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Am J Physiol Heart Circ Physiol 286: H1528-H1534, 2004; doi:10.1152/ajpheart.00879.2003
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Ascorbic acid does not affect large elastic artery compliance or central blood pressure in young and older men

Iratxe Eskurza,1 Kevin D. Monahan,1 Jed A. Robinson,1 and Douglas R. Seals1,2

1Department of Integrative Physiology, University of Colorado, Boulder 80309; and 2Divisions of Cardiology and Geriatric Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262

Submitted 14 September 2003 ; accepted in final form 12 December 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Large elastic artery compliance is reduced and arterial blood pressure (BP) is increased in the central (cardiothoracic) circulation with aging. Reactive oxygen species may tonically modulate central arterial compliance and BP in humans, and oxidative stress may contribute to adverse changes with aging. If so, antioxidant administration may have beneficial effects. Young (Y; 26 ± 1 yr, mean ± SE) and older (O; 63 ± 2 yr, mean ± SE) healthy men were studied at baseline and during acute (intravenous infusion; Y: n = 13, O: n = 12) and chronic (500 mg/day for 30 days; Y: n = 10, O: n = 10) administration of ascorbic acid (vitamin C). At baseline, peripheral (brachial artery) BP did not differ in the two groups, but carotid artery compliance was 43% lower (1.2 ± 0.1 vs. 2.1 ± 0.1 mm2/mmHg x 10–1, P < 0.01) and central (carotid) BP (systolic: 116 ± 5 vs. 101 ± 3 mmHg, P < 0.05, and pulse pressure: 43 ± 4 vs. 36 ± 3 mmHg, P = 0.16), carotid augmentation index (AIx; 27.8 ± 7.8 vs. –20.0 ± 6.6%, P < 0.001), and aortic pulse wave velocity (PWV; 950 ± 88 vs. 640 ± 38 cm/s, P < 0.01) were higher in the older men. Plasma ascorbic acid concentrations did not differ at baseline (Y: 71 ± 5 vs. O: 61 ± 7 µmol/l, P = 0.23), increased (P < 0.001) to supraphysiological levels during infusion (Y: 1,240 ± 57 and O: 1,056 ± 83 µmol/l), and were slightly elevated (P < 0.001 vs. baseline) with supplementation (Y: 96 ± 5 µmol/l vs. O: 85 ± 6). Neither ascorbic acid infusion nor supplementation affected peripheral BP, heart rate, carotid artery compliance, central BP, carotid AIx, or aortic PWV (all P > 0.26). These results indicate that the adverse changes in large elastic artery compliance and central BP with aging in healthy men are not 1) mediated by ascorbic acid-sensitive oxidative stress (infusion experiments) and 2) affected by short-term, moderate daily ascorbic acid (vitamin C) supplementation.

arterial stiffness; vitamin C; antioxidants; human aging

ONE OF THE MOST physiologically and clinically important changes that occurs with cardiovascular (CV) aging is a progressive reduction in the compliance (increase in stiffness) of the large elastic arteries in the central (i.e., cardiothoracic) circulation (e.g., the proximal aorta and carotid artery) (33, 35, 50). This process leads to several potentially adverse changes in CV structure and function including increases in central arterial blood pressure (BP), arterial intima-media thickening, increases in aortic impedance, left ventricular remodeling, reduced diastolic function, and decreased baroreflex responsiveness (28, 34, 35, 43, 44, 50). Indeed, reduced large elastic artery compliance is an independent risk factor for future CV disease (CVD) (25, 32).

Structural changes in the extracellular matrix of the vascular wall including increases in collagen content and cross-linking as well as fragmentation of elastin are important mechanisms underlying reductions in large elastic artery compliance with aging (33, 35). However, changes in factors that modulate vascular smooth muscle cell tone also affect large artery compliance (33, 35, 47).

Reactive oxygen species (ROS) are one such factor that may modulate central large elastic artery compliance in humans (45, 59). These effects may be mediated by reducing the bioavailability of nitric oxide (NO), a potent vasodilator released from the vascular endothelium (5, 33, 35, 52). Indeed, there is evidence that NO tonically enhances large artery compliance (13). Moreover, ROS could modulate the compliance of these arteries by augmenting the synthesis and release of endothelin-1 (4), a powerful endothelium-derived vasoconstrictor factor, and/or by indirectly increasing local vascular renin-angiotensin system bioactivity (20, 36). ROS may also have direct contraction-stimulating effects on vascular smooth muscle cells (30). Oxidative stress, i.e., excessive bioavailability of ROS, develops with aging (32, 57a, 49) and, therefore, could produce increased vascular smooth muscle tone-mediated reductions in arterial compliance in older adults.

The physiological effects of ROS and, therefore, oxidative stress can be revealed by administration of antioxidants such as ascorbic acid (vitamin C) (29). A change in physiological function with ascorbic acid should reflect the presence of a tonic influence of ROS bioactivity. Administration of ascorbic acid has been reported to reduce the augmentation index (AIx) derived from peripheral artery pulse wave analysis, an indirect measure of arterial stiffness, in both healthy young men (59) and in middle-aged and older patients with Type II diabetes (45). However, the effects of ROS/oxidative stress on proximal large elastic artery compliance and central BP have not been directly determined in humans in general and in older adults in particular.

Finally, if acute administration of ascorbic acid can increase large elastic artery compliance and, as a result, lower central BP, especially in older adults, it is possible that daily supplementation of ascorbic acid could be used therapeutically to sustain these improvements. However, currently no information is available on this possibility.

In the present investigation, we infused ascorbic acid to acutely raise plasma concentrations to supraphysiological levels in young and older healthy men to determine whether oxidative stress tonically modulates large elastic artery compliance and central BP. We then supplemented ascorbic acid oral intake for 30 days to identify any possible therapeutic benefits.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects

A total of 25 healthy men participated in protocol 1 (acute infusion of ascorbic acid): 13 young (aged 18–30 yr) and 12 older (aged 60–79 yr); 20 of these subjects (10 young and 10 older) also completed protocol 2 (chronic supplementation). Subjects were sedentary, nonobese, normotensive (brachial BP < 140/90 mmHg), and free of overt cardiovascular disease as assessed by medical history, physical examination, blood chemistry, and resting and exercise (older men only) ECG. Candidates who used antioxidants (vitamin C and E or any other type) within 6 wk of the time of recruitment or who were taking medications were excluded from participation. All subjects gave their written informed consent to participate. All procedures were revised and approved by the Human Research Committee of the University of Colorado (Boulder, CO).

General Experimental Procedures

Before the main experimental sessions, subjects fasted for 12 h. During these sessions subjects were positioned supine and instrumented with an intravenous catheter in the left arm for ascorbic acid infusions and acquisition of blood.

Carotid Artery Compliance and BP

Carotid arterial compliance was assessed noninvasively as previously described in detail (54). Briefly, common carotid artery diameters and contralateral carotid artery BP were simultaneously assessed by high-resolution ultrasonography (Toshiba 6000 Power Vision) and applanation tonometry, respectively. Carotid artery diameters were measured ~2 cm proximal to the carotid bulb with the transducer placed at a 90° angle to the vessel. Images were recorded on super-VHS videocassettes for subsequent off-line analysis with image analysis software. Maximal diameters (i.e., systolic expansion) and minimal diameters (e.g., diastolic relaxation) were measured based on carotid BP waveforms. All image analyses were performed by the same investigator (I. Eskurza), who was blinded to the identity of the subjects. Applanation tonometry was performed over the contralateral carotid artery with a pencil-type probe connected to a high-fidelity strain-gauge transducer (TCB-500, Millar Instruments). This technique provides waveforms with the same harmonic content as those obtained invasively in humans (31). Because this technique depends on hold-down pressure, to determine carotid BP the brachial artery was used to calibrate carotid artery waveforms (1). Carotid artery compliance was calculated as previously described (54). The reliability of measurements of carotid artery diameter, BP, and compliance in our laboratory have been established previously, with coefficients of variation of 2, 7, and 5%, respectively (54).

Arterial Stiffness

Carotid AIx and aortic pulse wave velocity (PWV), measures of overall and proximal large elastic arterial stiffness, respectively (45), were determined as described in detail previously (53). Briefly, AIx was determined by applanation tonometry of the carotid artery, and aortic PWV was determined using transcutaneous Doppler flowmeters positioned at the aortic arch and femoral artery. The reliability of these measurements in our laboratory have been established previously, with coefficients of variation ranging from 7 to 8% (53).

Brachial Artery BP

BP was measured over the brachial artery with the use of a semiautomated device (Dynamap XL, Johnson and Johnson).

Body Composition

The percent body fat was measured using dual-energy X-ray absorptiometry (DXA-GE, Lunar; Madison, WI, software version 5.60.003).

Blood Measurements

Plasma samples were analyzed for venous ascorbic acid concentrations (14), oxidized LDL, an indirect measure of oxidative stress (26), cathecholamines (48), and endothelin-1 (competitive radioimmunoassay) (37).

Protocols

Protocol 1. To determine whether ROS/oxidative stress tonically modulate central large elastic artery compliance, stiffness, and BP and contribute to adverse changes with age, measurements were obtained before (saline infusion) and after intravenous administration of a pharmacological dose of ascorbic acid (American Regent Laboratories): a priming bolus of 0.06 g/kg fat-free mass (FFM) dissolved in 100 ml saline infused at 5 ml/min for 20 min, followed by a "drip infusion" of 0.02 g/kg FFM dissolved in 30 ml saline administered over 60 min at 0.5 ml/min.

Protocol 2. To determine whether the age-associated changes in central large elastic artery compliance, stiffness, and BP can be at least partially reversed with oral ascorbic acid supplementation, subjects ingested 500 mg/day of ascorbic acid (time-release capsules, Goldline Laboratories) for 30 consecutive days as described previously (19). Chronic supplementation was started at least 72 h after the acute administration session. Adherence to the treatment was established by subject logs that were completed each day and by measuring plasma ascorbic acid concentration 2 wk after the treatment was started.

Statistical Analysis

Differences in subject characteristics between the two groups were determined by ANOVA. Repeated-measures ANOVA was used to examine the main effects of acute and chronic ascorbic acid administration. Univariate correlation analyses were performed to examine relations between variables of interest. All data are reported as means ± SE. Statistical significance was set at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Protocol 1: Acute Ascorbic Acid Infusion

Subject characteristics. Values are shown in Table 1. The groups did not differ in height, brachial systolic or mean BP, heart rate, or plasma HDL-cholesterol, insulin, or glucose. Body weight, percent body fat, brachial diastolic BP, plasma total cholesterol, LDL-cholesterol, and plasma oxidized LDL were greater in the older men (P < 0.05).


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  		Table 1. Subject characteristics for protocol 1: ascorbic acid infusion

 

Plasma ascorbic acid concentrations. At baseline, there were no group differences in plasma ascorbic acid concentrations (young: 71 ± 5 vs. older: 61 ± 7 µmol/l, P = 0.23). With infusion, plasma ascorbic acid concentrations increased above baseline (P = 0.0001) to supraphysiological levels in both groups (young: 1,240 ± 57 and older: 1,056 ± 83 µmol/l).

Carotid artery compliance, BP, AIx, and aortic PWV. Results are presented in Fig. 1 and Table 2. Baseline carotid artery compliance was 43% lower (P < 0.01) and carotid BP (systolic: +15 mmHg, P < 0.05, and pulse pressure: +7 mmHg, P = 0.12), AIx (+48%, P < 0.001), and aortic PWV (+48%, P < 0.001) were higher in the older men. Correction of the measures of arterial compliance and stiffness for central BP had no effect on the age-associated differences. Carotid artery diameter during diastole did not differ between the groups (Table 2). Ascorbic acid infusion had no effect on any of these CV functions.



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  		Fig. 1. Carotid artery compliance, aortic pulse wave velocity, and carotid augmentation index at baseline and during ascorbic acid infusion (protocol 1) in the young and older men. Values are means ± SE. *P < 0.01 vs. young men.

 

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  		Table 2. Protocol 1: peripheral and central BP, heart rate, and carotid artery diameters at baseline and during ascorbic acid infusion

 

Plasma catecholamine and endothelin-1 concentrations. At baseline, plasma concentrations of epinephrine were not different in the young (35 ± 12 pg/ml) and older (37 ± 12 pg/ml) men, but plasma norepinephrine (255 ± 39 vs. 138 ± 19 pg/ml) and endothelin-1 (6.8 ± 0.3 vs. 5.5 ± 0.4 pg/ml) concentrations were greater in the older men (both P < 0.05). There were no changes from these baseline values during ascorbic acid infusion (data not shown).

Correlates of baseline arterial stiffness. Baseline plasma norepinephrine concentrations were positively related to AIx (r = 0.61, P < 0.01) and aortic PWV (r = 0.54, P < 0.05). Baseline carotid systolic BP was positively related to AIx (r = 0.43, P = 0.06) and aortic PWV (r = 0.53, P < 0.05), and brachial systolic BP was positively related to aortic PWV (r = 0.55, P = 0.01).

Protocol 2: Chronic Ascorbic Acid Supplementation

Subject characteristics. Characteristics of the subset of subjects completing protocol 2 (10 young and 10 older) were not different from those for the overall group presented in Table 1.

Plasma ascorbic acid concentrations. At baseline, there were no group differences in plasma ascorbic acid concentrations for these subsets of the young and older men (young: 65 ± 5 vs. older: 60 ± 9 µmol/l, P = 0.64). Plasma concentrations of ascorbic acid measured 12 h after oral ingestion were modestly elevated compared with baseline (P < 0.01) and not different in the two groups (older: 85 ± 6 vs. young: 96 ± 5 µmol/l, P = 0.18).

Carotid artery compliance, BP, AIx, and aortic PWV. The same age group differences were observed at baseline for this subset of subjects as in the overall subject sample (Fig. 1 and Table 2). Chronic ascorbic acid supplementation had no effect on any of the CV functions compared with baseline (Table 3).


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  		Table 3. Protocol 2: peripheral and central BP, heart rate, and carotid artery diameters at baseline and at the end of 30 days of ascorbic acid supplementation

 

Plasma catecholamine and endothelin-1 concentrations. As in protocol 1, in these subgroups baseline plasma concentrations of norepinephrine and endothelin-1 were higher in the older men (P < 0.05), whereas plasma epinephrine concentrations did not differ. Chronic ascorbic acid supplementation had no effect on plasma concentrations compared with baseline values.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
There are two primary new findings from this investigation. First, the results of our infusion experiments indicate that ROS, at least those sensitive to ascorbic acid, do not tonically modulate large elastic artery compliance or central BP in young and older healthy men. As a result, our findings suggest that ascorbic acid-sensitive oxidative stress does not contribute mechanistically to the adverse changes in compliance and central BP with aging. Second, consistent with these observations from our infusion experiments, we found that short-term, moderate daily ascorbic acid supplementation did not affect central arterial compliance or BP and thus does not appear to provide any therapeutic benefits even in older adults.

Peripheral and Central Arterial Function and BP in Healthy Men with Aging

In the present study, carotid artery compliance was lower and measures of large artery stiffness and central BP were greater in the older compared with young men, consistent with previous findings (33, 35, 50). In contrast, peripheral BP was not different in the two age groups, confirming that the major effect of primary aging is on the large elastic arteries and systolic BP in the central circulation (33, 35, 50). Indeed, although peripheral systolic BP increases with age in the general adult population (33, 35, 50), we have demonstrated previously that peripheral large artery stiffness and systolic BP are not increased in rigorously screened healthy older men in whom elevations in central systolic BP are observed (44, 54, 55).

Role of ROS/Oxidative Stress in Large Elastic Artery Compliance and Central BP in Young and Older Healthy Men

At least three lines of evidence support the likelihood that the acute ascorbic acid infusion used in the present study reduced ROS/oxidative stress, particularly in our older subjects. First, it has been demonstrated that the plasma concentrations of ascorbic acid achieved during the infusions in the present study scavenge superoxide anions in vitro (29). Second, our laboratory recently demonstrated that the same intravenous infusion of ascorbic acid as used in the present study decreases plasma isoprostanes, a biomarker of lipid oxidation-associated oxidative stress, in a group of older healthy men similar to those studied here (2). Finally, coadministration of ascorbic acid restores impaired endothelium-dependent vasodilation in older humans via a NO-dependent mechanism (52). Moreover, recent findings from our laboratory show that the same intravenous infusion of ascorbic acid as used in the present study restores the impaired large artery flow-mediated dilation in healthy middle-aged and older men to levels observed in young adult controls (12).

Two previous investigations reported reductions in measures of arterial stiffness in response to ascorbic acid administration in humans, one in healthy young adults (59) and the other in middle-aged and older patients with Type 2 diabetes (45). This apparent discrepancy between the results of our study and those of earlier investigations could involve at least three factors. First, these studies used peripheral artery-derived estimates of arterial stiffness, not direct measures of central large elastic artery compliance as in the present investigation. Peripheral arteries have more vascular smooth muscle cells than the large central arteries and, therefore, are more likely to show changes in compliance in response to a stimulus that affects vascular smooth muscle cell tone. Second, in both of these previous studies, peripheral BP was reduced with ascorbic acid and therefore could have contributed to the reductions in the BP-sensitive measures of arterial stiffness used. In contrast, ascorbic acid infusion did not affect peripheral or central BP in the present investigation, and no changes in any measure of central arterial compliance or stiffness was observed in the absence of such reductions in BP. Finally, the present study involved healthy young and older men. Although oxidative stress appears to develop with age even in healthy adult humans (32, 49) and was present in our healthy older men as indicated by their higher baseline plasma oxidized LDL levels, Type 2 diabetes, particularly in middle-aged and older patients, is associated with much greater oxidative stress than that observed with primary aging (21). Ascorbic acid administration may reveal a significant contribution of oxidant stress to the marked increase in large artery stiffness associated with this more severe pathophysiological vascular state.

Effects of Chronic Oral Ascorbic Acid Supplementation in Healthy Older Men

To our knowledge, the present investigation is the first to determine the effects of daily ascorbic acid supplementation on large elastic artery compliance and central BP in healthy adults, including changes with aging. We found that daily supplementation of 500 mg of ascorbic acid for 1 mo had no effect on central arterial compliance, stiffness, or BP in either age group. These findings are not surprising given the lack of effect of supraphysiological doses of ascorbic acid on compliance and BP in our acute infusion experiments. These observations indicate that 30 days of moderate daily ascorbic acid supplementation has no obvious therapeutic efficacy for increasing large elastic artery compliance and lessening its adverse cardiovascular consequences (e.g., the increase in central BP) in older adults.

Experimental Considerations Regarding Ascorbic Acid Administration

We chose to use ascorbic because it is one of the most potent water-soluble antioxidants in humans. Ascorbic acid scavenges superoxide anions and many other ROS, including those produced by lipid peroxidation (3, 14, 46, 58). Moreover, ascorbic acid can be acutely infused at rates that attain supraphysiological plasma concentrations, which are known to reduce superoxide anions and increase NO bioavailability (29). Ascorbic acid consistently improves vascular endothelial function in groups with CVD risk factors and patients with clinical CVD (10, 19, 23, 25, 27, 38, 51, 56, 57). Importantly for the present study, ascorbic acid was the antioxidant used previously to determine the role of ROS/oxidative stress in modulating large elastic artery stiffness in human subjects (45, 59). Thus ascorbic acid administration is a well-established antioxidant model for reducing ROS/oxidative stress in human CV research.

In the present study, we also wanted to determine, for the first time, whether oral ascorbic acid supplementation could be used to reverse the adverse age-related changes in central BP and large elastic artery compliance. The dose (i.e., 500 mg/day) and treatment duration (30 days) were chosen on the basis that they previously had been shown to restore vascular endothelium-dependent dilation in patients with coronary artery disease (19). In addition, plasma ascorbic acid is tightly controlled by tissue transport, absorption, and excretion. When given orally, the relation between oral dose and plasma concentration is sigmoidal, and plasma is completely saturated at a dose of 400 mg/day (39, 40), with the kidney rapidly excreting any excess ascorbic acid. However, even with the use of slow-releasing tablets such as those used in the present study up to 80% of the ascorbic acid taken orally is excreted within 5 h (39). Given these facts, it is unlikely that a larger dose and/or longer period of ascorbic administration would have produced different results.

Finally, we cannot exclude the possibility that other antioxidants (e.g., vitamin E, glutathione, {beta}-carotene, and/or superoxide dismutase) may have produced improvements in compliance and central BP. Present experimental findings, however, are mixed regarding the effect of vitamin E (and, even more so, {beta}-carotene) on CV function (6, 11, 17, 24). Even combinations of antioxidants (normally ascorbic acid, vitamin E, and {beta}-carotenes) when given orally at physiological doses show conflicting results on CV outcomes (18, 42). Superoxide dismutase, perhaps the most important extra- and intracellular antioxidant against superoxide anions, does not improve endothelial function in humans, probably due to lack of penetration into the vascular wall (16). We recognize that the most effective approach to acutely reducing ROS/oxidative stress would be to inhibit the sources of production. With respect to the vascular wall, NADPH oxidase, uncoupled endothelial NO synthase (eNOS) (i.e., as occurs with tetrahydrobiopterin cofactor deficiency), and xanthine oxidase are the most important sources of oxidative stress. Unfortunately, currently there is no available method to selectively inhibit superoxide anion production by NADPH oxidase, the major source of ROS, although tetrahydrobiopterin and allopurinol (a xanthine oxidase inhibitor) administration, respectively, could be used to decrease superoxide anion from uncoupled eNOS and xanthine oxidase.

Physiological and Clinical Implications

The reduction in large elastic artery compliance (increase in stiffness) in the central circulation with aging is one of the primary contributors to age-associated CVD-related pathophysiology (28, 34, 35, 43, 44, 50). By failing to demonstrate a clear role for oxidative stress, the present findings point in part to the importance of structural factors in determining large elastic artery compliance and central arterial BP in healthy adult humans as well as their changes with aging. These structural alterations involve changes in key extracellular matrix proteins including increases in collagen content and cross-linking as well as fragmentation of elastin (34). Other local, humoral, and perhaps neural influences on vascular smooth muscle cell tone in the arterial wall may, however, also contribute. Local influences include vascular angiotensin II and endothelin-1 bioactivity (15, 60). Indeed, in the present investigation, plasma endothelin-1 concentrations were higher in the older men. Humoral influences include circulating vasoactive factors such as renin-angiotensin system hormones, catecholamines, and atrial natriuretic peptide (7, 22). Finally, augmented sympathetic nervous system stimulation of vascular smooth muscle cell tone may have played a role in the changes in large elastic artery function with aging. We have shown the importance of augmented sympathetic {alpha}-adrenergic tone in reduced femoral artery blood flow and vascular conductance with aging in healthy adult men (8, 9). Consistent with this possibility, in the present study, baseline plasma norepinephrine concentrations were elevated in the older men and were positively related to both AIx (r = 0.61) and aortic PWV (r = 0.54).

In conclusion, the results of the present study indicate that the adverse changes in large elastic artery compliance and central BP with aging in healthy men are neither mediated by ascorbic acid-sensitive oxidative stress nor affected by shortterm, moderate daily ascorbic acid (vitamin C) supplementation.


   ACKNOWLEDGMENTS
 
GRANTS

This study was supported by National Institutes of Health Grants AG-06537, AG-13038, AG-19365, AG-00828, RR-00051, and HL-76624.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. R. Seals, Dept. of Integrative Physiology, Univ. of Colorado-Boulder, UCB 354, Boulder, CO 80309 (E-mail: seals{at}spot.colorado.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Armentano R, Megnien JL, Simon A, Bellenfant F, Barra J, and Levenson J. Effects of hypertension on viscoelasticity of carotid and femoral arteries in humans. Hypertension 26: 48–54, 1995.[Abstract/Free Full Text]
  2. Bell C, Petitt DS, Jones PP, and Seals DR. Influence of adiposity on tonic sympathetic support of resting metabolism in healthy adults. Int J Obes Relat Metab Disord 27: 1315–1318, 2003.[CrossRef][ISI][Medline]
  3. Bodannes RS and Chan PC. Ascorbic acid as a scavenger of singlet oxygen. FEBS Lett 105: 195–196, 1979.[CrossRef][ISI][Medline]
  4. Boulanger CM, Tanner FC, Bea ML, Hahn AW, Werner A, and Luscher TF. Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium. Circ Res 70: 1191–1197, 1992.[Abstract/Free Full Text]
  5. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, and Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 24: 471–476, 1994.[Abstract]
  6. Chowienczyk PJ, Kneale BJ, Brett SE, Paganga G, Jenkins BS, and Ritter JM. Lack of effect of vitamin E on L-arginine-responsive endothelial dysfunction in patients with mild hypercholesterolaemia and coronary artery disease. Clin Sci (Lond) 94: 129–134, 1998.[Medline]
  7. Cody RJ, Atlas SA, Laragh JH, Kubo SH, Covit AB, Ryman KS, Shaknovich A, Pondolfino K, Clark M, Camargo MJ, Scarborough RM, and Lewicki JA. Atrial natriuretic factor in normal subjects and heart failure patients. Plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion. J Clin Invest 78: 1362–1374, 1986.[ISI][Medline]
  8. Dinenno FA, Jones PP, Seals DR, and Tanaka H. Limb blood flow and vascular conductance are reduced with age in healthy humans: relation to elevations in sympathetic nerve activity and declines in oxygen demand. Circulation 100: 164–170, 1999.[Abstract/Free Full Text]
  9. Dinenno FA, Tanaka H, Stauffer BL, and Seals DR. Reductions in basal limb blood flow and vascular conductance with human ageing: role for augmented alpha-adrenergic vasoconstriction. J Physiol 536: 977–983, 2001.[Abstract/Free Full Text]
  10. Duffy SJ, Gokce N, Holbrook M, Huang A, Frei B, Keaney JF Jr, and Vita JA. Treatment of hypertension with ascorbic acid. Lancet 354: 2048–2049, 1999.[CrossRef][ISI][Medline]
  11. Elliott TG, Barth JD, and Mancini GB. Effects of vitamin E on endothelial function in men after myocardial infarction. Am J Cardiol 76: 1188–1190, 1995.[CrossRef][ISI][Medline]
  12. Eskurza I, Monahan K, Robinson J, and Seals D. Effect of acute and chronic ascorbic acid on flow-mediated dilation with sedentary and physically active human aging. J Physiol. In press.
  13. Fitch RM, Vergona R, Sullivan ME, and Wang YX. Nitric oxide synthase inhibition increases aortic stiffness measured by pulse wave velocity in rats. Cardiovasc Res 51: 351–358, 2001.[Abstract/Free Full Text]
  14. Frei B, England L, and Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA 86: 6377–6381, 1989.[Abstract/Free Full Text]
  15. Ganten D, Hermann K, Unger T, and Lang RE. The tissue renin-angiotensin systems: focus on brain angiotensin, adrenal gland and arterial wall. Clin Exp Hypertens 5: 1099–1118, 1983.
  16. Garcia CE, Kilcoyne CM, Cardillo C, Cannon RO 3rd, Quyyumi AA, and Panza JA. Evidence that endothelial dysfunction in patients with hypercholesterolemia is not due to increased extracellular nitric oxide breakdown by superoxide anions. Am J Cardiol 76: 1157–1161, 1995.[CrossRef][ISI][Medline]
  17. Gazis A, White DJ, Page SR, and Cockcroft JR. Effect of oral vitamin E (alpha-tocopherol) supplementation on vascular endothelial function in Type 2 diabetes mellitus. Diabet Med 16: 304–311, 1999.[CrossRef][ISI][Medline]
  18. Gilligan DM, Sack MN, Guetta V, Casino PR, Quyyumi AA, Rader DJ, Panza JA, and Cannon RO 3rd. Effect of antioxidant vitamins on low density lipoprotein oxidation and impaired endothelium-dependent vasodilation in patients with hypercholesterolemia. J Am Coll Cardiol 24: 1611–1617, 1994.[Abstract]
  19. Gokce N, Keaney JF Jr, Frei B, Holbrook M, Olesiak M, Zachariah BJ, Leeuwenburgh C, Heinecke JW, and Vita JA. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 99: 3234–3240, 1999.[Abstract/Free Full Text]
  20. Griendling KK, Minieri CA, Ollerenshaw JD, and Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 74: 1141–1148., 1994.[Abstract/Free Full Text]
  21. Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, and Channon KM. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105: 1656–1662, 2002.[Abstract/Free Full Text]
  22. Hall JE, Guyton AC, Jackson TE, Coleman TG, Lohmeier TE, and Trippodo NC. Control of glomerular filtration rate by renin-angiotensin system. Am J Physiol Renal Fluid Electrolyte Physiol 233: F366–F372, 1977.[Free Full Text]
  23. Heitzer T, Just H, and Munzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 94: 6–9, 1996.[Abstract/Free Full Text]
  24. Heitzer T, Yla Herttuala S, Wild E, Luoma J, and Drexler H. Effect of vitamin E on endothelial vasodilator function in patients with hypercholesterolemia, chronic smoking or both. J Am Coll Cardiol 33: 499–505, 1999.[Abstract/Free Full Text]
  25. Hodes RJ, Lakatta EG, and McNeil CT. Another modifiable risk factor for cardiovascular disease? Some evidence points to arterial stiffness. J Am Geriatr Soc 43: 581–582, 1995.[ISI][Medline]
  26. Holvoet P, Vanhaecke J, Janssens S, Van de Werf F, and Collen D. Oxidized LDL and malondialdehyde-modified LDL in patients with acute coronary syndromes and stable coronary artery disease. Circulation 98: 1487–1494, 1998.[Abstract/Free Full Text]
  27. Hornig B, Arakawa N, Kohler C, and Drexler H. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 97: 363–368, 1998.[Abstract/Free Full Text]
  28. Hunt BE, Farquhar WB, and Taylor JA. Does reduced vascular stiffening fully explain preserved cardiovagal baroreflex function in older, physically active men? Circulation 103: 2424–2427, 2001.[Abstract/Free Full Text]
  29. Jackson TS, Xu A, Vita JA, and Keaney JF Jr. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 83: 916–922, 1998.[Abstract/Free Full Text]
  30. Katusic ZS and Vanhoutte PM. Superoxide anion is an endothelium-derived contracting factor. Am J Physiol Heart Circ Physiol 257: H33–H37, 1989.[Abstract/Free Full Text]
  31. Kelly R, Hayward C, Avolio A, and O'Rourke M. Noninvasive determination of age-related changes in the human arterial pulse. Circulation 80: 1652–1659, 1989.[Abstract/Free Full Text]
  32. Knight JA. The biochemistry of aging. Adv Clin Chem 35: 1–62, 2000.[ISI][Medline]
  33. Lakatta EG. Cardiovascular aging research: the next horizons. J Am Geriatr Soc 47: 613–625, 1999.[ISI][Medline]
  34. Lakatta EG. Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons. Heart Fail Rev 7: 29–49, 2002.[CrossRef][Medline]
  35. Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises. Part III: cellular and molecular clues to heart and arterial aging. Circulation 107: 490–497, 2003.[Free Full Text]
  36. Laursen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman BA, and Harrison DG. Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 95: 588–593, 1997.[Abstract/Free Full Text]
  37. Lerman A, Edwards BS, Hallett JW, Heublein DM, Sandberg SM, and Burnett JC Jr. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 325: 997–1001, 1991.[Abstract]
  38. Levine GN, Frei B, Koulouris SN, Gerhard MD, Keaney JF Jr, and Vita JA. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 93: 1107–1113, 1996.[Abstract/Free Full Text]
  39. Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, and Cantilena LR. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci USA 93: 3704–3709, 1996.[Abstract/Free Full Text]
  40. Levine M, Wang Y, Padayatty SJ, and Morrow J. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci USA 98: 9842–9846, 2001.[Abstract/Free Full Text]
  41. McKechnie R, Rubenfire M, and Mosca L. Antioxidant nutrient supplementation and brachial reactivity in patients with coronary artery disease. J Lab Clin Med 139: 133–139, 2002.[CrossRef][ISI][Medline]
  42. Monahan KD, Dinenno FA, Tanaka H, Clevenger CM, DeSouza CA, and Seals DR. Regular aerobic exercise modulates age-associated declines in cardiovagal baroreflex sensitivity in healthy men. J Physiol 529: 263–271, 2000.[Abstract/Free Full Text]
  43. Monahan KD, Tanaka H, Dinenno FA, and Seals DR. Central arterial compliance is associated with age- and habitual exercise-related differences in cardiovagal baroreflex sensitivity. Circulation 104: 1627–1632, 2001.[Abstract/Free Full Text]
  44. Mullan BA, Young IS, Fee H, and McCance DR. Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes. Hypertension 40: 804–809, 2002.[Abstract/Free Full Text]
  45. Nishikimi M. Oxidation of ascorbic acid with superoxide anion generated by the xanthine-xanthine oxidase system. Biochem Biophys Res Commun 63: 463–468, 1975.[CrossRef][ISI][Medline]
  46. Oliver JJ and Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 23: 554–566, 2003.[Abstract/Free Full Text]
  47. Peuler JD and Johnson GA. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci 21: 625–636, 1977.[CrossRef][ISI][Medline]
  48. Pollack M and Leeuwenburgh C. Molecular mechanisms of oxidative stress in aging: free radicals, aging, antioxidants and disease. In: Handbook of Oxidants and Antioxidants in Exercise, edited by Sen C, Packer L, and Hanninen O. Amsterdam: Elsevier, 1999, part X, chapt. 30, p. 881–923.
  49. Rowe JW. Clinical consequences of age-related impairments in vascular compliance. Am J Cardiol 60: 68G–71G, 1987.[CrossRef][Medline]
  50. Taddei S, Virdis A, Ghiadoni L, Magagna A, and Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 97: 2222–2229, 1998.[Abstract/Free Full Text]
  51. Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Fasolo CB, Sudano I, and Salvetti A. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 91: 1981–1987, 1995.[Abstract/Free Full Text]
  52. Tanaka H, DeSouza CA, and Seals DR. Absence of age-related increase in central arterial stiffness in physically active women. Arterioscler Thromb Vasc Biol 18: 127–132, 1998.[Abstract/Free Full Text]
  53. Tanaka H, Dinenno FA, Monahan KD, Clevenger CM, DeSouza CA, and Seals DR. Aging, habitual exercise, and dynamic arterial compliance. Circulation 102: 1270–1275, 2000.[Abstract/Free Full Text]
  54. Tanaka H, Dinenno FA, Monahan KD, DeSouza CA, and Seals DR. Carotid artery wall hypertrophy with age is related to local systolic blood pressure in healthy men. Arterioscler Thromb Vasc Biol 21: 82–87, 2001.[Abstract/Free Full Text]
  55. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, and Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 97: 22–28, 1996.[ISI][Medline]
  56. Ting HH, Timimi FK, Haley EA, Roddy MA, Ganz P, and Creager MA. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation 95: 2617–2622, 1997.[Abstract/Free Full Text]
  57. Van der Loo B, Labugger R, Skipper JN, Bachsmind M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky SD, Quaschning T, Malinski T, Gygi D, Ullrich V, and Luscher TF. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 192: 1731–1743, 2000.[Abstract/Free Full Text]
  58. Wasil M, Halliwell B, Moorhouse CP, Hutchison DC, and Baum H. Biologically-significant scavenging of the myeloperoxidase-derived oxidant hypochlorous acid by some anti-inflammatory drugs. Biochem Pharmacol 36: 3847–3850, 1987.[CrossRef][ISI][Medline]
  59. Wilkinson IB, Megson IL, MacCallum H, Sogo N, Cockcroft JR, and Webb DJ. Oral vitamin C reduces arterial stiffness and platelet aggregation in humans. J Cardiovasc Pharmacol 34: 690–693, 1999.[CrossRef][ISI][Medline]
  60. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, and Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415, 1988.[CrossRef][Medline]



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