Naloxone Inhibits A6 Cell Na ⁺/H ⁺ Exchange by Activating Protein Kinase C via the Mobilization of Intracellular Calcium

Abstract

The opioid receptor antagonist, naloxone, has been shown to have beneficial effects in the kidney and to be implicated in renal salt and water balance. In the present study the signal transduction pathways utilized by naloxone were studied in an epithelial cell line model of the cortical collecting duct, A6 cells. We found that naloxone has a dual effect depending on the concentration used: at a low concentration (10^–6 M) it antagonized the β-endorphin-dependent increase in cytoplasmic calcium [Ca²⁺]_i, while at higher concentrations (>10^–5 M) it increased [Ca²⁺]_i and intracellular inositol phosphate levels. While naloxone-induced increases in [Ca²⁺]_i occurred in the absence of external calcium, it was significantly stimulated by increasing the external calcium concentration, suggesting that naloxone increases [Ca²⁺]_i via both calcium release and calcium influx. In polarized A6 cell monolayers naloxone inhibited the activity of the Na⁺/H⁺ exchanger (NHE) only when added to the basolateral cell surface. This inhibition of the NHE was prevented by pretreatment of the cells with either the intracellular calcium chelator, BAPTA or with the protein kinase C inhibitor, calphostin C. These findings demonstrate that naloxone induces a rapid increase in intracellular calcium which inhibits the NHE via the calcium-dependent protein kinase C regulatory pathway.

Journal

Journal ID (publisher-id): EXN

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2001

Publication date (Print): 2001

Publication date (Electronic): 31 August 2001

Volume: 9

Issue: 5

Pages: 341-348

Affiliations

^aDepartment of General and Environmental Physiology and ^bDepartment of Animal Production, Section of Reproduction, University of Bari, Italy

Article

Publisher ID: 52630 Other ID: Exp Nephrol 2001;9:341–348

DOI: 10.1159/000052630

PubMed ID: 11549852

Copyright statement: © 2001 S. Karger AG, Basel

License:

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: 40, Pages: 8

Product

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Categories

Subject: Original Paper