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      Dopexamine Hydrochloride in the Human Kidney: Localization, Receptor Binding and Effect on 3’-5’-Cyclic Adenosine Monophosphate Generation

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          Abstract

          Dopexamine hydrochloride is a synthetic dopamine analogue recently developed to improve myocardial and renal performance in patients suffering from low cardiac output states. The present study was designed to assess the pharmacological profile and the anatomical localization of [<sup>3</sup>H]-dopexamine binding sites within the human nephron. The effects of dopexamine on the 3’-5’-cyclic adenosine monophosphate (cAMP)-generating system in membrane particles of the human kidney were also investigated. It was found that [<sup>3</sup>H]-dopexamine was specifically bound by sections of the human kidney. The binding was partly inhibited by the DA-1 receptor antagonist SCH 23390, by the β2-adrenoceptor antagonist ICI 118,551 and by the DA-2 receptor antagonist domperidone. The 3 antagonists in combination reduced [<sup>3</sup>H]-dopexamine binding to nonspecific values. Light microscope autoradiography revealed the accumulation of silver grains, corresponding to [<sup>3</sup>H]-dopexamine binding sites, within the different portions of the human nephron. The incubation of sections of the human kidney with [<sup>3</sup>H]-dopexamine plus SCH 23390 caused a remarkable reduction in the density of silver grains within the proximal tubule and the macula densa and a moderate decrease in the density of silver grains within the ascending and descending limbs of the loop of Henle as well as within the distal tubule. The incubation of sections of human kidney with [<sup>3</sup>H]-dopexamine plus ICI 118,551 caused a pronounced reduction in the density of silver grains within the glomerulus, the limbs of the loop of Henle, the distal tubule and the medullary collecting tubules and a moderate decrease in the density of silver grains within the macula densa and the proximal collecting tubule. The incubation of sections of the human kidney with [<sup>3</sup>H]-dopexamine plus domperidone caused a moderate decrease in silver grain accumulation within proximal and distal tubules as well as within medullary collecting tubules. Dopexamine caused a dose-dependent accumulation of cAMP levels in membrane particles of the human kidney. This effect was in part reduced by SCH 23390 or by ICI 118,551. A combination of SCH 23390 and ICI 118,551 reduced cAMP levels to basal values. The present results clearly show that dopexamine binds to dopamine DA-1 and DA-2 receptor sites and to β<sub>2</sub>-adrenoceptors in various regions of the human kidney. Moreover, they demonstrate that dopexamine stimulates cAMP formation in the human kidney by activating both DA-1 receptors and β<sub>2</sub>-adrenoceptors. Stimulation of some or all of these receptors may contribute to the renal actions of dopexamine in humans.

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          Author and article information

          Journal
          NEF
          Nephron
          10.1159/issn.1660-8151
          Nephron
          S. Karger AG
          1660-8151
          2235-3186
          1993
          1993
          12 December 2008
          : 65
          : 3
          : 385-391
          Affiliations
          aAnatomia Umana, Istituto di Farmacologia, Università di Camerino; bDipartimento di Scienze Cardiovascolari e Respiratorie, Università ‘La Sapienza’, Roma, Italy
          Article
          187518 Nephron 1993;65:385–391
          10.1159/000187518
          7904730
          © 1993 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
          Pages: 7
          Categories
          Original Paper

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