Background-High salt intake suppresses the effect of nitric oxide (NO) in the peripheral resistance vessels in animal models. We tested the hypothesis that the modulation of endogenous NO is related to salt sensitivity in human hypertension. Methods and Results-Inpatients with essential hypertension (nϭ24) were maintained on a normal-salt diet (12 g/d NaCl)for 3 days, a low-salt diet (2 g), a high-salt diet (20 to 23 g), and a low-salt diet for 7 days. Normotensive subjects (nϭ16) were maintained on the first 2 salt diets. The hypertensive patients whose average 24-hour blood pressure was increased by Ͼ5% by salt loading were assigned to group 1 (nϭ8) and the others to group 2 (nϭ16). Nitrate plus nitrite (NO x ) was measured by the Griess method, and asymmetrical dimethylarginine (ADMA) by high-performance liquid chromatography. The plasma NO x level during the normal-salt diet was lower in group 1 than in group 2 and the normotensive group. After salt loading, the plasma NO x level was decreased and reversed after the second salt restriction. Plasma ADMA level was increased after salt loading and decreased after salt restriction. The change in plasma NO x level was correlated inversely with those in blood pressure (rϭϪ0.59, Pϭ0.0007) and plasma ADMA level (rϭϪ0.64, Pϭ0.003) after salt loading and restriction. Conclusions-Modulation of NO synthesis by salt intake may be involved in a mechanism for salt sensitivity in human hypertension, presumably via the change in ADMA. (Circulation. 2000;101:856-861.)

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We tested the hypothesis that vessel homeostasis is maintained through the cross talk of shear-induced production of prostacyclin and nitric oxide (NO). Confluent human umbilical vein endothelial cells (HUVEC) were exposed to fluid shear stress at 15 dyn/cm(2) using a cone-plate device, and the concentrations of 6-keto-PGF(1alpha) and NO metabolites (nitrate and nitrite) in the medium were measured with radioimmunoassay and the Greiss method, respectively. Compared with static control, shear stress increased cumulative prostacyclin production by twofold after 90 min of exposure. Inhibition of NO synthase enhanced flow-induced prostacyclin production by twofold without affecting the baseline production. Guanylyl cyclase inhibitor enhanced flow-induced prostacyclin production to the same degree. In contrast, a stable agonist of cGMP attenuated the rapid early phase of flow-dependent prostacyclin production. Shear-induced NO metabolite production was unaffected even after indomethacin inhibited prostacyclin production. We conclude that NO shows an inhibitory effect on prostacyclin production under shear stress and that vessel homeostasis may be maintained through an increase in prostacyclin production when NO synthesis is impaired in endothelial cells.

Oxidative stress may play an important role in the regulation of MMP activity. Augmented MMP activity may be involved in the development of ventricular remodelling in patients with coronary artery disease.

Abstract-We demonstrated recently that plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, are increased by high salt intake concomitantly with a decrease in plasma levels of NO in human hypertension. We investigated the effect of shear stress on ADMA release in 2 types of cells: transformed human umbilical vein endothelial cells (HUVECs; cell line ECV-304) and HUVECs. Exposure of ECV-304 cells and HUVECs to shear stress with the use of a cone-plate viscometer enhanced gene expression of protein arginine methyltransferase (PRMT-1), ADMA synthase. In HUVECs, the ratio of PRMT-1 to glyceraldehyde 3-phosphate dehydrogenase mRNA was increased by 2-fold by a shear stress of Ն15 dyne/cm 2 . A dominant-negative mutant of IB kinase ␣ and troglitazone at 8 mol/L, an activator of peroxisome proliferator-activated receptor ␥, abolished the shear stress-induced increase in PRMT-1 gene expression in parallel with the blockade of nuclear factor (NF)-B translocation into the nucleus. The activity of dimethylarginine dimethylaminohydrolase, the degradation enzyme of ADMA, was unchanged after shear stress Յ15 dyne/cm 2 and was enhanced by 1.48Ϯ0.06-fold (PϽ0.05) by shear stress at 25 dyne/cm 2 . The release of ADMA was increased by 1.64Ϯ0.10-fold (PϽ0.05) by shear stress at 15 dyne/cm 2 but was not affected by shear stress at 25 dyne/cm 2 . These results indicate that shear stress enhances gene expression of PRMT-1 and ADMA release via activation of the NF-B pathway. Shear stress at higher magnitudes facilitates the degradation of ADMA, thus returning ADMA release levels to baseline. Key Words: stress, mechanical Ⅲ endothelium Ⅲ gene expression Ⅲ arginine Ⅲ nitric oxide Ⅲ nitric oxide synthase N itric oxide (NO) contributes to vessel homeostasis by inhibiting vascular smooth muscle tone and growth, platelet aggregation, and leukocyte adhesion to the endothelium. 1 Altered biosynthesis of NO has been implicated in the pathogenesis of atherosclerosis, and it is possible that accumulation of endogenous asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of NO synthase (NOS), underlies the reduced NO generation. We demonstrated recently that a high salt intake decreases the plasma concentrations of nitrite and nitrate (NO x ) concomitantly with an increase in plasma concentrations of ADMA in patients with essential hypertension. 2 A high salt intake causes a number of physiologic and pathologic effects, such as hemodynamic modulation, increased activity of the reninangiotensin-aldosterone system, and activation of the sympathetic nerve system. High salt intake-induced hemodynamic modulation includes augmentation of shear stress to the vascular wall, especially to endothelial cells, and we hypothesized that a high salt intake-induced decrease in plasma NO x levels might be caused by a shear stress-induced elevation of circulating ADMA.Vascular endothelial cells are capable of synthesizing ADMA, which is derived from the catabolism of proteins containi...