Background —Essential hypertension is associated with impaired endothelium-dependent vasodilation. Inactivation of endothelium-derived nitric oxide by oxygen free radicals participates in endothelial dysfunction in experimental hypertension. To test this hypothesis in humans, we evaluated the effect of antioxidant vitamin C on endothelium-dependent responses in essential hypertensive patients. Methods and Results —In 14 healthy subjects (47.1±4.8 years; blood pressure, 120.6±4.5/80.9±3.5 mm Hg) and 14 essential hypertensive patients (47.3±5.1 years; blood pressure, 153.9±7.1/102.3±4.1 mm Hg), we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg · 100 mL ⁻¹ · min ⁻¹ ) or sodium nitroprusside (1, 2, and 4 μg/100 mL forearm tissue per minute), an endothelium-dependent and -independent vasodilator, respectively, in basal conditions and during infusion of intrabrachial vitamin C (2.4 mg/100 mL forearm tissue per minute). In hypertensive patients but not in control subjects, vitamin C increased ( P <0.01) the impaired vasodilation to acetylcholine, whereas the response to sodium nitroprusside was unaffected. Moreover, in another 14 hypertensive patients (47.1±5.2 years; blood pressure, 155.2±6.9/103.7±4.5 mm Hg), the facilitating effect of vitamin C on vasodilation to acetylcholine was reversed by N ^G -monomethyl- l -arginine (100 μg/100 mL forearm tissue per minute), a nitric oxide synthase inhibitor, suggesting that in essential hypertension superoxide anions impair endothelium-dependent vasodilation by nitric oxide breakdown. Finally, because in adjunctive 7 hypertensive patients (47.8±6.1 years; blood pressure, 155.3±6.8/103.5±4.3 mm Hg), indomethacin (50 μg/100 mL forearm tissue per minute), a cyclooxygenase inhibitor, prevented the potentiating effect of vitamin C on vasodilation to acetylcholine, it is possible that in essential hypertension a main source of superoxide anions could be the cyclooxygenase pathway. Conclusions —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.

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 μg/100 mL per minute) and acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/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 μg/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 ( P 60 years). In young hypertensive patients (age 30 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.

Background —Mental stress has been linked to increased morbidity and mortality in coronary artery disease and to atherosclerosis progression. Experimental studies have suggested that damage to the endothelium may be an important mechanism. Methods and Results —Endothelial function was studied in 10 healthy men (aged 50.4±9.6 years) and in 8 non–insulin-dependent diabetic men (aged 52.0±7.2 years). Brachial artery flow-mediated dilation (FMD, endothelium dependent) and response to 50 μg of sublingual glyceryl trinitrate (GTN, endothelium independent) were measured noninvasively by use of high-resolution ultrasound before and after (30, 90, and 240 minutes) a standardized mental stress test. The same protocol without mental stress was repeated on a separate occasion in the healthy men. In healthy subjects, FMD (5.0±2.1%) was significantly ( P <0.01) reduced at 30 and 90 minutes after mental stress (2.8±2.3% and 2.3±2.4%, respectively) and returned toward normal after 4 hours (4.1±2.0%). Mental stress had no effect on the response to GTN. In the repeated studies without mental stress, FMD did not change. The diabetic subjects had lower FMD than did the control subjects (3.0±1.5% versus 5.0±2.1%, respectively; P =0.02) but showed no changes in FMD (2.7±1.1% after 30 minutes, 2.8±1.9% after 90 minutes, and 3.1±2.3% after 240 minutes) or GTN responses after mental stress. Conclusions —These findings suggest that brief episodes of mental stress, similar to those encountered in everyday life, may cause transient (up to 4 hours) endothelial dysfunction in healthy young individuals. This might represent a mechanistic link between mental stress and atherogenesis.

Background Experimental data from normotensive and hypertensive animals indicate that aging is associated with impaired endothelium-dependent relaxations to acetylcholine, and this possibility appears to be confirmed in the human coronary artery. In the present study, we evaluated the effect of age on endothelial responsiveness in the forearm vessels of either normotensive control subjects or essential hypertensive patients. Methods and Results Within the normotensive or hypertensive group (n=53 and n=57, respectively), subjects were selected with similar blood pressure, plasma cholesterol, and glucose values, and hypercholesterolemic subjects, diabetics, and smokers were excluded. We evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 μg/100 mL per minute), an endothelium-independent vasodilator. Acetylcholine caused a dose-dependent vasodilation that was significantly ( P <.01) lower in essential hypertensive patients than in normotensive control subjects. However, a significant negative correlation was observed between acetylcholine-induced vasodilation and patient age in both normotensive ( r =−.86, P <.001) and hypertensive ( r =−.85, P <.001) patients. In contrast, vasodilation to sodium nitroprusside was similar in normotensive control subjects and essential hypertensive patients with a poorer inverse correlation with patient age (normotensive control subjects, r =−.37; hypertensive patients, r =−.36) compared with acetylcholine. Conclusions 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.

Deficiency. For instance, endothelium- dependent vasodilation is warranted, although impaired, also in the presence of cardiovascular risk factors by the pro- duction and release of endothelium- derived vasodilators other than NO, such as prostanoids and other endothe- lium-derived hyperpolarizing factors. Along with NO deficiency, a dysfunc- tioning endothelium also becomes the source of other substances and media- tors that are detrimental to the arterial wall, including endothelin-1, trombox- ane A2, prostaglandin H2, and ROS (2). The presence of endothelial dysfunc- tion, whether primary or after cardiovas- cular risk factors, has been implicated in the pathogenesis of atherosclerosis and thrombosis, both for the loss of its pro- tective capability and for the induction of proatherothrombotic mechanisms (2,3). The regulation of the endothelial pro- cesses is largely vascular district-specific, thus producing different results in various organs and tissues. Within the same vas- cular district, it varies largely in relation to vessel size, i.e., large arteries (macrocircu- lation) versus arterioles (microcircula- tion). For this reason, the use of systemic circulating markers of endothelial func- tion is unreliable. Moreover, NO is a vol- atile substance, with a very short half-life, and therefore its moment-by-moment quantification in a specific vascular area is almost impossible. Therefore, its bioavail- ability is usually evaluated in humans by measuring the downstream effects, namely the vasodilation induced by the local stimulation of NO production by specific external mechanical and pharma- cological stimuli, i.e., through vascular

Cigarette smoking is a powerful cardiovascular risk factor and smoking cessation is the single most effective lifestyle measure for the prevention of a large number of cardiovascular diseases. Impairment of endothelial function, arterial stiffness, inflammation, lipid modification as well as an alteration of antithrombotic and prothrombotic factors are smoking-related major determinants of initiation, and acceleration of the atherothrombotic process, leading to cardiovascular events. Cigarette smoking acutely exerts an hypertensive effect, mainly through the stimulation of the sympathetic nervous system. As concern the impact of chronic smoking on blood pressure, available data do not put clearly in evidence a direct causal relationship between these two cardiovascular risk factors, a concept supported by the evidence that no lower blood pressure values have been observed after chronic smoking cessation. Nevertheless, smoking, affecting arterial stiffness and wave reflection might have greater detrimental effect on central blood pressure, which is more closely related to target organ damage than brachial blood pressure. Hypertensive smokers are more likely to develop severe forms of hypertension, including malignant and renovascular hypertension, an effect likely due to an accelerated atherosclerosis.