Pharmacological concentrations of ascorbic acid are required for the beneficial effect on endothelial vasomotor function in hypertension

Increased production of superoxide anion may contribute to impaired bioacti vity 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 ar e required to prevent superoxide-mediated vascular dysfunction. To seek kin etic evidence that superoxide anion contributes to endothelial vasomotor dy sfunction in human hypertension, we examined the effects of 2.4 or 24 mg/mi n 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 t o the highest dose of methacholine (10 mu g/min) of 12.3+/-6.7 compared wit h 16.1+/-5.8 mL.min(-1).dL tissue(-1) in the controls (P<0.001). The respon se to sodium nitroprusside was equivalent in the 2 groups. Ascorbic acid at 24 mg/min significantly improved the forearm blood flow response to methac holine 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 aci d concentration of 3.2+/-1.4 mmol/L. In contrast, ascorbic acid at 2.4 mg/m in had no effect on the methacholine response. Ascorbic acid at both doses had no effect on the vasodilator response to sodium nitroprusside in hypert ensive 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 con tribute to impaired endothelium-dependent vasodilation in patients with hyp ertension.