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.

No abstract

Subclinical hypothyroidism (sHT) is associated with dyslipidemia and enhanced cardiovascular risk. We assessed carotid artery intima-media thickness (IMT, high-resolution ultrasonography) and lipoprotein profile in 45 sHT patients (aged 37 +/- 11 yr) at baseline and after 6 months of randomized, placebo-controlled L-T(4) replacement. In comparison with 32 age- and sex-matched controls, sHT patients had elevated total and low-density lipoprotein (LDL) cholesterol and ApoB levels (P = 0.002, P = 0.0007, and P = 0.01, respectively) and higher mean-IMT values (P < 0.0001). In stepwise regression analysis, mean-IMT was positively related (r(2) = 0.71, P < 0.0001) to age, TSH, and LDL cholesterol. L-T(4) replacement significantly reduced both total and LDL cholesterol (P < 0.0001 for both) and mean-IMT (by 11%, P < 0.0001). The decrement in IMT was directly related to the decrements of both total cholesterol and TSH (P = 0.02 and P = 0.0001, respectively). We conclude that early carotid artery wall alterations are present in sHT patients. Whether such IMT increase is related to an early atherosclerotic involvement of the arterial wall cannot be clearly decided on the basis of the present results. However, the fact that L-T(4) replacement therapy was able to improve both the atherogenic lipoprotein profile and intima-media thickening suggests that lipid infiltration of arterial wall may represent a major mechanism underlying IMT increase in subclinical hypothyroidism.

Subclinical hypothyroidism (sHT) is associated with enhanced cardiovascular risk. To test the hypothesis that patients with sHT are characterized by endothelial dysfunction and impaired nitric oxide (NO) availability, in 14 patients [serum cholesterol, 218 +/- 41 mg/dl (5.6 +/- 0.9 mM)] and 28 euthyroid subjects, subdivided into groups A and B [serum cholesterol, 170 +/- 19 mg/dl (4.4 +/- 0.5 mM) and 217 +/- 21 mg/dl (5.6 +/- 0.5 mM), respectively], we studied the forearm blood flow (strain-gauge plethysmography) response to intrabrachial acetylcholine, an endothelium-dependent vasodilator, at baseline and during infusion of N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor. Response to sodium nitroprusside and minimal forearm vascular resistances were also evaluated. In sHT patients, vasodilation to acetylcholine was reduced, compared with group B (+358 +/- 29% vs. +503 +/- 19%, P = 0.0003) and group A (663 +/- 65%, P = 0.02 vs. group B and P = 0.0002 vs. sHT). L-NMMA blunted the vasodilation to acetylcholine in groups A and B (49.1 +/- 6.3% and 42.7 +/- 5.5% maximal forearm blood flow reduction, respectively, P < 0.0001 vs. acetylcholine), whereas it was ineffective in sHT patients (12.8 +/- 2.5%). Response to sodium nitroprusside and minimal vascular resistances were similar. In sHT (n = 9) patients, 6 months of euthyroidism by levothyroxine replacement increased acetylcholine-vasodilation and restored L-NMMA inhibition. Patients with sHT are characterized by endothelial dysfunction resulting from a reduction in NO availability, an alteration partially independent of dyslipidemia and reversed by levothyroxine supplementation.

Abstract-Angiotensin II plays an important role in vascular remodeling. We investigated the role of aldosterone, which is stimulated by angiotensin II, as a mediator of angiotensin II-induced vascular structural and functional alterations. Sprague-Dawley rats (nϭ8 to 12/group) received angiotensin II (120 ng/kg per minute, subcutaneously) for 14 days Ϯ spironolactone or hydralazine (25 mg/kg per day). An additional group received aldosterone (750 ng/h, subcutaneously) Ϯ spironolactone. Systolic blood pressure was increased by angiotensin II (PϽ0.001) and reduced by spironolactone and hydralazine (PϽ0.001). Aldosterone-induced increase of blood pressure was reduced by spironolactone (PϽ0.05).In mesenteric small arteries studied on a pressurized myograph, media/lumen ratio was increased (PϽ0.001) and acetylcholine-mediated relaxation was impaired in angiotensin II-infused rats (PϽ0.001); both were partially improved by spironolactone (PϽ0.05) but not by hydralazine. Aldosterone-induced increase of media/lumen ratio (PϽ0.001) and impaired response to acetylcholine (PϽ0.001) were normalized by spironolactone. Response to sodium nitroprusside was similar in all groups. Aortic NADPH oxidase activity was increased (PϽ0.01) by angiotensin II and reduced by spironolactone and hydralazine. Aldosterone also increased (PϽ0.05) activation of NADPH oxidase, an effect abolished by spironolactone. Plasma thiobarbituric acid-reactive substances (a marker of oxidative stress), higher in angiotensin II and aldosterone rats (PϽ0.001), were normalized by spironolactone. In conclusion, spironolactone, which inhibited aldosterone actions, partially corrected structural and functional angiotensin II-induced abnormalities. These effects were associated with reduced vascular NADPH oxidase activity and decreased plasma markers of oxidative stress. Our findings suggest that aldosterone may mediate some of angiotensin II-induced vascular effects in hypertension, in part via increased oxidative stress.