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      Enhanced 5-HT 2 Receptor Mediated Contractions in Diabetic Rat Aorta: Participation of Ca 2+ Channels Associated with Protein Kinase C Activity

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          Abstract

          The aim of this study was to determine how the contractile responses to 5-hydroxytryptamine (5-HT) are altered in aortas from rats with streptozotocin-induced diabetes and to explore the possible mechanisms of the altered vascular reactivity to 5-HT in diabetes. In the presence of extracellular Ca<sup>2+</sup> (2.5 m M), the contractile responses to stimulation of 5-HT<sub>2</sub> receptors with 5-HT were greater in aortas from diabetic rats as compared with those from age-matched controls. Similarly, phorbol-12, 13-dibutyrate (PDBu) (≧30 n M) induced significantly greater contractions in diabetic aortas. The enhanced contractile responses of diabetic aortas to 5-HT and PDBu were abolished in the presence of 1 µ M nifedipine. Pretreatment with 20 n M staurosporine caused a complete inhibition of the contractile responses to 5-HT in both control and diabetic aortas. In contrast to those to 5-HT and PDBu, the contractile responses to high K<sup>+</sup> (40 m M) were markedly diminished in diabetic aortas. The nifedipine-sensitive uptake of <sup>45</sup>Ca<sup>2+</sup> induced by 5-HT was significantly greater in diabetic aortas than in controls, whereas that induced by high K<sup>+</sup> was significantly less in diabetics. The phasic contractions produced by 5-HT in Ca<sup>2+</sup>-free medium were significantly attenuated in diabetic aortas, but those produced by norepinephrine were unchanged. Accumulation of [<sup>3</sup>H]inositol monophosphate (IP<sub>1</sub>) in aortic strips prelabeled with myo-[<sup>3</sup>H] inositol was increased to a similar extent by 5-HT and norepinephrine in control rats, but the 5-HT-induced increase in [<sup>3</sup>H]IP<sub>1</sub> accumulation was significantly less than the norepinephrine-induced one in diabetics. These findings indicate that the extracellular Ca<sup>2+</sup>-dependent contractions mediated by 5-HT<sub>2</sub> receptors are enhanced in aortas from diabetic rats, and this is presumably related to a greater influx of Ca<sup>2+</sup> through transmembrane Ca<sup>2+</sup> channels as a consequence of increased protein kinase C activated processes. On the other hand, the contraction induced by release of Ca<sup>2+</sup> from intracellular stores in response to 5-HT is diminished in these tissues, possibly due to the impaired phosphoinositide response.

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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
          1995
          1995
          24 September 2008
          : 32
          : 4
          : 220-229
          Affiliations
          Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan
          Article
          159096 J Vasc Res 1995;32:220–229
          10.1159/000159096
          7654879
          c71587f7-e51e-40c2-9efb-063a0ed13977
          © 1995 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
          : 28 November 1994
          : 06 March 1995
          Page count
          Pages: 10
          Categories
          Research Paper

          General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
          Vascular contraction,5-Hydroxytryptamine,Diabetes mellitus,5-HT2 receptors,Ca2+ channels,Phosphoinositide turnover,Protein kinase C

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