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      Beraprost Upregulates K V Channel Expression and Function via EP 4 Receptor in Pulmonary Artery Smooth Muscle Cells Obtained from Rats with Hypoxia-Induced Pulmonary Hypertension

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          Abstract

          The reduced expression and function of voltage-dependent potassium (K<sub>V</sub>) channels have been involved in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH), leading to pulmonary vasoconstriction and vascular remodeling, while the upregulation of K<sub>V</sub> channels is of therapeutic significance for pulmonary hypertension. Beraprost sodium (BPS) has been shown to be effective in patients with pulmonary hypertension. However, the effect of BPS on O<sub>2</sub>-sensitive K<sub>V</sub> channels in pulmonary artery smooth muscle cells (PASMCs) remains unclear. In the present study, the effect of BPS on rats with HPH was observed, and the influence of BPS on the expression and function of O<sub>2</sub>-sensitive K<sub>V</sub> channels in PASMCs was investigated. The results revealed that BPS reduced mean pulmonary artery pressure, suppressed right ventricular hypertrophy, and attenuated the remodeling of pulmonary arteries in rats exposed to discontinuous hypoxia for 4 weeks (8 h/day). This was accompanied with the significantly upregulated expression of K<sub>V</sub> channel α-subunits (K<sub>V</sub>1.2, K<sub>V</sub>1.5 and K<sub>V</sub>2.1) and O<sub>2</sub>-sensitive voltage-gated K<sup>+</sup> (K<sub>V</sub>) channel current ( I<sub>K(V)</sub>) in small pulmonary arteries in HPH model rats, as well as in hypoxia-induced PASMCs. Furthermore, in vitrostudies have revealed that the upregulation of BPS on O<sub>2</sub>-sensitive K<sub>V</sub> channels was significantly inhibited after treatment with prostaglandin E<sub>2</sub> receptor subtype EP<sub>4</sub> antagonist GW627368X. Taken together, these results suggest that BPS attenuates the development of HPH through the upregulation of O<sub>2</sub>-sensitive K<sub>V</sub> channels, which was probably via the EP<sub>4</sub> receptor-related pathway.

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          An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.

          Constriction of small pulmonary arteries and arterioles and focal vascular injury are features of pulmonary hypertension. Because thromboxane A2 is both a vasoconstrictor and a potent stimulus for platelet aggregation, it may be an important mediator of pulmonary hypertension. Its effects are antagonized by prostacyclin, which is released by vascular endothelial cells. We tested the hypothesis that there may be an imbalance between the release of thromboxane A2 and prostacyclin in pulmonary hypertension, reflecting platelet activation and an abnormal response of the pulmonary vascular endothelium. We used radioimmunoassays to measure the 24-hour urinary excretion of two stable metabolites of thromboxane A2 and a metabolite of prostacyclin in 20 patients with primary pulmonary hypertension, 14 with secondary pulmonary hypertension, 9 with severe chronic obstructive pulmonary disease (COPD) but no clinical evidence of pulmonary hypertension, and 23 normal controls. The 24-hour excretion of 11-dehydro-thromboxane B2 (a stable metabolite of thromboxane A2) was increased in patients with primary pulmonary hypertension and patients with secondary pulmonary hypertension, as compared with normal controls (3224 +/- 482, 5392 +/- 1640, and 1145 +/- 221 pg per milligram of creatinine, respectively; P less than 0.05), whereas the 24-hour excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha (a stable metabolite of prostacyclin) was decreased (369 +/- 106, 304 +/- 76, and 644 +/- 124 pg per milligram of creatinine, respectively; P less than 0.05). The rate of excretion of all metabolites in the patients with COPD but no clinical evidence of pulmonary hypertension was similar to that in the normal controls. An increase in the release of the vasoconstrictor thromboxane A2, suggesting the activation of platelets, occurs in both the primary and secondary forms of pulmonary hypertension. By contrast, the release of prostacyclin is depressed in these patients. Whether the imbalance in the release of these mediators is a cause or a result of pulmonary hypertension is unknown, but it may play a part in the development and maintenance of both forms of the disorder.
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            Updated treatment algorithm of pulmonary arterial hypertension.

            The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conflicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientific evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH, nurses, patients and patients' associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy, and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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              Advances in therapeutic interventions for patients with pulmonary arterial hypertension.

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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
                2019
                September 2019
                12 June 2019
                : 56
                : 4
                : 204-214
                Affiliations
                [_a] aDepartment of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
                [_b] bDepartment of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an, China
                Author notes
                *Prof. Hongyan Tian or Dr. Fenling Fan, Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277, Yan Tower West Road, Xi’an, Shaanxi 710061 (China), E-Mail tianhongyan_xjtu@163.com or happyling@mail.xjtu.edu.cn
                Article
                500424 J Vasc Res 2019;56:204–214
                10.1159/000500424
                31189158
                05e50d73-69cf-4a30-9895-2635a1169369
                © 2019 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.

                History
                : 11 July 2018
                : 15 April 2019
                Page count
                Figures: 6, Tables: 2, Pages: 11
                Categories
                Research Article

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Hypoxic pulmonary hypertension,Pulmonary artery smooth muscle cells,O2-sensitive KV channels,Beraprost sodium,Prostaglandin E2 receptor subtype EP4

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