This study tested the hypothesis that superoxide levels are elevated in isolated mesenteric resistance arteries (100–300 µm) from rats fed a short-term high-salt (HS) diet (4% NaCl for 3 days) compared to controls fed a low-salt (LS) diet (0.4% NaCl). Vascular relaxation induced by the superoxide dismutase mimetic tempol (4-hydroxytetramethylpiperidine-1-oxyl), the NADPH oxidase inhibitor apocynin and the xanthine/xanthine oxidase inhibitor oxypurinol was significantly larger in mesenteric arteries from animals fed HS diet compared to arteries from animals fed LS diet. Basal superoxide levels assessed via dihydroethidine (DHE) fluorescence were significantly elevated in arteries from rats fed HS diet, and were reduced by tempol, apocynin and oxypurinol, but not by L-NAME. Basal and methacholine-induced NO production (assessed by DAF-2T fluorescence) was significantly reduced in arteries from rats fed HS diet versus arteries from rats on LS diet. Impaired methacholine-induced NO release and vascular relaxation were restored by tempol and apocynin, but not by oxypurinol. These data suggest that the elevated production of superoxide by NADPH oxidase and xanthine/xanthine oxidase contribute to elevated basal superoxide levels, reduced NO release and impaired vascular relaxation in mesenteric resistance arteries of rats fed HS diet.
Sprague-Dawley rats were fed either a high-salt (HS) diet (4.0% NaCl) or a low-salt (LS) diet (0.4% NaCl) for 3 days. Nitric oxide (NO) and superoxide production were assessed in the thoracic aorta by evaluating the fluorescence signal intensity from 4,5-diaminofluorescein (DAF-2DA) and dihydroethidine, respectively. Methacholine caused increased NO release in the aortas from rats on a LS but not HS diet. The SOD mimetic tempol restored methacholine-induced NO release in aortas from rats on a HS diet. Methacholine also caused superoxide production in the aortas of rats on a HS diet but not in the aortas of rats on a LS diet. Tempol and N(G)-monomethyl-l-arginine eliminated methacholine-induced superoxide production in the aortas of rats on a HS diet. Aortic rings from rats on the HS diet showed impaired methacholine-induced relaxation, which was improved by tempol. Tempol alone caused a NO-dependent relaxation of norepinephrine-precontracted aortas that was significantly greater in the aortas of rats on the HS diet than in vessels from rats on the LS diet. These data suggest that a HS diet impairs endothelium-dependent relaxation via reduced NO levels and increased superoxide production.
Male Sprague-Dawley rats were maintained on a low-salt (LS) diet (0.4% NaCl) or changed to a high-salt (HS) diet (4% NaCl) for 3 days. Increases in intracellular Ca 2ϩ ([Ca 2ϩ ]i) in response to methacholine (10 M) and histamine (10 M) were significantly attenuated in aortic endothelial cells from rats fed a HS diet, whereas thapsigargin (10 M)-induced increases in [Ca 2ϩ ]i were unaffected. Methacholineinduced nitric oxide (NO) production was eliminated in endothelial cells of aortas from rats fed a HS diet. Low-dose ANG II infusion (5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 iv) for 3 days prevented impaired [Ca 2ϩ ]i signaling response to methacholine and histamine and restored methacholineinduced NO production in aortas from rats on a HS diet. Adding Tempol (500 M) to the tissue bath to scavenge superoxide anions increased NO release and caused N -nitro-L-arginine methyl estersensitive vascular relaxation in aortas from rats fed a HS diet but had no effect on methacholine-induced Ca 2ϩ responses. Chronic treatment with Tempol (1 mM) in the drinking water restored NO release, augmented vessel relaxation, and increased methacholine-induced Ca 2ϩ responses significantly in aortas from rats on a HS diet but not in aortas from rats on a LS diet. These findings suggest that 1) agonist-induced Ca 2ϩ responses and NO levels are reduced in aortas of rats on a HS diet; 2) increased vascular superoxide levels contribute to NO destruction, and, eventually, to impaired Ca 2ϩ signaling in the vascular endothelial cells; and 3) reduced circulating ANG II levels during elevated dietary salt lead to elevated superoxide levels, impaired endothelial Ca 2ϩ signaling, and reduced NO production in the endothelium. endothelium; sodium; dietary salt intake; vascular relaxation; nitric oxide A VARIETY OF AGENTS, including muscarinic agonists such as ACh, dilate blood vessels by stimulating the synthesis of nitric oxide (NO) by endothelial NO synthase. Endothelial cell activation in response to agonists and autacoids leads to NO formation via receptor-mediated increases in intracellular calcium ion concentration ([Ca 2ϩ ] i ). However, emerging evidence indicates that endothelial NO synthase activity can be affected by a variety of other mechanisms that are independent of [Ca 2ϩ ] i (7,12,21,26,27). This raises the possibility that changes in NO production under some physiological conditions may be independent of changes in endothelial [Ca 2ϩ ] i . Endothelium-dependent relaxation in response to ACh is impaired in the aorta, resistance arteries, and microvessels of rats fed a high-salt (HS) diet (2-5, 15, 16, 18, 28). Elevated dietary salt intake causes suppression of plasma ANG II levels (8, 9), and previous studies (18,30,31) have demonstrated that the impaired vascular relaxation in Sprague-Dawley rats fed a HS diet can be prevented by a continuous intravenous infusion of a low dose of ANG II to maintain normal circulating levels of ANG II.In the present study, we tested the hypothesis that receptormediated increases in [Ca 2ϩ ] i and/or...
The present study identifies the specific pattern of cytochrome P450-4A isoform expression in arterioles and parenchymal cells of the skeletal muscle microcirculation, and supports the hypothesis that the cytochrome P-450 enzymes may play a role in the regulation of microvascular function in the skeletal muscle microcirculation.
Recent studies have demonstrated that cerebral arteries from rats fed a high-salt (HS) diet exhibit impaired vasodilation and altered electrophysiological response to reduction in PO2. The present study examined whether an increase in salt intake alters the response of vascular smooth muscle cells (VSMC) to prostacyclin, a crucial mediator of hypoxic dilation in cerebral arteries. VSMC were isolated from cerebral arteries of male Sprague-Dawley rats maintained on an HS (4% NaCl) or a low-salt diet (0.4% NaCl) for 3 days. The stable prostacyclin analog iloprost (10 ng/ml) inhibited serotonin (0.1-10 microM)-induced contractions and the increase in intracellular Ca2+ concentration ([Ca2+]i) in VSMC isolated from arteries of animals fed the low-salt diet. In contrast, iloprost had no effect on serotonin-induced contractions and increases in [Ca2+]i in VSMC isolated from arteries of rats fed the HS diet. Preventing the fall in ANG in rats fed the HS diet by infusion of a low dose of ANG II (5 ng.kg(-1).min(-1) i.v.) restored the inhibitory effect of iloprost on serotonin-induced contractions and increases in [Ca2+]i in VSMC from animals fed the HS diet. These effects were reversed by AT1 receptor blockade with losartan. These results indicate that ANG II suppression secondary to elevated dietary salt intake impairs vascular relaxation and Ca2+ regulation by prostacyclin.
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