(Hypertension. 2000;35:936.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Pharmacological Concentrations of Ascorbic Acid Are Required for the Beneficial Effect on Endothelial Vasomotor Function in Hypertension
From the Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass.
Correspondence Joseph A. Vita, MD, Cardiology C-8, Boston Medical Center, 88 E Newton St, Boston, MA 02118. E-mail jvita{at}bu.edu
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Abstract |
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Abstract—Increased production of superoxide anion may contribute to impaired bioactivity of endothelium-derived nitric oxide in hypertension. Ascorbic acid is capable of scavenging superoxide anion; however, experimental studies have shown that high physiological concentrations (>1 mmol/L) of ascorbic acid are required to prevent superoxide-mediated vascular dysfunction. To seek kinetic evidence that superoxide anion contributes to endothelial vasomotor dysfunction in human hypertension, we examined the effects of 2.4 or 24 mg/min ascorbic acid intra-arterial infusions on forearm blood flow responses to methacholine or sodium nitroprusside in 30 patients with hypertension and 22 age-matched controls. Endothelium-dependent vasodilation to methacholine was significantly impaired in the hypertensive patients, with a response to the highest dose of methacholine (10 µg/min) of 12.3±6.7 compared with 16.1±5.8 mL · min-1 · dL tissue-1 in the controls (P<0.001). The response to sodium nitroprusside was equivalent in the 2 groups. Ascorbic acid at 24 mg/min significantly improved the forearm blood flow response to methacholine in hypertensive patients with a peak response of 16.1±7.1 mL · min-1 · dL tissue-1 (P=0.001). This dose produced a cephalic vein ascorbic acid concentration of 3.2±1.4 mmol/L. In contrast, ascorbic acid at 2.4 mg/min had no effect on the methacholine response. Ascorbic acid at both doses had no effect on the vasodilator response to sodium nitroprusside in hypertensive patients or the methacholine response in the controls. These results agree with the predicted kinetics for superoxide anion–mediated impairment of endothelium-derived nitric oxide action. Thus, superoxide anion may contribute to impaired endothelium-dependent vasodilation in patients with hypertension.
Key Words: ascorbic acid • endothelium • hypertension, essential • superoxide
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Introduction |
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The endothelium controls vascular homeostasis through the release of a number of regulatory substances, including nitric oxide.1 With one exception,2 the majority of studies suggests that the bioactivity of endothelium-derived nitric oxide (EDNO) is impaired in essential hypertension.3 4 5 Loss of EDNO action may contribute to the pathogenesis of the vascular complications of hypertension, including coronary artery disease and stroke.6
The bioactivity of nitric oxide is limited by its reaction with superoxide anion to form peroxynitrite.7 Vascular production of superoxide anion is increased in animal models of hypertension,8 9 and endothelial vasomotor dysfunction in this setting is reversed with superoxide dismutase.9 Previous studies have demonstrated that acute intra-arterial administration of ascorbic acid improves EDNO-mediated vasodilation in forearm microvessels of patients with hypertension,10 diabetes mellitus,11 or hypercholesterolemia,12 all conditions associated with increased production of reactive oxygen species. Because ascorbic acid is capable of scavenging superoxide anion, one assumption has been that it improves EDNO action in hypertension and other disease states by this mechanism. Using an in vitro model of superoxide-mediated vascular dysfunction, we recently demonstrated that high physiological concentrations (>1 mmol/L) of ascorbic acid are required to prevent superoxide-mediated impairment of EDNO action.13 The purpose of the present study was to investigate the dose-dependent effects of ascorbic acid on endothelial vasomotor function in patients with hypertension and to seek kinetic evidence that superoxide anion contributes to endothelial dysfunction in this setting.
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Methods |
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Research Subjects
Patients with a clinical history of essential hypertension (on treatment for hypertension or with diastolic blood pressure >95 mm Hg) and age-matched nonhypertensive volunteers were recruited for study by newspaper advertisement. Patients were excluded if they had a history of cigarette smoking, diabetes mellitus (on hypoglycemic treatment or with fasting glucose >140 mg/dL), hypercholesterolemia (on lipid-lowering treatment or with fasting LDL cholesterol greater than the 75th percentile for age and gender14 ), coronary artery disease, peripheral vascular disease, hormone replacement therapy, or use of antioxidant vitamins (vitamins C or E). All subjects provided informed consent.
Study Protocol
Patients discontinued all medications for at least 48 hours,
aspirin for 2 weeks, and alcohol and caffeine for 12 hours before
participating in the present study. Patients were studied in the
postabsorptive state in a quiet, dimmed, temperature-controlled
vascular laboratory (24°C). With the use of
sterile conditions and 1% lidocaine local anesthesia, a
20-gauge polyethylene catheter (Arrow International) was inserted into
the nondominant brachial artery for measurement of blood pressure and
infusion of drugs. After catheter insertion, 5% dextrose in water
(Baxter Healthcare Co) was infused at 0.4 mL/min for at least 30
minutes while stable baseline flow and blood pressure conditions were
established. Forearm blood flow was measured by venous occlusion
plethysmography with calibrated mercury-in-silastic strain gauges and
automatic venous-cuff occlusion at 40 mm Hg (Hokanson, Inc).
Circulation to the hand was excluded by inflating a wrist cuff to
suprasystolic pressure 1 minute before initiation of flow
measurements. At least 5 separate measurements were made and averaged
for each flow determination. Blood pressure was measured via the
arterial catheter by use of a pressure transducer (Maxxim
Medical) and physiological recorder (Gould
Instrument Systems). Forearm vascular resistance was calculated as the
ratio of mean blood pressure to flow.
The following drug infusion protocol was completed: (1) serial 5-minute
infusions of methacholine (0.3, 1.0, 3.0, and 10 µg/min; Roche
Laboratories) or sodium nitroprusside (0.3, 1.0, 3.0, and 10 µg/min;
Elkins-Sinn, Inc), (2) dextrose control for 30 minutes to reestablish
control conditions, (3) ascorbic acid (Abbott Laboratories) at 2.4
mg/min or 24 mg/min for 10 minutes, and (4) repeat methacholine or
nitroprusside infusions while continuing the ascorbic acid infusion.
Forearm blood flow and blood pressure were measured at the end of each
infusion. The doses of ascorbic acid were selected to provide a final
plasma concentration of 
1 and 10 mmol/L, on the basis of
measured baseline blood flow of 2.5 mL ·
min-1 · dL
tissue-1, an estimated forearm volume of 1 L,
and the assumption that ascorbic acid is excluded from red blood cells
during the short-term infusion. The effects of the 2 doses of ascorbic
acid on the flow responses to methacholine or nitroprusside were
examined on separate days in separate subjects.
Biochemical Analyses
Total cholesterol, HDL cholesterol,
triglycerides, glucose, and creatinine were
measured with an automated analyzer (Hitachi model 717, Hitachi
Instruments). LDL cholesterol was calculated by the
Friedewald formula.15 Ascorbic acid concentration in
metaphosphoric acid–precipitated plasma at baseline was measured by
high-pressure liquid chromatography and electrochemical
detection as previously described.16 Ascorbic acid
concentrations were also determined in samples collected from the
cephalic vein in the same arm during ascorbic infusion in arbitrarily
selected patients receiving the 24 mg/min dose of ascorbic acid as an
indirect measure of the achieved arterial ascorbic acid
concentration.
Statistical Analysis
The effects of ascorbic acid on the forearm blood flow responses
to methacholine and nitroprusside were examined by repeated-measures
ANOVA with Student-Newman-Keuls post hoc comparison. Clinical
characteristics for the hypertensive and normal groups were compared by
the 2-tailed unpaired t test or the
2 test as appropriate. We explored the
relations between ascorbic acid concentration, conventional risk
factors for atherosclerosis, methacholine responses,
and improvement after ascorbic acid infusion by use of linear
regression analysis. Analyses were performed with the
use of SigmatStat for Windows Version 2.03 (SPSS Inc). Data are
presented as mean±SD unless otherwise indicated.
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Results |
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Subjects
A total of 30 hypertensive patients and 22 normotensive subjects were enrolled in the study. Their clinical characteristics are displayed in the Table. The 2 groups were matched for age, gender, and total and LDL cholesterol. As expected, blood pressure was significantly higher in the hypertensive group. In addition, the hypertensive group had significantly higher body mass index and fasting glucose levels and significantly lower HDL cholesterol levels. There also was a trend for higher triglyceride concentrations in the hypertensive group (P=0.07). Baseline ascorbic acid levels were similar in the hypertensive and normotensive patients (P=0.14).
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Comparison of Forearm Blood Flow Responses in Normotensive and
Hypertensive Subjects
As shown in Figure 1, baseline
forearm blood flow was comparable in hypertensive and normotensive
groups (2.6±1.1 and 2.5±1.0 mL ·
min-1 · dL
tissue-1, respectively).
Intra-arterial infusion of methacholine increased forearm
blood flow in both groups; however, the vasodilator response was lower
in the hypertensive subjects (P<0.001 by repeated-measures
ANOVA). The response to the highest dose of methacholine (10 µg/min)
was 12.3±6.7 mL · min-1 · dL
tissue-1 in the hypertensive subjects and
16.1±5.8 mL · min-1 · dL
tissue-1 in the normotensive subjects. By linear
regression analysis, glucose, triglycerides, body
mass index, and HDL cholesterol did not correlate with the
methacholine response. The vasodilator responses to
intra-arterial nitroprusside were equivalent in the 2
groups (Figure 1), with responses to the highest dose (10
µg/min) of 12.4±2.5 and 12.8±4.9 mL ·
min-1 · dL
tissue-1, respectively. Blood pressure was not
affected by methacholine or nitroprusside at any dose, and forearm
vascular resistance paralleled the forearm blood flow responses
(data not shown).
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Effect of Ascorbic Acid on Forearm Blood Flow Responses in
Hypertensive Subjects
As shown in Figure 2, ascorbic acid
infusion in 9 patients at 2.4 mg/min had no effect on the forearm blood
flow response to methacholine in hypertensive patients. At peak doses
of methacholine, the forearm blood flow responses were 12.7±5.8 and
12.5±5.8 mL · min-1 · dL
tissue-1 before and during ascorbic acid
infusion, respectively. In contrast, ascorbic acid infusion in 12
patients at 24 mg/min improved the forearm blood flow response to
methacholine (P<0.001 by repeated-measures ANOVA). At peak
methacholine dose, the forearm blood flow response increased from
12.1±7.8 to 16.1±7.1 mL · min-1
· dL tissue-1. The response during high-dose
ascorbic acid infusion was equivalent to the response of the
age-matched normal controls (P=0.93). By linear regression
analysis, glucose, triglycerides, and HDL
cholesterol did not correlate with the extent of
improvement.
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As shown in Figure 3, ascorbic acid at 24 mg/min had no effect on the forearm blood flow response to methacholine in the age-matched normal subjects. At peak methacholine doses, the forearm blood flow responses were 15.9±6.8 and 14.4±5.7 mL · min-1 · dL tissue-1 before and during ascorbic acid infusion, respectively. Furthermore, this dose of ascorbic acid had no effect on the forearm blood flow response to sodium nitroprusside in hypertensive patients. At peak nitroprusside dose, the forearm blood flow responses were 12.9±5.3 and 12.0±4.2 mL · min-1 · dL tissue-1 before and during ascorbic acid infusion, respectively.
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During ascorbic acid infusions at 24 mg/min, the ascorbic acid concentration in blood collected from the cephalic vein in 9 patients was 3.2±1.4 mmol/L. This concentration is compatible with the predicted concentration of 10 mmol/L, because the cephalic vein concentration likely does not fully reflect the local concentration in forearm resistance vessels. There was no correlation between baseline ascorbic acid concentration and the response to methacholine (data not shown). There also was no correlation between baseline ascorbic acid concentration and the extent of improvement in methacholine response (data not shown).
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Discussion |
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The present study demonstrates that the forearm blood flow response to methacholine infusion is impaired in patients with hypertension compared with age-matched controls, whereas the blood flow response to sodium nitroprusside is intact. These findings are consistent with impaired EDNO action in forearm microvessels. Concomitant infusion of ascorbic acid at 24 mg/min produced a high physiological concentration in the forearm circulation (at least 3.2 mmol/L) and restored the methacholine response to normal, whereas infusion of a 10-fold lower concentration had no effect on the methacholine response. Ascorbic acid had no effect on the response to nitroprusside in hypertensive subjects and no effect on the response to methacholine in normal subjects. Thus, the high-dose ascorbic acid infusion reversed endothelial dysfunction in patients with hypertension. Although there was a trend for lower baseline plasma ascorbic acid concentrations in the hypertensive patients, there was no correlation between this parameter and endothelium-dependent dilation at baseline or the extent of improvement during ascorbic acid infusion. These findings suggest that the improvement in endothelial vasomotor function with ascorbic acid cannot be explained by correction of an absolute deficiency of ascorbic acid.
The findings of the present study support the results of previous studies demonstrating impaired forearm blood flow responses to endothelium-dependent vasodilators in patients with hypertension.3 4 Although HDL cholesterol concentrations were lower and plasma glucose and triglyceride concentrations were higher in the hypertensive patients compared with the controls, linear regression analysis suggests that these factors did not explain the observed differences in the response to methacholine. The association of these factors with hypertension has been previously recognized.14
Previous studies have also demonstrated beneficial effects of high
concentrations of ascorbic acid on endothelial
vasomotor function in patients with risk factors for coronary
artery disease. Ting and colleagues11 12 observed improved
forearm blood flow responses to methacholine during infusion of
ascorbic acid (24 mg/min) in patients with diabetes
mellitus11 and
hypercholesterolemia.12 In a
recent study, Taddei et al10 demonstrated that ascorbic
acid at 0.8 to 16 mg · min-1 · 100
mL forearm tissue-1 (8 to 160 mg/min)
produced a dose-dependent improvement in forearm blood flow responses
to acetylcholine in patients with essential hypertension. In that
study, the beneficial effect of ascorbic acid was eliminated by
concomitant infusion of
NG-monomethyl-L-arginine,
confirming its dependence on nitric oxide synthesis. The present
study confirms those findings and provides further information about
the potential role of superoxide anion as a cause of vascular
dysfunction in hypertension.
Previous experimental studies suggest that vascular production of superoxide anion contributes to impaired EDNO action and elevated blood pressure in hypertension.8 9 There is evidence that xanthine oxidase8 and/or angiotensin II–induced NADH/NADPH oxidases9 may be enzymatic sources of superoxide anion in this disease. Acute elevations in blood pressure17 and pulsatile stretch of endothelial cells18 are also associated with increased production of superoxide anion.
Despite this experimental evidence, it has been difficult to confirm a role for superoxide anion in the vascular dysfunction associated with human hypertension. Garcia et al19 demonstrated no improvement in acetylcholine-mediated dilation of forearm resistance vessels in hypertensive patients during infusion of bovine copper-zinc superoxide dismutase, which reacts with superoxide anion in a highly specific manner. However, failure of this enzymatic preparation to gain access to the intimal or intracellular site of superoxide-nitric oxide interaction might account for these findings. Indeed, in animal studies, beneficial effects of superoxide dismutase are observed only after modification of the enzyme to allow improved access to the endothelial surface.8 20 Inhibition of a possible enzymatic source of superoxide anion (xanthine oxidase) also had no effect on endothelial function in hypertensive patients.21
Ascorbic acid has the potential to scavenge superoxide anion and prevent formation of peroxynitrite,13 and investigators have suggested that improved endothelial vasomotor function after ascorbic acid treatment reflects this mechanism.10 11 16 To address this question, we recently examined the effects of short-term (20- to 30-minute) ascorbic acid exposure on endothelial vasomotor function by using in vitro models of superoxide-mediated vascular dysfunction.13 When an extracellular source of superoxide anion was used, an ascorbic acid concentration of 10 mmol/L was required to restore acetylcholine-mediated vascular relaxation. Under these conditions, 1 mmol/L ascorbic acid had no effect. However, even 10 mmol/L ascorbic acid failed to improve EDNO action when endogenous superoxide anion production was enhanced by treating isolated arterial segments with diethyldithiocarbamate to inhibit superoxide dismutase. This latter finding likely reflects incomplete intracellular transport of ascorbic acid during the relatively short time course of the experiment, in view of the fact that a cell-permeable mimic of superoxide dismutase did restore EDNO action under these conditions. Overall, the findings were consistent with the kinetic prediction that the reaction between ascorbic acid and superoxide anion is too slow [k=3.3x105 (mol/L)-1 · s-1] to compete effectively with the extremely rapid reaction between nitric oxide and superoxide anion [k=1.9x1010 (mol/L)-1 · s-1] unless high physiological concentrations (>1 mmol/L) of ascorbic acid are present.13
The present clinical study was designed to parallel the conditions of our in vitro study and involved a short-term (20- to 30-minute) intra-arterial infusion of ascorbic acid. On the basis of our experimental data, we hypothesized that if superoxide anion contributed to impaired EDNO action in human hypertension, then plasma ascorbic acid concentrations >1 mmol/L would be required to improve the forearm blood flow responses to methacholine. The findings of the present study are consistent with this hypothesis: direct measurements in the forearm suggested that the 24-mg/min infusion produces ascorbic acid concentrations in this range. Also consistent are the findings of Taddei et al,10 who observed improved vasodilator responses to acetylcholine during ascorbic acid infusion of >8 mg/min (estimated plasma concentration 3.3 mmol/L). Thus, increased production of superoxide anion may account for impaired EDNO action in patients with hypertension, and scavenging of superoxide anion may account for the beneficial effects of ascorbic acid in this setting. However, we acknowledge that ascorbic acid also has activity against a variety of other reactive oxygen species22 and that our findings are not specific for superoxide anion.
The observation that the vasodilator response to sodium nitroprusside is preserved in hypertensive patients appears to contradict the conclusion that increased production of superoxide anion accounts for impaired nitric oxide action in hypertension. One would expect that nitric oxide released from sodium nitroprusside should also be susceptible to inactivation by vascular-derived superoxide anion. Because the endothelium has been implicated as a cellular source of superoxide anion,23 investigators have argued that nitric oxide produced within endothelial cells might be more susceptible to inactivation than nitric oxide released from nitroprusside.10 However, this suggestion would not explain the improved response to EDNO agonists observed after treatment with enzymatic superoxide dismutase in animal models of hypertension.20 Ascorbic acid is likely to also be acting extracellularly, in view of the fact that it was ineffective against an endogenous source of superoxide in isolated aorta,13 and uptake into endothelial cells is probably minimal during the 20- to 30-minute time course of the study.24 As an alternative explanation for preserved nitroprusside responses and the lack of ascorbic acid effect on nitroprusside responses in hypertensive patients, one might consider that nitroprusside and EDNO may produce vasodilation by different mechanisms. In support of this possibility, vasodilator responses to authentic NO are impaired in hypercholesterolemia,25 whereas responses to sodium nitroprusside are preserved in this condition, which is known to be associated with increased production of superoxide anion.26
Regarding clinical implications, epidemiological studies suggest links between ascorbic acid status and blood pressure27 and cardiovascular disease.28 Chronic ascorbic acid treatment has been shown to improve EDNO action in patients with coronary artery disease29 and congestive heart failure.30 Although it is tempting to conclude that chronic ascorbic acid improves endothelial function by scavenging superoxide anion, it is unlikely that this mechanism is operative with the plasma levels achieved with chronic oral treatment (60 to 100 µmol/L). Thus, alternative mechanisms for the beneficial effects of chronic oral ascorbic acid should be considered.
In conclusion, the present study demonstrates that high physiological levels of ascorbic acid are required to restore EDNO action in patients with hypertension. These results agree with the predicted kinetics for superoxide anion–mediated impairment of endothelium-derived nitric oxide action. Thus, superoxide anion may contribute to impaired endothelium-dependent vasodilation in patients with hypertension.
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health (HL-53398, HL-55993, and HL-52936 to Dr Vita and HL-59634 and HL-55854 to Dr Keaney). Dr Keaney is the recipient of a Clinical Investigator Development Award (HL-03195) from the National Institutes of Health. Dr Duffy is the recipient of the National Health and Medical Research Council of Australia’s Neil Hamilton Fairley Fellowship (No. 007139). Dr Vita is an Established Investigator of the American Heart Association. We acknowledge the superb technical work of Todd Jewett, Beth Hankin, and Timi Mannion.
Received September 8, 1999; first decision October 12, 1999; accepted November 15, 1999.
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S. Mak, C. B. Overgaard, and G. E. Newton Effect of vitamin C and L-NMMA on the inotropic response to dobutamine in patients with heart failure Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2424 - H2428. [Abstract] [Full Text] [PDF]
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 S. J. Duffy, E. S. Biegelsen, R. T. Eberhardt, D. F. Kahn, B. A. Kingwell, and J. A. Vita Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation Hypertension, October 1, 2005; 46(4): 707 - 713. [Abstract] [Full Text] [PDF]
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 T. Heitzer, S. Baldus, Y. von Kodolitsch, V. Rudolph, and T. Meinertz Systemic Endothelial Dysfunction as an Early Predictor of Adverse Outcome in Heart Failure Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1174 - 1179. [Abstract] [Full Text] [PDF]
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K. D. Monahan, I. Eskurza, and D. R. Seals Ascorbic acid increases cardiovagal baroreflex sensitivity in healthy older men Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2113 - H2117. [Abstract] [Full Text] [PDF]
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 S. Kinlay, D. Behrendt, J. C. Fang, D. Delagrange, J. Morrow, J. L. Witztum, N. Rifai, A. P. Selwyn, M. A. Creager, and P. Ganz long-term effect of combined vitamins e and c on coronary and peripheral endothelial function J. Am. Coll. Cardiol., February 18, 2004; 43(4): 629 - 634. [Abstract] [Full Text] [PDF]
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S. Mak and G. E. Newton Redox modulation of the inotropic response to dobutamine is impaired in patients with heart failure Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H789 - H795. [Abstract] [Full Text] [PDF]
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A. K. Nightingale, M. Schmitt, M. P. Frenneaux, G. Piccirillo, M. Nocco, A. Moise, M. Lionetti, C. Naso, and S. D. C. V. Marigliano Letter: Vitamin C in Heart Failure: Hype or Hope? Hypertension, February 1, 2004; e6(2): . [Full Text] [PDF]
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G. E. Callera, R. M. Touyz, S. A. Teixeira, M. N. Muscara, M. H. C. Carvalho, Z. B. Fortes, D. Nigro, E. L. Schiffrin, and R. C. Tostes ETA Receptor Blockade Decreases Vascular Superoxide Generation in DOCA-Salt Hypertension Hypertension, October 1, 2003; 42(4): 811 - 817. [Abstract] [Full Text] [PDF]
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M. E. Widlansky, D. T. Price, N. Gokce, R. T. Eberhardt, S. J. Duffy, M. Holbrook, C. Maxwell, J. Palmisano, J. F. Keaney Jr, J. D. Morrow, et al. Short- and Long-Term COX-2 Inhibition Reverses Endothelial Dysfunction in Patients With Hypertension Hypertension, September 1, 2003; 42(3): 310 - 315. [Abstract] [Full Text] [PDF]
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D. F. Kahn, S. J. Duffy, D. Tomasian, M. Holbrook, L. Rescorl, J. Russell, N. Gokce, J. Loscalzo, and J. A. Vita Effects of Black Race on Forearm Resistance Vessel Function Hypertension, August 1, 2002; 40(2): 195 - 201. [Abstract] [Full Text] [PDF]
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 J. Pleiner, G. Schaller, F. Mittermayer, M. Bayerle-Eder, M. Roden, and M. Wolzt FFA-Induced Endothelial Dysfunction Can Be Corrected by Vitamin C J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2913 - 2917. [Abstract] [Full Text] [PDF]
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 M. Rathaus and J. Bernheim Oxygen species in the microvascular environment: regulation of vascular tone and the development of hypertension Nephrol. Dial. Transplant., February 1, 2002; 17(2): 216 - 221. [Abstract] [Full Text] [PDF]
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R. Wu, D. Lamontagne, and J. de Champlain Antioxidative Properties of Acetylsalicylic Acid on Vascular Tissues From Normotensive and Spontaneously Hypertensive Rats Circulation, January 22, 2002; 105(3): 387 - 392. [Abstract] [Full Text] [PDF]
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N. Gokce, M. Holbrook, S. J. Duffy, S. Demissie, L.A. Cupples, E. Biegelsen, J. F. Keaney Jr, J. Loscalzo, and J. A. Vita Effects of Race and Hypertension on Flow-Mediated and Nitroglycerin-Mediated Dilation of the Brachial Artery Hypertension, December 1, 2001; 38(6): 1349 - 1354. [Abstract] [Full Text] [PDF]
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X. Chen, R. M. Touyz, J. B. Park, and E. L. Schiffrin Antioxidant Effects of Vitamins C and E Are Associated With Altered Activation of Vascular NADPH Oxidase and Superoxide Dismutase in Stroke-Prone SHR Hypertension, September 1, 2001; 38(3): 606 - 611. [Abstract] [Full Text] [PDF]
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S. J. Duffy, E. S. Biegelsen, M. Holbrook, J. D. Russell, N. Gokce, J. F. Keaney Jr, and J. A. Vita Iron Chelation Improves Endothelial Function in Patients With Coronary Artery Disease Circulation, June 12, 2001; 103(23): 2799 - 2804. [Abstract] [Full Text] [PDF]
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M. Grossmann, D. Dobrev, H. M. Himmel, U. Ravens, and W. Kirch Ascorbic Acid-Induced Modulation of Venous Tone in Humans Hypertension, March 1, 2001; 37(3): 949 - 954. [Abstract] [Full Text] [PDF]
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M. M. Givertz, D. B. Sawyer, and W. S. Colucci Antioxidants and Myocardial Contractility : Illuminating the "Dark Side" of {{beta}}-Adrenergic Receptor Activation? Circulation, February 13, 2001; 103(6): 782 - 783. [Full Text] [PDF]
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S. Mak and G. E. Newton Vitamin C Augments the Inotropic Response to Dobutamine in Humans With Normal Left Ventricular Function Circulation, February 13, 2001; 103(6): 826 - 830. [Abstract] [Full Text] [PDF]
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S. J. Duffy, N. Gokce, M. Holbrook, L. M. Hunter, E. S. Biegelsen, A. Huang, J. F. Keaney Jr., and J. A. Vita Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H528 - H534. [Abstract] [Full Text] [PDF]
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