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      Thromboxane A 2 Contributes to the Mediation of Flow-Induced Responses of Skeletal Muscle Venules: Role of Cyclooxygenases 1 and 2

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          Abstract

          Background: It has been shown that increases in intraluminal flow elicit dilation in venules, but the mediation of response is not yet clarified. We hypothesized that – in addition to nitric oxide (NO) and dilator prostaglandins (PGI<sub>2</sub>/ PGE<sub>2</sub>) – thromboxane A<sub>2</sub> (TxA<sub>2</sub>) contributes to the mediation of flow-induced responses of venules. Methods and Results: Isolated rat gracilis muscle venules (259 ± 11 μm at 10 mm Hg) dilated as a function of intraluminal flow, which was augmented in the presence of the TxA<sub>2</sub> receptor antagonist SQ 29,548 or the TxA<sub>2</sub> synthase inhibitor ozagrel. In the presence of SQ 29,548, indomethacin or Nω-nitro- L-arginine methyl-ester decreased flow-induced dilations, whereas in their simultaneous presence dilations were abolished. The selective cyclooxygenase (COX) 1 inhibitor SC 560 reduced, whereas the selective COX-2 inhibitor NS 398 enhanced flow-induced dilations. Immunohistochemistry showed that both COX-1 and COX-2 are present in the wall of venules. Conclusion: In skeletal muscle venules, increases in intraluminal flow elicit production of constrictor TxA<sub>2</sub>, in addition to the dilator NO and PGI<sub>2</sub>/PGE<sub>2</sub>, with an overall effect of limited dilation. These mediators are likely to have important roles in the multiple feedback regulation of wall shear stress in venules during changes in blood flow velocity and/or viscosity.

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          Most cited references 15

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          Flow effects on prostacyclin production by cultured human endothelial cells.

          Endothelial cell functions, such as arachidonic acid metabolism, may be modulated by membrane stresses induced by blood flow. The production of prostacyclin by primary human endothelial cell cultures subjected to pulsatile and steady flow shear stress was measured. The onset of flow led to a sudden increase in prostacyclin production, which decreased to a steady rate within several minutes. The steady-state production rate of cells subjected to pulsatile shear stress was more than twice that of cells exposed to steady shear stress and 16 times greater than that of cells in stationary culture.
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            Cloning two isoforms of rat cyclooxygenase: differential regulation of their expression.

             P Chanmugam,  Y Xia,  L Feng (1993)
            Two isoforms of cyclooxygenase (COX) have been identified in eukaryotic cells: COX-1 encoded by a 2.8-kb mRNA, and a mitogen-inducible COX-2 encoded by a 4-kb mRNA. We have cloned the COX-1 and COX-2 cDNAs from the cDNA library constructed from lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages. The deduced amino acid sequence showed that COX-1 contained 602 amino acids, whereas COX-2 contained 604 amino acids. There is 95% conservation of the nucleotide sequence in the open reading frame of COX-1 between the rat and the mouse, while the homology of the 3' untranslated region is 68% except for a 150 bp segment adjacent to the stop codon which is nonhomologous with the mouse. Transfection of both COX cDNAs into Cos-7 cells resulted in increased COX activity. In rat vascular smooth muscle cells, interleukin-1 beta selectively increased the expression of COX-2, but not that of COX-1, as assessed by enzyme activity, immunoprecipitation of COX proteins, and mRNA analysis. Only the brain among tissues tested exhibits basal expression of COX-2 as the major form of the enzyme. However, COX-2 mRNA was expressed in vivo in the lung and kidney, but not in the heart, after systemic administration of LPS, suggesting that COX-2 but not COX-1 plays a major role in producing COX-derived products of arachidonic acid during endotoxic shock. Thus, the two COX isoforms were differentially expressed, and COX-2 was selectively induced in response to inflammatory stimuli in rats.
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              • Abstract: not found
              • Article: not found

              Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2

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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
                2009
                August 2009
                21 January 2009
                : 46
                : 5
                : 397-405
                Affiliations
                aDepartment of Pathophysiology, Semmelweis University, Budapest, bDivision of Clinical Physiology, Institute of Cardiology, Medical and Health Science Center, University of Debrecen, Debrecen, and cDepartment of Physiology and Gerontology, University of Pécs, Pécs, Hungary; dDepartment of Physiology, New York Medical College, Valhalla, N.Y., USA
                Article
                194270 PMC2790754 J Vasc Res 2009;46:397–405
                10.1159/000194270
                PMC2790754
                19155631
                © 2009 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, References: 34, Pages: 9
                Categories
                Research Paper

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