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.

Abstract-To compare the effect of antihypertensive drugs on endothelium-dependent vasodilation in the peripheral conduit arteries of patients with essential hypertension, in a prospective, randomized, parallel group study, endothelial function was assessed in 168 hypertensive patients before and after 6-month treatment with randomly assigned nifedipine GITS (30 to 60 mg, nϭ28), amlodipine (5 to 10 mg, nϭ28), atenolol (50 to 100 mg, nϭ29), nebivolol (5 to 10 mg, nϭ28), telmisartan (80 to 160 mg, nϭ29), and perindopril (2 to 4 mg, nϭ28). If necessary, hydrochlorothiazide (25 mg) was added to each compound. We evaluated brachial artery flow-mediated, endothelium-dependent dilation (high-resolution ultrasound) compared with endothelium-independent response to glyceryl trinitrate (25 g/s). Brachial artery diameter was measured by automatic computerized analysis. Forty healthy subjects were evaluated as a control group. Oxidative stress production was evaluated by measuring plasma malondialdehyde and plasma lipoperoxides; plasma antioxidant capacity was assessed as ferric-reducing antioxidant power. Hypertensive patients showed a significantly (PϽ0.01) lower flow-mediated dilation (5.2Ϯ1.9%) as compared with healthy control subjects (7.1Ϯ2.6%). Response to glyceryl trinitrate was similar in control subjects and patients. At baseline, blood pressure, diameter, flow-mediated dilation, and response to glyceryl trinitrate were similar in the different treatment groups. All treatments similarly reduced blood pressure, but only perindopril increased flow mediated dilation (from 5.1Ϯ2 to 6.4Ϯ2.4%; PϽ0.01) without modifying the response to glyceryl trinitrate. Perindopril but also telmisartan nifedipine and amlodipine reduced oxidative stress and increased plasma antioxidant capacity. In patients with essential hypertension, ACE inhibitors appear to be the only compounds able to improve conduit artery endothelium-dependent vasodilation.

Abstruct To evaluate whether cyclooxygenase constructor substances can nnparr mtnc oxide-mediated vasodrlatron m essentral hypertension, in seven normotensive sublects (43 324 1 years, BP, 117-+6/81t2 mm Hg) and seven essential hypertensave patients (47 l-t5 2 years, BP, 151C8/98+4 mm Hg) we studied forearm blood flow (strain-gauge plethysmography) modrficatrons induced by mtrabrachral acetylcholme (0.15, Cl 45, 1 5, 4 5, 15 pg 100 mL-' mm-') m basal condrtrons, durmg mfuston of NC-monomethyl-L-argnnne (L-NMMA, 100 pg 100 mL-' mn-'), a mtnc oxide synthase mhrbrtor, or mdomethacm (50 /-lg 100 mL-' mm-'), a cyclooxygenase mhrbrtor, or srmultaneous mdomethacm and L-NMMA In normotensrves, vasodrlatron to acetylcholme was blunted by L-NMMA (maximum flow increase' 671+64% and 386+42%, respectrvely, P< Ol), and this effect was unchanged by mdomethacm In contrast, m hypertensrve patients, vasoddatron to acetylcholme (maxrmum llow increase 458233%) was unchanged by L-NMMA Indomethacm stgmficantly (P< 01) increased the response to acetylcholme (maximum flow increase 635t53%) and restored the mhrbrtory effect of L-NMMA (maximum flow Increase 445&36%, P< 01 versus mdomethacm alone) In an adJunctive seven normotensaves (51 4t4 2 years, BP, 114+5/79+3 mm Hg) and seven essential hypertenstves (53 247 6 years, BP, 153?9/100&3 mm Hg) we repeated the same protocol by replacmg L-NMMA with L-argmme (200 pg 100 mL-r mn-'), the substrate for NO synthase In normotensrves, vasodrlatron to acetylchohne was mcreased by L-argmme (maximum flow Increase 539~48% and 806?61%, respectrvely) and this effect was unchanged by mdomethacm In hypertensive patrents, vasodrlatron to acetylchohne (maximum flow Increase 339532%) was unchanged by L-argnnne but was srgnrficantly (P< 01) increased by mdomethacm (maxrmum flow increase 592238%)Moreover, mdomethacm restored the facrlrtatory effect of L-argmme (maxrmum flow increase 804?56%, P< 01 versus mdomethacm alone) Therefore, cyclooxygenase mhrbrtron restores mtrrc oxide-mediated vasodrlatron m essential hypertension, suggestmg that cyclooxygenase-dependent substances can rmparr mtnc oxide productron (Hypertenszon. 1997;29[part 21: 274-279.) Key Words l hypertension l endothelmm l mtrrc oxtde l endothehum-derived factors l mdomethacm E ndothelmm plays a major role m the modulation of vascular tone through the productton and release of different relaxing and constricting factors acting on the underlying smooth muscle cells r The major endothehum-derived relaxing factor is NO,* a labile substance derived from L-argmine by the activity of the enzyme NO synthase.3 Importantly, this process can be competitively mhtbited by r.-argmme analogues such as L-NMMA.4.5 Moreover, EDCF are mainly cyclooxygenase-dependent prostanoids (thromboxane A2 and prostaglandm H2)6-9 or superoxrde anions 10The crucial role of endothehal cells in vascular homeostasis is further emphasized by the evidence of tmpaired endotheltum-dependent responses m cardtovascular disease such as essential hypertension Thus, m essential hyper...

Combined treatment with vitamins C and E has beneficial effects on endothelium-dependent vasodilation and arterial stiffness in untreated, essential hypertensive patients. This effect is associated with changes in plasma markers of oxidative stress.