1565 - H1572. [Abstract] [Full Text] [PDF]
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T. I. Musch, K. E. Eklund, K. S. Hageman, and D. C. Poole Altered regional blood flow responses to submaximal exercise in older rats J Appl Physiol, January 1, 2004; 96(1): 81 - 88. [Abstract] [Full Text] [PDF]
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 P. E. Gates, H. Tanaka, J. Graves, and D. R. Seals Left ventricular structure and diastolic function with human ageing: Relation to habitual exercise and arterial stiffness Eur. Heart J., December 2, 2003; 24(24): 2213 - 2220. [Abstract] [Full Text] [PDF]
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M. E. Widlansky, N. Gokce, J. F. Keaney Jr, and J. A. Vita The clinical implications of endothelial dysfunction J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1149 - 1160. [Abstract] [Full Text] [PDF]
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J. H. Walsh, G. Yong, C. Cheetham, G. F. Watts, G. J. O'Driscoll, R. R. Taylor, and D. J. Green Effects of exercise training on conduit and resistance vessel function in treated and untreated hypercholesterolaemic subjects Eur. Heart J., September 2, 2003; 24(18): 1681 - 1689. [Abstract] [Full Text] [PDF]
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 I. K. Moppett, J. A. Davies, and R. P. Mahajan Non-selective and cyclo-oxygenase-2-specific non-steroidal anti-inflammatory drugs impair the hyperaemic response of skin to brief axillary artery occlusion Br. J. Anaesth., September 1, 2003; 91(3): 353 - 356. [Abstract] [Full Text] [PDF]
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L. Lawrenson, J. G. Poole, J. Kim, C. Brown, P. Patel, and R. S. Richardson Vascular and metabolic response to isolated small muscle mass exercise: effect of age Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1023 - H1031. [Abstract] [Full Text] [PDF]
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J. H. Walsh, W. Bilsborough, A. Maiorana, M. Best, G. J. O'Driscoll, R. R. Taylor, and D. J. Green Exercise training improves conduit vessel function in patients with coronary artery disease J Appl Physiol, July 1, 2003; 95(1): 20 - 25. [Abstract] [Full Text] [PDF]
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D. N. Proctor, S. C. Newcomer, D. W. Koch, K. U. Le, D. A. MacLean, and U. A. Leuenberger Leg blood flow during submaximal cycle ergometry is not reduced in healthy older normally active men J Appl Physiol, May 1, 2003; 94(5): 1859 - 1869. [Abstract] [Full Text] [PDF]
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J. G. Poole, L. Lawrenson, J. Kim, C. Brown, and R. S. Richardson Vascular and metabolic response to cycle exercise in sedentary humans: effect of age Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1251 - H1259. [Abstract] [Full Text] [PDF]
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K. L Moreau, A. J Donato, D. R Seals, C. A DeSouza, and H. Tanaka Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women Cardiovasc Res, March 1, 2003; 57(3): 861 - 868. [Abstract] [Full Text] [PDF]
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W. H. Capell, C. A. DeSouza, P. Poirier, M. L. Bell, B. L. Stauffer, K. M. Weil, T. L. Hernandez, and R. H. Eckel Short-Term Triglyceride Lowering With Fenofibrate Improves Vasodilator Function in Subjects With Hypertriglyceridemia Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 307 - 313. [Abstract] [Full Text] [PDF]
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D. T Smith, G. L Hoetzer, J. J Greiner, B. L Stauffer, and C. A DeSouza Effects of ageing and regular aerobic exercise on endothelial fibrinolytic capacity in humans J. Physiol., January 1, 2003; 546(1): 289 - 298. [Abstract] [Full Text] [PDF]
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G. L. Hoetzer, B. L. Stauffer, J. J. Greiner, Y. Casas, D. T. Smith, and C. A. DeSouza Influence of oral contraceptive use on endothelial t-PA release in healthy premenopausal women Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E90 - E95. [Abstract] [Full Text] [PDF]
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M. T. E. Hopman, J. T. Groothuis, M. Flendrie, K. H. L. Gerrits, and S. Houtman Increased vascular resistance in paralyzed legs after spinal cord injury is reversible by training J Appl Physiol, December 1, 2002; 93(6): 1966 - 1972. [Abstract] [Full Text] [PDF]
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J. M. Muller-Delp, S. A. Spier, M. W. Ramsey, and M. D. Delp Aging impairs endothelium-dependent vasodilation in rat skeletal muscle arterioles Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1662 - H1672. [Abstract] [Full Text] [PDF]
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C. A DeSouza, C. M Clevenger, J. J Greiner, D. T Smith, G. L Hoetzer, L. F Shapiro, and B. L Stauffer Evidence for agonist-specific endothelial vasodilator dysfunction with ageing in healthy humans J. Physiol., July 1, 2002; 542(1): 255 - 262. [Abstract] [Full Text] [PDF]
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C. J. Rodriguez, R. L. Sacco, R. R. Sciacca, B. Boden-Albala, S. Homma, and M. R. Di Tullio Physical activity attenuates the effect of increased left ventricular mass on the risk of ischemic stroke: The Northern Manhattan Stroke Study J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1482 - 1488. [Abstract] [Full Text] [PDF]
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P. P. Jones, L. F Shapiro, G. A Keisling, R. A Quaife, and D. R Seals Is autonomic support of arterial blood pressure related to habitual exercise status in healthy men? J. Physiol., April 15, 2002; 540(2): 701 - 706. [Abstract] [Full Text] [PDF]
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N. N. Chan, H. M. Colhoun, and P. Vallance Cardiovascular risk factors as determinants of endothelium-dependent and endothelium-independent vascular reactivity in the general population J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1814 - 1820. [Abstract] [Full Text] [PDF]
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J. T. Kuvin, A. R. Patel, K. A. Sliney, N. G. Pandian, W. M. Rand, J. E. Udelson, and R. H. Karas Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1843 - 1849. [Abstract] [Full Text] [PDF]
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M. Imamura, S. Biro, T. Kihara, S. Yoshifuku, K. Takasaki, Y. Otsuji, S. Minagoe, Y. Toyama, and C. Tei Repeated thermal therapy improves impaired vascular endothelial function in patients with coronary risk factors J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1083 - 1088. [Abstract] [Full Text] [PDF]
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D. K. McGuire, B. D. Levine, J. W. Williamson, P. G. Snell, C. G. Blomqvist, B. Saltin, and J. H. Mitchell A 30-Year Follow-Up of the Dallas Bed Rest and Training Study: II. Effect of Age on Cardiovascular Adaptation to Exercise Training Circulation, September 18, 2001; 104(12): 1358 - 1366. [Abstract] [Full Text] [PDF]
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 Regular Aerobic Exercise Reverses Age-Related Vascular Changes Journal Watch (General), September 26, 2000; 2000(926): 8 - 8. [Full Text]
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P. P. Jones, L. F. Shapiro, G. A. Keisling, R. A. Quaife, and D. R. Seals Is autonomic support of arterial blood pressure related to habitual exercise status in healthy men? J. Physiol., February 15, 2002; (2002) 200101366. [Abstract] [PDF]
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