Deferoxamine improved nitric oxide-mediated, endothelium-dependent vasodilation in patients with coronary artery disease. These results suggest that iron availability contributes to impaired nitric oxide action in atherosclerosis.

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 (Ͼ1 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 g/min) of 12.3Ϯ6.7 compared with 16.1Ϯ5.8 mL ⅐ min Ϫ1 ⅐ dL tissue Ϫ1 in the controls (PϽ0.001). 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 16.1Ϯ7.1 mL ⅐ min Ϫ1 ⅐ dL tissue Ϫ1 (Pϭ0.001). This dose produced a cephalic vein ascorbic acid concentration of 3.2Ϯ1.4 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 Ⅲ endothelium Ⅲ hypertension, essential Ⅲ superoxide T he 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. 3-5 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 hy...

Abstract-Black Americans have increased morbidity and mortality rates from cardiovascular disease, greater prevalence of hypertension, and altered responses to vasodilator medications compared with those of white Americans. Hypertension and black race have been linked to impaired vascular function in the microcirculation. To examine these effects and their interaction in the conduit vasculature, we examined vasomotor responses of the brachial artery by using high-resolution vascular ultrasound in 228 subjects (48% hypertensive, 54% black). Subjects had no history of diabetes mellitus and were matched for age and gender.

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 micromol/l and were maintained at 99 +/- 33 micromol/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.

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