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Am J Physiol Heart Circ Physiol 280: H528-H534, 2001;
0363-6135/01 $5.00
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Vol. 280, Issue 2, H528-H534, February 2001

Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension

Stephen J. Duffy, Noyan Gokce, Monika Holbrook, Liza M. Hunter, Elizabeth S. Biegelsen, Annong Huang, John F. Keaney Jr., and Joseph A. Vita

Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118


    ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Hypertension is associated with low plasma ascorbic acid levels and impaired endothelial function. Recent evidence suggests that increased vascular oxidative stress contributes to the pathophysiology of endothelial dysfunction and hypertension. We recently showed that chronic oral ascorbic acid therapy lowers blood pressure in hypertensive patients. We hypothesized that it would also improve endothelial vasomotor function. In a randomized, double-blind, placebo-controlled study, we examined the effect of acute (2 g po) and chronic (500 mg/day for 1 mo) ascorbic acid treatment on brachial artery flow-mediated dilation in 39 patients with hypertension. Compared with 82 age- and gender-matched normotensive controls, these patients had impaired endothelium-dependent, flow-mediated dilation of the brachial artery [8.9 ± 6.1 vs. 11.2 ± 5.7% (SD), P < 0.04]. After therapy, plasma ascorbic acid concentrations increased acutely from 50 ± 12 to 149 ± 51 µmol/l and were maintained at 99 ± 33 µmol/l with chronic treatment (both P < 0.001). As previously reported, chronic ascorbic acid therapy reduced systolic and mean blood pressure in these patients. However, acute or chronic ascorbic acid treatment had no effect on brachial artery endothelium-dependent, flow-mediated dilation or on endothelium-independent, nitroglycerin-mediated dilation. These results demonstrate that conduit vessel endothelial dysfunction secondary to hypertension is not reversed by acute or chronic treatment with oral ascorbic acid. The effects of this treatment on resistance vessel vasomotor function warrant further investigation.

antioxidants; endothelium-derived factors; nitric oxide


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ESSENTIAL HYPERTENSION AFFECTS one-fourth of the US adult population (4), and its effective treatment substantially reduces cardiovascular morbidity (8). Recent studies have demonstrated that hypertension is associated with endothelial dysfunction in conduit and resistance vessels (5, 17, 24, 33, 42, 43), and inhibition of endothelium-derived nitric oxide (NO) synthesis is known to elicit hypertension (20). The endothelium plays a critical role in regulating vasomotor tone, platelet activity, and leukocyte adhesion through the release of a number of paracrine factors, including NO and prostacyclin (36). Therefore, investigators have postulated that endothelial dysfunction contributes to the pathogenesis of hypertension and to the macrovascular complications of the disease, including coronary artery and cerebral vascular disease.

Studies suggest that increased oxidative stress may play a role in the pathophysiology of endothelial dysfunction in hypertension (34). Experimental hypertension is associated with increased production of superoxide anion, which can react with NO and eliminate its biological activity (32). In addition, products of lipid peroxidation may decrease NO and prostacyclin formation (28) and have direct vasoconstrictor properties (2).

Recognition of the potential relation between oxidative stress and vascular dysfunction in hypertension has led to investigations into the link between antioxidant status and blood pressure. Epidemiological studies (11, 15, 29, 37) demonstrate that the dietary intake and plasma concentrations of ascorbic acid, a potent water-soluble antioxidant (13), correlate inversely with hypertension and its clinical sequelae, namely, stroke and cardiovascular disease. A diet containing antioxidant-rich foods can substantially lower blood pressure (1), and we recently demonstrated that treatment with ascorbic acid (500 mg po) for 1 mo lowers systolic and mean blood pressure in patients with hypertension (10). These effects likely reflect improved function of resistance vessels (39, 41).

Ascorbic acid also has been shown to improve conduit vessel endothelial function in coronary artery disease (18, 26). Therefore, the purpose of the present study was to examine the effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Study subjects. Otherwise healthy patients with hypertension and nonhypertensive controls were recruited by advertisement. Hypertension was defined as a history of antihypertensive treatment or untreated diastolic blood pressure >90 mmHg on at least three separate occasions. Nonhypertensive controls were selected by age and gender to match the hypertensive group. Exclusion criteria included a history of coronary artery disease, diabetes mellitus (clinical history or a fasting glucose >140 mg/dl), uncontrolled hypertension (diastolic blood pressure >110 mmHg), congestive cardiac failure, and use of antioxidant vitamins or estrogen replacement therapy within 1 mo. All patients provided written, informed consent as approved by the Institutional Review Board of Boston Medical Center. We recently reported the blood pressure outcome data for this hypertensive group of patients (10).

Study design. All patients fasted overnight and, if applicable, did not smoke for 24 h before two visits, 1 mo apart. Antihypertensive medications were maintained before and during the 1-mo study period, although short- and long-acting vasoactive medications were withheld for 12 and 24 h before each visit, respectively. Blood and urine samples were collected at each visit, and vital signs were measured after 10 min of rest in a semirecumbent position, using an automated monitor (Dinamap XL, Johnson and Johnson Medical, Arlington, TX), and the average of three measurements was recorded. Endothelium-dependent, flow-mediated dilation of the brachial artery was determined using high-resolution vascular ultrasound, with the cuff on the upper arm, as previously described (18, 26). Conduit vessel flow-mediated dilation with this cuff position has been shown to be NO dependent (27).

Patients were then randomized to treatment with 2 g of ascorbic acid or matched placebo tablets (Leiner Health Products, Carson, CA). After 2 h, a blood sample was collected, vital signs were measured again, and flow-mediated dilation was reassessed. Brachial diameter was then determined before and after sublingual nitroglycerin (0.4 mg), except in patients who declined. After 1 mo of double-blind treatment with ascorbic acid (500 mg daily) or matching placebo, patients returned for testing of blood and urine, measurement of vital signs, and reassessment of endothelium-dependent and -independent vasodilation. Compliance was assessed by tablet count and plasma ascorbic acid levels. Healthy controls attended on one occasion and underwent the same vascular function protocol.

Biochemical analyses. Serum total cholesterol, high-density lipoprotein cholesterol, triglycerides, and glucose were measured using an automated analyzer (model 717, Hitachi Instruments, Indianapolis, IN). Low-density lipoprotein cholesterol was calculated using the Friedewald formula (14). Plasma ascorbic acid concentrations were determined as previously described (13). Urine concentrations of 8-epiprostaglandin F2alpha were determined using a commercially available ELISA (Cayman, Ann Arbor, MI) as previously described (18). Plasma concentrations of cGMP (18) and urinary concentrations of 2,3-dinor-6-ketoprostaglandin F1alpha (12) were determined using commercially available ELISA kits (Cayman).

Statistical analysis. Values are means ± SD (text and Tables 1-3) and means ± SE (Fig. 1). Baseline characteristics were compared with the unpaired Student's t-test, chi 2 test, or Fisher's exact test as appropriate. The effect of treatment on vascular measurements, blood pressure, and biochemical markers was compared by two-way repeated-measures ANOVA, with post hoc Student-Newman-Keuls comparison to discriminate differences between treatment and time of the measurements. Univariate clinical and biochemical predictors of flow-mediated dilation in control and hypertensive participants were determined by linear regression. To identify independent predictors of flow-mediated dilation, all variables with a univariate P < 0.10 were then entered into a stepwise multivariate regression model. The study was designed to have 80% power to detect an improvement in flow-mediated dilation of 2.8% with ascorbic acid treatment on the basis of our previous studies (18). Statistical significance was accepted at P < 0.05. 

                              
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  		Table 1.   Clinical and hemodynamic characteristics of healthy controls and patients with hypertension


                              
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  		Table 2.   Baseline characteristics of patients according to treatment assignment


                              
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  		Table 3.   Effect of treatment on brachial artery, hemodynamic, and biochemical parameters



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  		Fig. 1.   Effect of treatment and time on brachial artery dilation. A: effect of treatment and time on endothelium-dependent, flow-mediated dilation. Neither placebo nor ascorbic acid affected flow-mediated dilation (P = 0.37, by 2-way repeated-measures ANOVA). B: effect of treatment on brachial artery dilation in response to sublingual nitroglycerin (NTG). Neither placebo nor ascorbic acid affected endothelium-independent vasodilation in response to nitroglycerin (P = 0.56, by 2-way repeated-measures ANOVA).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subject characteristics. Vascular function was initially assessed in a total of 127 volunteers, including 82 healthy volunteers and 45 patients with hypertension who participated in the treatment phase of the study. One hypertensive patient's vascular study was excluded before unblinding because of poor ultrasound image quality (although biochemical and clinical data were included), and three subjects from each treatment group did not return for the follow-up visit. Clinical and hemodynamic data from the cross-sectional aspect of the study are shown in Table 1. The ascorbic acid (n = 19) and placebo (n = 20) groups were similar with respect to their baseline clinical characteristics (Table 2). The blood pressure responses to treatment have previously been reported (10) but are also shown in Table 3, along with heart rate and biochemical data.

Hypertensive vs. normotensive participants. Systolic and diastolic blood pressure and heart rate were higher in hypertensive patients than in healthy controls (Table 1). Other clinical characteristics were well matched except fasting glucose level, which was higher in the hypertensive patient group, and a trend for body mass index and fasting triglycerides (both P = 0.07), consistent with essential hypertension-associated metabolic syndrome (35). Brachial artery flow-mediated dilation was impaired in the patients with hypertension compared with otherwise healthy, normotensive controls (8.9 ± 6.1 and 11.2 ± 5.7%, respectively, P < 0.04), although nitroglycerin-mediated dilation was similar. The ischemia-induced reactive hyperemic stimulus for flow-mediated dilation tended to be less in the patients with hypertension (Table 1; P = 0.053), consistent with impaired resistance vessel vasomotor function (21, 33, 39, 41).

Univariate predictors of flow-mediated dilation in the whole cohort were resting arterial diameter (r = -0.60, P < 0.0001), female gender (r = 0.50, P < 0.0001), diastolic blood pressure (r = -0.37, P < 0.0001), systolic blood pressure (r = -0.32, P = 0.001), history of smoking (r = -0.24, P = 0.009), history of hypertension (r = -0.19, P = 0.04), and triglyceride levels (r = -0.16, P = 0.08). However, the ischemia-induced reactive hyperemia was not a predictor of flow-mediated dilation. By stepwise multiple regression analysis, resting arterial diameter (P < 0.0001), systolic blood pressure (P < 0.001), diastolic blood pressure (P = 0.002), and history of hypertension (P = 0.01) were independent predictors of flow-mediated dilation (adjusted multiple R2 for model = 0.42).

Brachial artery responses in patients with hypertension. As shown in Fig. 1, acute and chronic ascorbic acid treatment had no effect on brachial artery flow-mediated dilation (P = 0.37, by 2-way repeated-measures ANOVA) or nitroglycerin-mediated dilation (P = 0.56). Flow-mediated dilation in the placebo group was 8.5 ± 5.5% (SD) at baseline, 9.6 ± 6.5% after 2 h, and 9.4 ± 6.5% after 1 mo. In the ascorbic acid group, flow-mediated dilation was 9.2 ± 6.8% at baseline, 7.3 ± 3.8% after 2 h, and 7.8 ± 5.3% after 1 mo. Similarly, ascorbic acid had no effect on baseline brachial artery diameter or hyperemic flow after cuff release (Table 3). Analysis of the patients treated with ascorbic acid to ascertain whether other risk factors (such as hypercholesterolemia, history of smoking, and family history of atherosclerosis) or treatment with conventional antihypertensive therapy predicted change in flow-mediated dilation in response to ascorbic acid did not demonstrate any relationship, although the numbers analyzed were small. In a previous study from our laboratory (26), it was found that patients with coronary artery disease and markedly impaired baseline flow-mediated dilation (<5%) derived the most benefit from ascorbic acid therapy. Inasmuch as there were too few patients with a baseline response <5% in this study for meaningful analysis, we analyzed the data from 25 patients with hypertension (13 ascorbic acid, 12 placebo) with a baseline response of <10%. Ascorbic acid did not augment flow-mediated dilation in this subgroup. Flow-mediated dilation was 5.5 ± 2.7% at baseline, 5.8 ± 3.0% after 2 h, and 7.0 ± 4.6% after 1 mo and was also similar in the placebo subgroup (data not shown; P = 0.70, by 2-way repeated-measures ANOVA). Sublingual nitroglycerin reduced mean blood pressure significantly in both groups to a similar extent during the acute and chronic treatment phases (data not shown).

Ascorbic acid, cGMP, and eicosanoids. Plasma ascorbic acid concentrations were similar in the two groups at baseline. Acute and chronic supplementation with ascorbic acid increased plasma concentrations within the physiological range (P < 0.001; Table 3). Plasma cGMP levels, an index of the L-arginine-NO pathway activity, were not altered by chronic ascorbic acid therapy (Table 3). Urinary concentrations of the stable prostacyclin metabolite 2,3-dinor-6-ketoprostaglandin F1alpha (12) were also not altered by treatment with ascorbic acid (Table 3). Urinary 8-epiprostaglandin F2alpha concentrations, an index of lipid peroxidation (18), were not affected by ascorbic acid treatment (Table 3). Serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and glucose were not altered by ascorbic acid or placebo treatment (data not shown).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

This randomized, double-blind, placebo-controlled study demonstrated that acute and chronic oral ascorbic acid treatment has no beneficial effect on conduit vessel endothelium-dependent, flow-mediated dilation or on the response to nitroglycerin. Comparison of these patients to a group of age- and gender-matched normotensive control subjects confirmed that endothelial dysfunction was present at baseline in patients with essential hypertension. In addition, there was no effect of treatment on plasma cGMP (an index of NO activity) or urinary prostacyclin metabolite concentrations, suggesting that ascorbic acid did not augment the bioavailability of these endothelium-derived vasodilators. Despite the lack of effect on conduit vessel vasomotor function or systemic markers of the bioavailability of endothelium-dependent vasodilators, there was a significant reduction in systolic and mean blood pressure at 1 mo.

Several previous studies have demonstrated that endothelial vasodilator function is impaired in conduit (17, 24, 43) and resistance vessels (5, 33, 41, 42) of patients with essential hypertension. This impairment is believed to contribute to blood pressure elevation (20) and to the vascular complications of the disease, including coronary artery and cerebral vascular disease (19). The hypertensive patients participating in the present study had relatively preserved brachial artery flow-mediated dilation (8.9%) compared with patients with coronary artery disease studied in our laboratory (6.3-7.2%) (18, 26, 44) and compared with patients with other risk factors as reported by other investigators (6, 45). For this reason, we confirmed that impairment of endothelial function was present by examining age- and gender-matched controls. Although we excluded patients with diabetes mellitus, it is interesting that the hypertensive patients in the present study had modestly higher body mass index, fasting glucose, and triglycerides than the controls. This essential hypertension-associated metabolic syndrome has been well described (35). A multivariate analysis suggests that it is unlikely that these metabolic factors account for the observed impairment in flow-mediated dilation in these patients. Indeed, the only clinical factors that predicted endothelial function were systolic and diastolic blood pressure and a history of hypertension.

In contrast to the present study, several prior studies demonstrated a beneficial effect of ascorbic acid treatment on endothelium-dependent vasodilation in essential hypertension. For example, Taddei and colleagues (41) and a study from our own laboratory (39) demonstrated improved forearm microvascular endothelial function during intra-arterial ascorbic acid infusion. Solzbach and colleagues (40) observed improved conduit coronary artery responses to ACh after intravenous infusion of 3 g of ascorbic acid. All those studies used a parenteral route of administration and likely achieved supraphysiological plasma ascorbic acid concentrations (39). Thus the discrepant results may be explained by differences in the studied vasculature and treatment regimen. Interestingly, chronic treatment with oral ascorbic acid in combination with alpha -tocopherol has recently been shown to reduce endothelial activation, as assessed by levels of plasminogen activator inhibitor, and to decrease the occurrence of preeclampsia in pregnant women at risk of the disorder (7). However, vasomotor function was not assessed in that study.

The present study involved physiological concentrations of ascorbic acid and demonstrated absolutely no improvement, or even a trend for improvement, in brachial artery flow-mediated dilation. We had anticipated that the treatment regimen would have a beneficial effect on endothelial function in patients with hypertension, because we recently observed improved flow-mediated dilation acutely and after 1 mo of treatment with the same regimen in a group of patients with proven coronary artery disease (18, 26). There was sufficient power to detect an improvement in flow-mediated dilation with ascorbic acid treatment, consistent with the effect seen in our previous studies (18, 26). This apparent discrepancy may relate to the greater burden of risk factors for atherosclerosis (possibly resulting in greater oxidative stress) and the slightly lower flow-mediated dilation at baseline in the prior studies (18, 26). These findings suggest that the mechanisms of conduit vessel endothelial dysfunction in patients with hypertension are distinct from those in patients with advanced atherosclerosis. Since blood pressure was significantly improved in the present study, it remains possible that microvascular endothelial function was, in fact, improved, but examination of this question was beyond the scope of the present study. It also remains possible that ascorbic acid might have improved endothelial function in a group of patients with a more severe impairment of flow-mediated dilation at baseline.

Ascorbic acid treatment had no effect on cGMP, a systemic marker of NO bioactivity. Previous human studies in which ascorbic acid has improved endothelium-dependent vasodilation have suggested that ascorbic acid augments NO bioavailability, and this may occur by scavenging superoxide anion (39-41). Superoxide anion is known to rapidly inactivate NO and has been demonstrated to be increased in conditions such as hypertension (32, 34). Indeed, it has been suggested that increased production of superoxide anion in hypertension in response to ANG II (34), cyclic strain (23), and pulsatile stretch (22), and the resulting enhanced quenching of NO may be important in the pathophysiology of hypertension. While ascorbic acid is an effective scavenger of superoxide anion, we recently showed in an experimental model that supraphysiological concentrations of extracellular ascorbic acid would be required to enhance NO bioavailability in vivo (25). This requirement was confirmed in several recent human studies (39, 41) in which increasing intra-arterial doses of ascorbic acid progressively increased endothelium-dependent vasodilation in response to ACh or methacholine. However, the estimated extracellular concentrations of ascorbic acid achieved in the study by Taddei et al. (41) (up to 10 mmol/l) and the documented level (3.2 ± 1.4 mmol/l) in the antecubital vein in the study by Sherman et al. (39) substantially exceeded the levels achieved in the present study. Thus the present data showing no effect of a lower dose of ascorbic acid are still consistent with the hypothesis that excess superoxide anion in the vascular wall contributes to the genesis of impaired endothelial function in hypertension.

Ascorbic acid treatment also had no effect on a systemic marker of prostacyclin production, urinary 2,3-dinor-6-ketoprostaglandin F1alpha . Plasma ascorbic acid has been shown to have a positive, independent association with plasma 6-ketoprostaglandin F1alpha concentrations and an inverse association with blood pressure in epidemiological studies (37), suggesting that increased production of the vasodilator prostacyclin may account for the relationship with blood pressure. There is also experimental evidence that ascorbic acid may increase the production of prostacyclin (3). Synthesis of this potent vasodilator by prostacyclin synthase is glutathione dependent and may be inhibited by lipid peroxides (28, 30). However, there also was no evidence that ascorbic acid reduced lipid peroxidation and production of vasoconstrictor F2 isoprostanes. Despite these observations, all these systemic markers are limited by the fact that they may not accurately reflect events in the vascular wall.

The reduction of blood pressure achieved with ascorbic acid treatment in the present study was similar in magnitude to that predicted by previous population-based studies. These studies suggested that an increase in ascorbic acid concentration of 38 µmol/l would be associated with a systolic blood pressure reduction of ~7 mmHg (37) and is consistent with a preliminary intervention study that used a combination of antioxidants, including alpha -tocopherol, beta -carotene, and ascorbic acid (500 mg/day) plus zinc sulfate (16). However, the present study offers no definitive mechanism for the effect of ascorbic acid on blood pressure.

A potential limitation of this study is the possibility that we may have improved endothelium-dependent vasodilation with ascorbic acid if treatment had been extended for a longer period. For example, endothelial function has been enhanced in a number of studies where antihypertensive treatment was extended for >= 6 mo (31, 38), although not in some studies of <2 mo (9). However, ascorbic acid has been shown to improve endothelial function in a number of studies acutely (26, 39-41) and to maintain this benefit over a 1-mo period (18). Thus we are unlikely to have missed a significant treatment benefit.

In conclusion, this study has shown that acute and chronic treatment with oral ascorbic acid in a dose sufficient to double plasma levels did not have a beneficial effect on conduit vessel endothelial dysfunction in patients with hypertension. This lack of effect occurred, despite a significant reduction in systolic and mean blood pressure. The effect of chronic supplementation of ascorbic acid on resistance vessel endothelial function warrants further investigation.


    ACKNOWLEDGEMENTS

This work was supported by National Heart, Lung, and Blood Institute Grants HL-53398, HL-55993, HL-52936, HL-59634, HL-55854, and HL-03195. S. J. Duffy is supported by National Health and Medical Research Council of Australia Neil Hamilton Fairley Fellowship 007139. N. Gokce is the recipient a National Institutes of Health National Research Service Award. E. S. Biegelsen is supported by an American College of Cardiology/Merck Fellowship and a National Institutes of Health National Research Service Award. J. F. Keaney, Jr., and J. A. Vita are the recipients of American Heart Association Established Investigator Awards.


    FOOTNOTES

Address for reprint requests and other correspondence: J. A. Vita, Section of Cardiology, Boston Medical Center, 88 East Newton St., Boston, MA 02118 (E-mail: jvita{at}bu.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.

Received 1 March 2000; accepted in final form 6 September 2000.


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Am J Physiol Heart Circ Physiol 280(2):H528-H534
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