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(Hypertension. 1996;27:849-853.)
© 1996 American Heart Association, Inc.
Articles |
Aging Progressively Impairs Endothelium-Dependent Vasodilation in Forearm Resistance Vessels of Humans
From the Vascular Medicine and Atherosclerosis Unit of the Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass.
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Abstract |
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Abstract Studies in experimental models suggest that endothelium-derived nitric oxide is reduced with aging, and this circumstance may be relevant to atherogenesis. The aim of this study was to determine whether increasing age resulted in altered endothelium-dependent vasodilation in the forearm resistance vessels of healthy humans. Forearm blood flow was measured in 119 healthy subjects, aged 19 to 69 years, by venous occlusion plethysmography. Brachial artery infusions of methacholine chloride (0.03 to 10.0 µg/min) were used to assess endothelium-dependent vasodilation and of sodium nitroprusside (0.03 to 10.0 µg/min) to assess endothelium-independent vasodilation. The slope of the dose–blood flow response relation was calculated in each subject for each drug. Univariate and multiple stepwise regression analyses were used to relate vascular reactivity to selected variables, including age, lipids, and blood pressure. Endothelium-dependent vasodilation was progressively impaired with increasing age, assessed as a reduction in slope from 2.25±0.16 to 0.34±0.11 (mL/100 mL tissue per minute)/(µg/min) (P<.001). The decline in endothelium-dependent vasodilation was already evident by the fourth decade (age 30 to 39 years). Endothelium-independent vasodilation did not change with age. Age, total cholesterol, and low-density lipoprotein cholesterol were univariate predictors of endothelium-dependent vasodilation. Age remained the most significant predictor of endothelium-dependent vasodilator responses by multiple stepwise regression analysis. From these observations, it can be concluded that endothelium-dependent vasodilation declines steadily with increasing age in healthy human subjects. Age is a strong univariate and multivariate predictor of endothelium-dependent vasodilation. This finding may be a marker for more widespread endothelial dysfunction.
Key Words: aging • vasodilation • nitric oxide • atherosclerosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The prevalence of atherosclerosis increases in the elderly population, and the incidence of myocardial infarction, stroke, and limb ischemia is high in older individuals even after controlling for the presence of other cardiovascular risk factors, such as hypercholesterolemia, cigarette smoking, and hypertension.1 2 3 We have postulated that the aging blood vessel is less able to protect itself from injury, a situation analogous to that which occurs in patients with diseases such as hypercholesterolemia and diabetes. Specifically, we have hypothesized that the availability of ED-NO is reduced in older individuals. ED-NO is synthesized in endothelial cells from its precursor L-arginine by the enzyme NO synthase and induces vasorelaxation by activating guanylate cyclase on vascular smooth muscle. NO not only regulates vascular tone4 5 but also inhibits platelet aggregation, leukocyte adhesion to the endothelial surface, and vascular smooth muscle proliferation, properties that maintain vascular homeostasis and reduce injury.4 5 6 7 8 Therefore, limited availability of ED-NO may contribute to atherogenesis.
A number of studies in experimental models in animals suggest that the release or activity of ED-NO is reduced with aging.9 10 Furthermore, in humans, aging is associated with abnormal endothelium-dependent vasodilation to agents that stimulate the release of ED-NO, such as acetylcholine.11 12 13 Age appears to be a predictor of impaired endothelium-dependent vasodilation of epicardial coronary arteries, coronary resistance vessels, and peripheral conduit vessels.11 12 13 14 Nonetheless, although some of these observations are made in the presence of vascular disease or lipid disorders or with small sample sizes, this finding is not unlike those observed in disease states associated with atherosclerosis, such as hypercholesterolemia, diabetes, and hypertension.15 16 17
The purpose of this study was to determine whether endothelium-dependent vasodilation decreases in limb resistance vessels of humans who are otherwise healthy. We chose to study limb resistance vessels because these are not typically affected by atheroma, and abnormalities in these vessels would give evidence to the premise that impaired endothelial function is a diffuse process in the elderly. Furthermore, we enrolled a large number of subjects to ensure adequate statistical power for the study of age-related changes in vascular reactivity.
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Methods |
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Subjects
Studies were performed on 119 healthy subjects (62 men and 57 women) who ranged in age from 19 to 69 years. Each subject was evaluated by history, physical examination, and screening laboratory tests. No subject had evidence of hypercholesterolemia, diabetes, or hypertension; smoked cigarettes; or had any history of cardiovascular disease. No subject was taking diuretics, vasoactive medications, or nonsteroidal anti-inflammatory medications. These subjects served as a control population for a number of research protocols conducted in this laboratory, all of which had the approval of the Human Research Committee of Brigham and Women's Hospital. No subject received any pharmacological intervention before administration of methacholine and nitroprusside. Written informed consent was obtained from each subject.
Experimental Protocol
Each subject was studied in a 22°C temperature-controlled
room in the postabsorptive state. Alcohol and caffeine were prohibited
within 12 hours of the study. The brachial artery of each subject was
cannulated with a 1.5-in polyethylene catheter under sterile conditions
with the use of local anesthesia. The indwelling
arterial cannula was used for BP measurements and
vasoactive drug infusions. The vascular research laboratory was kept
quiet, and the lights were dimmed. All subjects rested for at least 30
minutes after catheter placement for establishment of a stable baseline
before data collection.
For assessment of endothelium-dependent vasodilation, methacholine chloride was administered via the brachial artery in increasing doses ranging from 0.03 to 10.0 µg/min. For assessment of endothelium-independent vasodilation, intra-arterial infusion of sodium nitroprusside was administered at doses ranging from 0.03 to 10.0 µg/min. This agent acts directly on vascular smooth muscle by stimulating soluble guanylate cyclase and inducing hyperpolarization. Each drug was delivered at a rate of 0.4 mL/min. FBF measurements were made under baseline conditions until stability was assured and then during the 3rd to 5th minutes of infusion of each drug. Basal conditions were reestablished between drug infusions. The doses of each drug were chosen to achieve increases in FBF without causing systemic effects.
Bilateral FBF was determined by venous occlusion strain-gauge plethysmography using calibrated mercury-in-Silastic strain gauges and was expressed as milliliters per 100 mL of tissue per minute (DE Hokanson, Inc). Each arm was supported above heart level. Venous occlusion pressure averaged 35 mm Hg. Circulation to the hand was stopped by inflation of a wrist cuff to suprasystolic pressure before each FBF determination. Each FBF determination comprised at least five separate measurements performed at 10- to 15-second intervals. The direct effect of a vasoactive drug was determined by measurement of blood flow in the infused arm. One can ascertain that systemic effects have not occurred if blood flow in the contralateral forearm does not change during the infusion. Forearm vascular resistance was calculated as the ratio of mean BP to FBF and expressed as millimeters of mercury per milliliter per 100 mL tissue per minute. BP was measured via an indwelling arterial cannula attached to a Gould P23 pressure transducer aligned to an amplifier on a Gould physiological recorder.
The slope of the dose–blood flow response relation to drug
infusion was calculated with a least-squares linear regression
analysis for each drug infusion in each subject and expressed
as (milliliters per 100 mL tissue per minute) per (micrograms per
minute). A linear relationship was evident within the dose ranges used
in these studies. An example of an individual slope calculation is
shown in Fig 1
. In this manner, the dose-response
relationship for each drug in each subject was characterized by its
slope.
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Statistical Analysis
Values are presented as mean±SE. Subjects were grouped
by age into 10-year intervals, and ANOVA for repeated measures was used
to compare the means of the groups. If a difference was detected among
the means, Dunnett's test was used to identify significant differences
between means. The association between the continuous variables of
age and the dose response was evaluated by linear regression
analysis. In addition, univariate analysis
of the effects of vascular risk factors and the methacholine response
relationship for continuous variables (age, total
cholesterol, LDL cholesterol, HDL
cholesterol, triglycerides, body mass index,
mean BP, heart rate) was performed with linear regression. The
interaction between these risk factors and the methacholine
dose-response slope was then examined with multiple stepwise
regression analysis run both forward and
backward.18 Correlation coefficients were determined for
age and the following variables: total cholesterol, LDL
cholesterol, HDL cholesterol,
triglycerides, weight, and mean arterial
pressure. Statistical significance was accepted at a value of
P
.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Basal hemodynamic measurements including FBF, forearm vascular resistance, and mean BP for each decade of age are provided in Table 1
. These variables did not differ
significantly among the groups comprising each decade. The subjects
aged 60 to 69 years appeared to have the lowest mean FBF and mean BP as
well as the highest forearm vascular resistance, but these values did
not differ significantly from those of the other decade intervals.
Total, LDL, and HDL cholesterol concentrations,
triglyceride concentrations, weight, and heart rate did not
significantly differ among the age groups.
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Endothelium-Dependent Vasodilation
Endothelium-dependent vasodilation was defined
as the slope of the FBF response in milliliters per 100 mL tissue per
minute to methacholine dose in micrograms per minute. This slope
decreased significantly with each decade of age (P<.001 by
ANOVA, Fig 2). Indeed,
endothelium-dependent vasodilation decreased
progressively with each decade studied (a significant difference was
detected between all the means). Even by the fourth decade (30 to 39
years), the methacholine dose-response relationship decreased
significantly from 2.25±0.16 (in the third decade) to 1.46±0.10
(mL/100 mL tissue per minute)/(µg/min) (P<.05).
Subsequently, the slope decreased further to 1.05±0.18, 0.48±0.06,
and 0.34±0.11 (mL/100 mL tissue per minute)/(µg/min) for the fifth,
sixth, and seventh decades, respectively. A significant relationship
between the methacholine response and exact age was also detected by
linear regression analysis (Fig 3a), confirming
that endothelium-dependent vasodilation declines
progressively with aging (R=-.81, P<.001).
The impairment in endothelium-dependent
vasodilation with advancing age occurred irrespective of sex, being
evident in both men and women.
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Endothelium-Independent Vasodilation
Endothelium-independent vasodilation was
defined as the slope of the FBF response in milliliters per 100 mL
tissue per minute to nitroprusside dose in micrograms per minute. In
contrast to the findings with methacholine, the slope of this
dose-response relationship did not change significantly with each
decade of age (Fig 4). The mean slope was 1.11±0.21,
0.79±0.11, 0.76±0.13, 0.81±0.21, and 0.90±0.26 for the third,
fourth, fifth, sixth, and seventh decades, respectively
(P=NS by ANOVA). Linear regression demonstrated no
significant relationship between
endothelium-independent vasodilation and age
(P=NS, Fig 3b
).
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Univariate and Multivariate
Models
To further evaluate the decline in endothelium-dependent
vasodilation with advancing age, we evaluated relevant associations
with the blood flow response to methacholine by univariate
analysis (Table 2). Age was a strong
univariate predictor of the FBF response to methacholine.
Even though all subjects had total cholesterol less than
5.18 mmol/L and LDL cholesterol measurements less than the
75th percentile for their age and sex, both total
cholesterol and LDL cholesterol were also
univariate predictors of the
endothelium-dependent response. There was no
association, however, between endothelium-dependent
vasodilation and mean BP or heart rate in these healthy subjects. We
then included these variables in a multivariate
stepwise regression analysis of methacholine response to
determine whether age remains a significant predictor of methacholine
response in their presence. In this stepwise multiple regression model
and all the models we used (Table 3), age remained the
most significant predictor of endothelium-dependent
vasodilation.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The important finding in this study is that endothelium-dependent vasodilation in forearm resistance vessels declines progressively with increasing age. This abnormality is present in healthy adults who have no other cardiovascular risk factors, such as diabetes, hypertension, or hypercholesterolemia. We found that impairment of endothelium-dependent vasodilation was clearly evident by the fourth decade. In contrast, endothelium-independent vasodilation did not change significantly with aging. These observations enable us to conclude that reduced availability of ED-NO may occur as humans age and speculate that this abnormality may create a vascular milieu that is conducive to atherogenesis.
Experimental Models of Aging
Our findings are supported by studies of vascular reactivity in
experimental models of aging. In aged rats, vasodilator responses of
cerebral arterioles to agonists that release
endothelium-derived relaxing factor are
reduced.9 In large cerebral arteries, the vasoconstrictor
response to serotonin is increased significantly in aged
rats when compared with younger adult rats.19 This may
occur because the endothelium-dependent
vasodilation to serotonin is diminished, allowing less
opposition to its direct vasoconstricting action.
Endothelium-dependent vasodilation also
decreases with age in the rat aorta, femoral artery, and carotid
artery.20 21 22 Also,
endothelium-dependent vasodilation to acetylcholine
but not endothelium-independent relaxation to an NO
donor, decreases with increasing age in the resistance arteries of
rats.23 Endothelial thickness is known to
decrease with age in rats,24 which may partly explain
these findings. In contrast, aging does not impair
endothelium-dependent vasodilation in beagle
hindlimb resistance vessels.25
Aging and Endothelial Function in
Humans
Aging is a determinant of abnormal
endothelium-dependent vasodilation in epicardial
coronary arteries as well as in coronary resistance
vessels of patients with multiple risk factors for
atherosclerosis. Vita and colleagues11
demonstrated that increasing age was one predictor of abnormal
endothelium-dependent vasodilation in
atherosclerotic human epicardial coronary arteries. Similarly,
Yasue and colleagues26 demonstrated impaired
endothelium-dependent vasodilation of
angiographically normal coronary arteries in subjects more than
30 years old, but 44% of these subjects had risk factors for
atherosclerosis. Zeiher et al12 reported
that age as well as total serum cholesterol levels were
independent predictors of reduced
endothelium-dependent vasorelaxation to
acetylcholine in human coronary resistance vessels in vivo, but
many of these patients had multiple risk factors for
atherosclerosis. Similarly, aging-associated
impairment in endothelium-dependent vasodilation in
coronary resistance vessels has been described by Egashira et
al13 in a small study of 18 subjects. Celermajer et
al14 reported that aging is associated with impaired
flow-mediated, endothelium-dependent
vasodilation in the brachial artery. Progressive
endothelial dysfunction in this conduit artery occurred
even in the absence of cardiovascular risk factors. One
small study did not find that age affects
endothelium-dependent vasodilation of forearm
resistance vessels, but it may have lacked sufficient statistical
power.27 Our findings are similar to those recently
reported by Taddei and colleagues,28 who evaluated
endothelium-dependent responses to acetylcholine in
both normotensive and hypertensive subjects.
In our study, increasing age was accompanied by a progressive decline in endothelium-dependent vasodilation in human limb resistance vessels, extending observations made in previous studies to resistance vessels of healthy subjects. Our findings are not confounded by the presence of atheroma or other risk factors for atherosclerosis, such as diabetes, hypercholesterolemia, and hypertension. This observation underscores the likelihood that diffuse and progressive impairment of endothelial function occurs with aging, creating a milieu that predisposes to vascular injury.
Potential Mechanisms of Aging-Induced
Endothelial Dysfunction
The mechanism or mechanisms of endothelial
dysfunction that occur with age have not been elucidated. Potential
mechanisms include reduced synthesis and release of ED-NO, increased
activity of vasoconstrictive prostanoids, poor
diffusion of NO to smooth muscle because of increased intimal
thickness, degradation of ED-NO by oxygen-derived free radicals, or
advanced glycosylation end products.
Of these possibilities, we believe that the most plausible involve increased degradation of NO. Free radicals such as superoxide anion and hydrogen peroxide may decrease the half-life of released NO.29 Acute or cumulative response to environmental pollutants can expose the vessel wall to higher levels of free radicals.30 31 Oxidant stresses, and therefore free radical concentration, also may be greater in older individuals because of changes in diet.32 33 Advanced glycosylation end products increase with age and may contribute to decreased endothelium-dependent vasodilation by inactivating ED-NO, as they do with diabetes.34 35
Structural changes occur in the vasculature with aging and could contribute to altered vascular responses. These changes are particularly evident in large and medium-sized arteries36 and include decreased distensibility with age.37 Morphological changes occur in the media, where the orderly arrangement of laminae and elastin fibers is lost38 and elastin is replaced with collagen.39 These structural changes do not contribute to the findings in this study, as endothelium-independent vasodilation did not decline with aging.
Conclusion
Endothelium-dependent vasodilation becomes
progressively impaired as individuals age. This abnormality occurs in
resistance vessels and as such may be a marker for more widespread
endothelial dysfunction. Therapeutic strategies
directed at improving endothelial function should be
studied because they may reduce the incidence of
atherosclerosis that occurs with aging.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by a National Institutes of Health Program Project Grant in Vascular Biology and Medicine (HL-48743) and a Grant-in-Aid from the American Heart Association (90-871). M.A.C. is a recipient of a National Heart, Lung, and Blood Institute Academic Award in Systemic and Pulmonary Vascular Disease (HL-02663). The authors very gratefully acknowledge Joanne Normandin for manuscript preparation.
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Footnotes |
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Reprint requests to Mark A. Creager, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
Received November 10, 1995; first decision December 1, 1995; accepted December 1, 1995.
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S. M.L. Wallace, Yasmin, C. M. McEniery, K. M. Maki-Petaja, A. D. Booth, J. R. Cockcroft, and I. B. Wilkinson Isolated Systolic Hypertension Is Characterized by Increased Aortic Stiffness and Endothelial Dysfunction Hypertension, July 1, 2007; 50(1): 228 - 233. [Abstract] [Full Text] [PDF]
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L. Azadbakht, M. Kimiagar, Y. Mehrabi, A. Esmaillzadeh, F. B. Hu, and W. C. Willett Soy Consumption, Markers of Inflammation, and Endothelial Function: A cross-over study in postmenopausal women with the metabolic syndrome Diabetes Care, April 1, 2007; 30(4): 967 - 973. [Abstract] [Full Text] [PDF]
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S. J. Ridout, B. A. Parker, and D. N. Proctor Age and regional specificity of peak limb vascular conductance in women J Appl Physiol, December 1, 2005; 99(6): 2067 - 2074. [Abstract] [Full Text] [PDF]
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K. Kublickiene, E. Svedas, B.-M. Landgren, M. Crisby, N. Nahar, H. Nisell, and L. Poston Small Artery Endothelial Dysfunction in Postmenopausal Women: In Vitro Function, Morphology, and Modification by Estrogen and Selective Estrogen Receptor Modulators J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6113 - 6122. [Abstract] [Full Text] [PDF]
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L. Lind, N. Fors, J. Hall, K. Marttala, and A. Stenborg A Comparison of Three Different Methods to Evaluate Endothelium-Dependent Vasodilation in the Elderly: The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2368 - 2375. [Abstract] [Full Text] [PDF]
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S. S. Najjar, A. Scuteri, and E. G. Lakatta Arterial Aging: Is It an Immutable Cardiovascular Risk Factor? Hypertension, September 1, 2005; 46(3): 454 - 462. [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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M. Schmitt, A. Avolio, A. Qasem, C. M. McEniery, M. Butlin, I. B. Wilkinson, and J. R. Cockcroft Basal NO Locally Modulates Human Iliac Artery Function In Vivo Hypertension, July 1, 2005; 46(1): 227 - 231. [Abstract] [Full Text] [PDF]
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C. Heiss, S. Keymel, U. Niesler, J. Ziemann, M. Kelm, and C. Kalka Impaired Progenitor Cell Activity in Age-Related Endothelial Dysfunction J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1441 - 1448. [Abstract] [Full Text] [PDF]
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M. R. Skilton, N. T. Lai, K. A. Griffiths, L. M. Molyneaux, D. K. Yue, D. R. Sullivan, and D. S. Celermajer Meal-related increases in vascular reactivity are impaired in older and diabetic adults: insights into roles of aging and insulin in vascular flow Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1404 - H1410. [Abstract] [Full Text] [PDF]
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R. A. Malik, I. J. Schofield, A. Izzard, C. Austin, G. Bermann, and A. M. Heagerty Effects of Angiotensin Type-1 Receptor Antagonism on Small Artery Function in Patients With Type 2 Diabetes Mellitus Hypertension, February 1, 2005; 45(2): 264 - 269. [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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T. Kurotobi, H. Sato, K. Kinjo, D. Nakatani, H. Mizuno, M. Shimizu, K. Imai, A. Hirayama, K. Kodama, M. Hori, et al. Reduced collateral circulation to the infarct-related artery in elderly patients with acute myocardial infarction J. Am. Coll. Cardiol., July 7, 2004; 44(1): 28 - 34. [Abstract] [Full Text] [PDF]
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O. W. H. van der Heijden, Y. P. G. Essers, L. H. J. Simkens, Q. G. A. Teunissen, L. L. H. Peeters, J. G. R. De Mey, and G. J. J. M. van Eys Aging Blunts Remodeling of the Uterine Artery During Murine Pregnancy Reproductive Sciences, July 1, 2004; 11(5): 304 - 310. [Abstract] [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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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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M. Ogami, Y. Ikura, M. Ohsawa, T. Matsuo, S. Kayo, N. Yoshimi, E. Hai, N. Shirai, S. Ehara, R. Komatsu, et al. Telomere Shortening in Human Coronary Artery Diseases Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 546 - 550. [Abstract] [Full Text]
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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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C. R. Woodman, E. M. Price, and M. H. Laughlin Selected Contribution: Aging impairs nitric oxide and prostacyclin mediation of endothelium-dependent dilation in soleus feed arteries J Appl Physiol, November 1, 2003; 95(5): 2164 - 2170. [Abstract] [Full Text] [PDF]
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C. R. Woodman, E. M. Price, and M. H. Laughlin Aging induces muscle-specific impairment of endothelium-dependent dilation in skeletal muscle feed arteries J Appl Physiol, November 1, 2002; 93(5): 1685 - 1690. [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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N. Singh, J. Graves, P. D Taylor, R. J MacAllister, and D. R.J Singer Effects of a 'healthy' diet and of acute and long-term vitamin C on vascular function in healthy older subjects Cardiovasc Res, October 1, 2002; 56(1): 118 - 125. [Abstract] [Full Text] [PDF]
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Y. Mukai, H. Shimokawa, M. Higashi, K. Morikawa, T. Matoba, J. Hiroki, I. Kunihiro, H. M.A. Talukder, and A. Takeshita Inhibition of Renin-Angiotensin System Ameliorates Endothelial Dysfunction Associated With Aging in Rats Arterioscler. Thromb. Vasc. Biol., September 1, 2002; 22(9): 1445 - 1450. [Abstract] [Full Text] [PDF]
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I. B. Wilkinson, D. J. Webb, J. R. Cockcroft, S. Kinlay, P. Ganz, and M. A. Creager Nitric Oxide and Regulation of Arterial Elasticity: Right Idea, Wrong Vascular Bed? * Response Hypertension, September 1, 2002; e4(3): . [Full Text] [PDF]
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J. Gomez-Cerezo, J. J. Rios Blanco, I. Suarez Garcia, P. Moreno Anaya, P. Garcia Raya, E. Vazquez-Munoz, and F. J. Barbado Hernandez Noninvasive Study of Endothelial Function in White Coat Hypertension Hypertension, September 1, 2002; 40(3): 304 - 309. [Abstract] [Full Text] [PDF]
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M. Eren, C. A. Painter, J. B. Atkinson, P. J. Declerck, and D. E. Vaughan Age-Dependent Spontaneous Coronary Arterial Thrombosis in Transgenic Mice That Express a Stable Form of Human Plasminogen Activator Inhibitor-1 Circulation, July 23, 2002; 106(4): 491 - 496. [Abstract] [Full Text] [PDF]
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A. M. Kenny, K. M. Prestwood, C. A. Gruman, G. Fabregas, B. Biskup, and G. Mansoor Effects of Transdermal Testosterone on Lipids and Vascular Reactivity in Older Men With Low Bioavailable Testosterone Levels J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2002; 57(7): M460 - 465. [Abstract] [Full Text]
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K. E. Gould, G. E. Taffet, L. H. Michael, R. M. Christie, D. L. Konkol, J. S. Pocius, J. P. Zachariah, D. F. Chaupin, S. L. Daniel, G. E. Sandusky Jr., et al. Heart failure and greater infarct expansion in middle-aged mice: a relevant model for postinfarction failure Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H615 - H621. [Abstract] [Full Text] [PDF]
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J. H. Stein, C. M. Carlsson, K. Papcke-Benson, S. E. Aeschlimann, A. Bodemer, M. Carnes, and P. E. McBride The effects of lipid-lowering and antioxidant vitamin therapies on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemia J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1806 - 1813. [Abstract] [Full Text] [PDF]
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N. H. Buus, M. Bottcher, F. Hermansen, M. Sander, T. T. Nielsen, and M. J. Mulvany Influence of Nitric Oxide Synthase and Adrenergic Inhibition on Adenosine-Induced Myocardial Hyperemia Circulation, November 6, 2001; 104(19): 2305 - 2310. [Abstract] [Full Text] [PDF]
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D. Baldassarre, M. Amato, C. Palombo, C. Morizzo, L. Pustina, and C. R. Sirtori Time course of forearm arterial compliance changes during reactive hyperemia Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1093 - H1103. [Abstract] [Full Text] [PDF]
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S. Taddei, A. Virdis, L. Ghiadoni, G. Salvetti, G. Bernini, A. Magagna, and A. Salvetti Age-Related Reduction of NO Availability and Oxidative Stress in Humans Hypertension, August 1, 2001; 38(2): 274 - 279. [Abstract] [Full Text] [PDF]
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J. C. Sullivan and C. A. Davison Effect of age on electrical field stimulation (EFS)-induced endothelium-dependent vasodilation in male and female rats Cardiovasc Res, April 1, 2001; 50(1): 137 - 144. [Abstract] [Full Text] [PDF]
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J. A. Beckman, A. Thakore, B. H. Kalinowski, J. R. Harris, and M. A. Creager Radiation therapy impairs endothelium-dependent vasodilation in humans J. Am. Coll. Cardiol., March 1, 2001; 37(3): 761 - 765. [Abstract] [Full Text] [PDF]
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A. D. Hingorani, J. Cross, R. K. Kharbanda, M. J. Mullen, K. Bhagat, M. Taylor, A. E. Donald, M. Palacios, G. E. Griffin, J. E. Deanfield, et al. Acute Systemic Inflammation Impairs Endothelium-Dependent Dilatation in Humans Circulation, August 29, 2000; 102(9): 994 - 999. [Abstract] [Full Text] [PDF]
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M. Preik, M. Kelm, P. Rosen, D. Tschope, and B. E. Strauer Additive Effect of Coexistent Type 2 Diabetes and Arterial Hypertension on Endothelial Dysfunction in Resistance Arteries of Human Forearm Vasculature Angiology, July 1, 2000; 51(7): 545 - 554. [Abstract] [PDF]
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S. Taddei, F. Galetta, A. Virdis, L. Ghiadoni, G. Salvetti, F. Franzoni, C. Giusti, and A. Salvetti Physical Activity Prevents Age-Related Impairment in Nitric Oxide Availability in Elderly Athletes Circulation, June 27, 2000; 101(25): 2896 - 2901. [Abstract] [Full Text] [PDF]
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K. Asai, R. K. Kudej, Y.-T. Shen, G.-P. Yang, G. Takagi, A. B. Kudej, Y.-J. Geng, N. Sato, J. B. Nazareno, D. E. Vatner, et al. Peripheral Vascular Endothelial Dysfunction and Apoptosis in Old Monkeys Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1493 - 1499. [Abstract] [Full Text] [PDF]
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H. O. Steinberg, G. Paradisi, J. Cronin, K. Crowde, A. Hempfling, G. Hook, and A. D. Baron Type II Diabetes Abrogates Sex Differences in Endothelial Function in Premenopausal Women Circulation, May 2, 2000; 101(17): 2040 - 2046. [Abstract] [Full Text] [PDF]
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B. M. Balletshofer, K. Rittig, M. D. Enderle, A. Volk, E. Maerker, S. Jacob, S. Matthaei, K. Rett, and H. U. Haring Endothelial Dysfunction Is Detectable in Young Normotensive First-Degree Relatives of Subjects With Type 2 Diabetes in Association With Insulin Resistance Circulation, April 18, 2000; 101(15): 1780 - 1784. [Abstract] [Full Text] [PDF]
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M. R. Rinder, R. J. Spina, and A. A. Ehsani Enhanced endothelium-dependent vasodilation in older endurance-trained men J Appl Physiol, February 1, 2000; 88(2): 761 - 766. [Abstract] [Full Text] [PDF]
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J. Case and C. A. Davison Estrogen Alters Relative Contributions of Nitric Oxide and Cyclooxygenase Products to Endothelium-Dependent Vasodilation J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 524 - 530. [Abstract] [Full Text]
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S. J Duffy, G. New, R. W Harper, and I. T Meredith Metabolic vasodilation in the human forearm is preserved in hypercholesterolemia despite impairment of endothelium-dependent and independent vasodilation Cardiovasc Res, August 15, 1999; 43(3): 721 - 730. [Abstract] [Full Text] [PDF]
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G. E. McVeigh, C. W. Bratteli, D. J. Morgan, C. M. Alinder, S. P. Glasser, S. M. Finkelstein, and J. N. Cohn Age-Related Abnormalities in Arterial Compliance Identified by Pressure Pulse Contour Analysis : Aging and Arterial Compliance Hypertension, June 1, 1999; 33(6): 1392 - 1398. [Abstract] [Full Text] [PDF]
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G. Dell'Omo, L. Ferrini, M. Morale, F. De Negri, E. Melillo, F. Carmassi, and R. Pedrinelli Acetylcholine-Mediated Vasodilatation and Tissue-type Plasminogen Activator Release in Normal and Hypertensive Men Angiology, April 1, 1999; 50(4): 273 - 282. [Abstract] [PDF]
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M. D. Delp, M. V. Evans, and C. Duan Effects of aging on cardiac output, regional blood flow, and body composition in Fischer-344 rats J Appl Physiol, November 1, 1998; 85(5): 1813 - 1822. [Abstract] [Full Text] [PDF]
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M. Hausberg, R. P. Hoffman, V. K. Somers, C. A. Sinkey, A. L. Mark, and E. A. Anderson Contrasting Autonomic and Hemodynamic Effects of Insulin in Healthy Elderly Versus Young Subjects Hypertension, March 1, 1997; 29(3): 700 - 705. [Abstract] [Full Text]
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S. Pinto, A. Virdis, L. Ghiadoni, G. Bernini, M. Lombardo, F. Petraglia, A. R. Genazzani, S. Taddei, and A. Salvetti Endogenous Estrogen and Acetylcholine-Induced Vasodilation in Normotensive Women Hypertension, January 1, 1997; 29(1): 268 - 273. [Abstract] [Full Text] [PDF]
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