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...
Blood flow before and after occlusion of cannulated left circumflex coronary arteries of anesthetized open-chest dogs was studied using a continuously recording rotameter. Five- to one hundred and eighty-second occlusion periods were performed. Flow in excess of control flow (reactive hyperemia), peak flow, and duration of reactive hyperemia increased in magnitude following occlusions up to approximately 2 minutes. Flow debts estimated from control flows before occlusion were almost always overpaid. Series of 30-second occlusions showed that the reactive hyperemic blood flow responses were uniform in the same dog. In 15 dogs, the effect of drugs on myocardial reactive hyperemia was variable, isoproterenol, levarterenol and epinephrine usually did not alter or increased, while Pitressin decreased, reactive hyperemic blood flow. It is concluded that the myocardial response to anoxia is a reproducible phenomenon, increases with lengthening periods of anoxia, is variably affected by drugs and that the estimated flow debt for myocardial anoxia is overpaid.
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