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      Purinergic Component in the Coronary Vasodilatation to Acetylcholine after Ischemia-Reperfusion in Perfused Rat Hearts

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          Abstract

          To determine the involvement of purinergic receptors in coronary endothelium-dependent relaxation, the response to acetylcholine (1 × 10<sup>-8</sup> to 3 × 10<sup>-7</sup><smlcap>M</smlcap>) was recorded in isolated rat hearts perfused according to the Langendorff procedure before and after 30 min of ischemia and 15 min of reperfusion and after the inhibition of nitric oxide synthesis with <smlcap>L</smlcap>-NAME (10<sup>-4</sup><smlcap>M</smlcap>), in the absence and presence of the antagonist of purinergic P2X receptors, PPADS (3 × 10<sup>-6</sup><smlcap>M</smlcap>), and of the antagonist of purinergic P2Y receptors, Reactive Blue 2 (3 × 10<sup>-7</sup><smlcap>M</smlcap>). In control conditions, the relaxation to acetylcholine was not altered by PPADS or Reactive Blue 2. The relaxation to acetylcholine was reduced after ischemia-reperfusion, and, in this condition, it was further reduced by treatment with PPADS or Reactive Blue 2. Likewise, the relaxation to acetylcholine was reduced by <smlcap>L</smlcap>-NAME, and reduced further by Reactive Blue 2 but not by PPADS. These results suggest that the relaxation to acetylcholine may be partly mediated by purinergic receptors after ischemia-reperfusion, due to the reduction of nitric oxide release in this condition.

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          Most cited references 34

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          Purinergic signalling: Its unpopular beginning, its acceptance and its exciting future.

          Adenosine 5'-triphosphate (ATP) was identified in 1970 as the transmitter responsible for non-adrenergic, non-cholinergic neurotransmission in the gut and bladder and the term 'purinergic' was coined. Purinergic cotransmission was proposed in 1976 and ATP is now recognized as a cotransmitter in all nerves in the peripheral and central nervous systems. P1 (adenosine) and P2 (ATP) receptors were distinguished in 1978. Cloning of these receptors in the early 1990s was a turning point in the acceptance of the purinergic signalling hypothesis. There are both short-term purinergic signalling in neurotransmission, neuromodulation and secretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation and death in development and regeneration. Much is known about the mechanisms of ATP release and its breakdown by ectonucleotidases. Recently, there has been emphasis on purinergic pathophysiology, including neurodegenerative and neuropsychiatric disorders. Purinergic therapeutic strategies are being developed for treatment of gut, kidney, bladder, lung, skeletal and reproductive system disorders, pain and cancer. Copyright © 2012 WILEY Periodicals, Inc.
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            The isolated blood and perfusion fluid perfused heart.

            The isolated heart is deservedly one of the most popular experimental models in cardiovascular research, both in terms of cost and the quality and quantity of data it provides. However, it is a deceptively simple model, capable of throwing many problems in the path of the inexperienced or unwary perfuser. The following article discusses the advantages and disadvantages of the various types of isolated heart perfusion (Langendorff and working; blood and buffer perfused). We attempt to give an insight into the many factors which must be taken into consideration when first establishing these preparations, we identify the range of indices that can be measured and the potential pitfalls which, with a little care, can be readily avoided. Copyright 2000 Academic Press.
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              Thrombin-induced ATP release from human umbilical vein endothelial cells.

              ATP and its degradation products play an important role as signaling molecules in the vascular system, and endothelial cells are considered to be an important source of nucleotide release. To investigate the mechanism and physiological significance of endothelial ATP release, we compared different pharmacological stimuli for their ability to evoke ATP release from first passage cultivated human umbilical vein endothelial cells (HUVECs). Agonists known to increase intracellular Ca(2+) levels (A23187, histamine, thrombin) induced a stable, non-lytic ATP release. Since thrombin proved to be the most robust and reproducible stimulus, the molecular mechanism of thrombin-mediated ATP release from HUVECs was further investigated. ATP rapidly increased with thrombin (1 U/ml) and reached a steady-state level after 4 min. Loading the cells with BAPTA-AM to capture intracellular calcium suppressed ATP release. The thrombin-specific, protease-activated receptor 1 (PAR-1)-specific agonist peptide TFLLRN (10 μM) fully mimicked thrombin action on ATP release. To identify the nature of the ATP-permeable pathway, we tested various inhibitors of potential ATP channels for their ability to inhibit the thrombin response. Carbenoxolone, an inhibitor of connexin hemichannels and pannexin channels, as well as Gd(3+) were highly effective in blocking the thrombin-mediated ATP release. Specifically targeting connexin43 (Cx43) and pannexin1 (Panx1) revealed that reducing Panx1 expression significantly reduced ATP release, while downregulating Cx43 was ineffective. Our study demonstrates that thrombin at physiological concentrations is a potent stimulus of endothelial ATP release involving PAR-1 receptor activation and intracellular calcium mobilization. ATP is released by a carbenoxolone- and Gd(3+)- sensitive pathway, most likely involving Panx1 channels.
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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
                2014
                October 2014
                16 September 2014
                : 51
                : 4
                : 283-289
                Affiliations
                Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
                Author notes
                *Dr. Angel Luis García-Villalón, Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, C/Arzobispo Morcillo No. 2, ES-28029 Madrid (Spain), E-Mail angeluis.villalon@uam.es
                Article
                365928 J Vasc Res 2014;51:283-289
                10.1159/000365928
                25228127
                © 2014 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: 5, Pages: 7
                Categories
                Research Paper

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