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      Decreased Endothelium-Dependent Vasodilation in Diabetic Female Rats: Role of Prostanoids

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          Abstract

          Overproduction of vasoconstrictor prostanoids and reduced prostacyclin levels have been related to the male diabetic-linked vascular dysfunction. However, it is not clear yet if these changes also occur in diabetic females. The aim of this study was to verify the role of prostanoids in the vascular dysfunction of diabetic female rats. The parameters studied were the mesenteric arteriolar reactivity (intravital microscopy and isolated perfused arteriolar bed), prostanoid measurement (enzyme immunoassay), superoxide generation (intravital fluorescence microscopy), and the presence of peroxynitrite (Western blot for nitrotyrosine-containing proteins). The response to acetylcholine was decreased in arterioles of diabetic female rats and diclofenac, but not ridogrel, corrected the altered response. The unstimulated (basal) release of thromboxane B<sub>2</sub> (TXB<sub>2</sub>), but not prostaglandin F<sub>2</sub><sub>α</sub> (PGF<sub>2</sub><sub>α</sub>) or 6-keto-PGF<sub>1</sub><sub>α</sub>, was increased in the mesenteric perfusate from diabetic female rats. Increased production of PGF<sub>2</sub><sub>α</sub> and 6-keto-PGF<sub>1</sub><sub>α</sub>, but not TXB<sub>2</sub>, was induced by acetylcholine in diabetic arterioles. The superoxide generation was increased in diabetic female rats and diclofenac corrected it. Diabetes increased nitrotyrosine-containing proteins in mesenteric microvessels. In conclusion, our data show that the increase of constrictor prostanoid release, most likely PGF<sub>2</sub><sub>α</sub>, could be involved in the reduced endothelium-dependent vasodilation of diabetic female rats. In addition, the enhanced activation of cyclooxygenase may be a source of superoxide anion generation in this model.

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          Most cited references 13

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          Detection and imaging of nitric oxide with novel fluorescent indicators: diaminofluoresceins.

          Nitric oxide is a gaseous, free radical which plays a role as an intracellular second messenger and a diffusable intercellular messenger. To obtain direct evidence for NO functions in vivo, we have designed and synthesized diaminofluoresceins (DAFs) as novel fluorescent indicators for NO. The fluorescent chemical transformation of DAFs is based on the reactivity of the aromatic vicinal diamines with NO in the presence of dioxygen. The N-nitrosation of DAFs, yielding the highly green-fluorescent triazole form, offers the advantages of specificity, sensitivity, and a simple protocol for the direct detection of NO (detection limit 5 nM). The fluorescence quantum efficiencies are increased more than 100 times after the transformation of DAFs by NO. Fluorescence detection with visible light excitation and high sensitivity enabled the practical assay of NO production in living cells. Membrane-permeable DAF-2 diacetate (DAF-2 DA) can be used for real-time bioimaging of NO with fine temporal and spatial resolution. The dye was loaded into activated rat aortic smooth muscle cells, where the ester bonds are hydrolyzed by intracellular esterase, generating DAF-2. The fluorescence in the cells increased in a NO concentration-dependent manner.
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            Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study.

            We report here the 14-year sex-specific effect of non-insulin-dependent diabetes mellitus on the risk of fatal ischemic heart disease in a geographically defined population of men and women aged 40 through 79 years. There were 207 men and 127 women who had diabetes at baseline based on medical history or fasting hyperglycemia. They were compared with 2137 adults who had fasting euglycemia and a negative personal and family history of diabetes. The relative hazard of ischemic heart disease death in diabetics vs nondiabetics was 1.8 in men and 3.3 in women, after adjusting for age, and 1.9 and 3.3, respectively, after adjusting for age, systolic blood pressure, cholesterol, body mass index, and cigarette smoking using the Cox regression model. The sex difference in the independent contribution of diabetes to fatal heart disease was largely explained by the persistently more favorable survival rate of women (than men) without diabetes.
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              Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function.

               Z Katusic,  S Milstien (1999)
              Subsaturating levels of tetrahydrobiopterin (BH(4)), an essential cofactor for nitric oxide synthase (NOS), can lead to endothelial dysfunction as a result of decreased production of nitric oxide. Furthermore, insufficient BH(4) can also result in NOS-uncoupled production of reactive oxygen intermediates, such as superoxide anion and hydrogen peroxide. Nitric oxide and superoxide react rapidly to form peroxynitrite, which may be the reactive species responsible for many of the toxic effects of nitric oxide. Here we show that BH(4) is a primary target for peroxynitrite-catalyzed oxidation because at pH 7.4, physiologically relevant concentrations of BH(4) are oxidized rapidly by low concentrations of peroxynitrite. Peroxynitrite oxidizes BH(4) to quinonoid 5,6-dihydrobiopterin and a large proportion of the quinonoid isomer readily loses its side chain to form 7,8-dihydropterin which is not a cofactor for nitric oxide synthase. Thus, abnormally low levels of BH(4) can promote a cycle of its own destruction mediated by nitric oxide synthase-dependent formation of peroxynitrite. This mechanism might contribute to vascular endothelial dysfunction induced by oxidative stress. Copyright 1999 Academic Press.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2006
                September 2006
                20 September 2006
                : 43
                : 5
                : 401-410
                Affiliations
                Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
                Article
                94790 J Vasc Res 2006;43:401–410
                10.1159/000094790
                16877872
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 6, Tables: 1, References: 29, Pages: 10
                Categories
                Research Paper

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