Abstract-Age-related endothelial dysfunction could be caused by an alteration in the L-arginine-NO system and the production of oxidative stress in both normotensive and hypertensive individuals. In 47 normotensive subjects and 49 patients with essential hypertension, we evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial sodium nitroprusside (1, 2, and 4 g/100 mL per minute) and acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 g/100 mL per minute), an endothelium-independent vasodilator and an endothelium-dependent vasodilator, respectively. Acetylcholine was repeated in the presence of the NO synthase inhibitor N G -monomethyl-L-arginine (L-NMMA, 100 g/100 mL per minute), the antioxidant vitamin C (8 mg/100 mL per minute), or both. Vasodilation to acetylcholine, but not to sodium nitroprusside, was lower (PϽ0.01) in hypertensive patients compared with control subjects. Moreover, in both groups, endothelium-dependent vasodilation declined with aging. In normotensive subjects, the inhibiting effect of L-NMMA on response to acetylcholine decreased in parallel with advancing age, whereas vitamin C increased vasodilation to acetylcholine in only the oldest group (age Ͼ60 years). In young hypertensive patients (age Ͻ30 years), vasodilation to acetylcholine was sensitive to L-NMMA, whereas in hypertensive patients age Ͼ30 years, vitamin C enhanced endothelium-dependent vasodilation and restored the inhibiting effect of L-NMMA on response to acetylcholine. In normotensive individuals, an earlier primary dysfunction of the NO system and a later production of oxidative stress cause age-related reduction in endothelium-dependent vasodilation. These alterations are similar but anticipated in hypertensive patients compared with normotensive subjects. Moreover, these vascular changes associated with essential hypertension are generally considered to be an accelerated form of the changes seen with aging. 5 Endothelial cells play an important local regulatory role by secreting substances that control both vascular tone and structure, 3 including NO, which is derived from the metabolism of L-arginine by NO synthase, 6 a constitutive enzyme that is present in endothelial cells. NO is produced and released under the influence of endothelial agonists-including acetylcholine, bradykinin, and others-acting on specific receptors, and by mechanical forces, such as shear stress. 3 Experimental evidence indicates that almost the totality of cardiovascular risk factors, such as aging and hypertension, are characterized by the presence of endothelial dysfunction, which is mainly induced by the production and release of oxygen-derived free radicals, 7 which cause NO breakdown. 8 In humans, the association of impaired endotheliumdependent vasodilation with essential hypertension and aging has been well documented in different vascular beds. 9 -17 In patients with essential hypertension, one of the main mechanisms leading to impaired endothelium-dependent vasodilation is the production of oxida...

In essential hypertensive patients, impaired endothelial vasodilation can be improved by the antioxidant vitamin C, an effect that can be reversed by the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine. These findings support the hypothesis that nitric oxide inactivation by oxygen free radicals contributes to endothelial dysfunction in essential hypertension.

The present data indicate that there is a blunted response to acetylcholine with advancing age in both normotensive control subjects and essential hypertensive patients, suggesting that aging is associated with reduced endothelium-dependent vasodilation in humans.

These results suggest that regular physical activity can at least in part prevent the age-induced endothelial dysfunction, probably the restoration of nitric oxide availability consequent to prevention of production of oxidative stress.

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