Characterization of Endothelium- Dependent Relaxation in Guinea Pig Basilar Artery – Effect of Hypoxia and Role of Cytochrome P ₄₅₀ Mono-Oxygenase

Abstract

In the guinea pig basilar artery, acetylcholine and the calcium ionophore A23187 induced endothelium-dependent relaxations, which were not significantly affected by the nitric oxide (NO) synthase inhibitor N^ω-nitro- L-arginine ( L-NOARG; 0.3 m M) or the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one; 1-10 µ M), or by these inhibitors combined. However, acetylcholine (10 µ M) and A23187 (3 µ M) each significantly increased the tissue level of cGMP in the absence but not in the presence of L-NOARG, suggesting that NO is released from the vascular endothelium in this blood vessel. Treatment with the potassium (K) channel inhibitors charybdotoxin (0.1 µ M) plus apamin (0.1 µ M), a toxin mixture previously shown to inhibit relaxations mediated by endothelium-derived hyperpolarizing factor (EDHF) in this artery, had no effect on the A23187-induced relaxation but slightly inhibited the response to acetylcholine (E_max was reduced by 24%). When the action of EDHF was prevented by these K channel inhibitors, the remaining relaxation was abolished by either ODQ (1 µ M) or L-NOARG (0.3 m M), indicating that NO, apart from EDHF, contributes to the endothelium-dependent relaxations. Furthermore, ODQ (10 µ M) abolished the relaxation induced by the NO donor S-nitroso-N-acetylpenicillamine. Thus, activation of soluble guanylate cyclase seems to be the only mechanism through which NO causes relaxation in this artery. When vessels were exposed to grave hypoxia (pO₂ = 6 mm Hg), the NO-mediated relaxation (induced by acetylcholine in the presence of charybdotoxin plus apamin) disappeared. In contrast, EDHF-mediated responses (elicited by acetylcholine in the presence of L-NOARG) were only marginally affected by hypoxia (E_max was reduced by 16%). 17-Octadecynoic acid (50 µ M) and 5,8,11,14-eicosatetraynoic acid (10 µ M), inhibitors of cytochrome P₄₅₀-dependent oxidation of arachidonic acid, failed to inhibit the acetylcholine-induced relaxation in the presence of L-NOARG. The cytochrome P₄₅₀-dependent arachidonic acid metabolite 11,12-epoxyecosatrienoic acid (0.3–3.0 µ M) had no relaxant effect per se. In conclusion, EDHF and NO are both mediators of endothelium-dependent relaxations in the guinea pig basilar artery. However, during grave hypoxia, EDHF alone mediates acetylcholine-induced relaxation. The results further suggest that EDHF is not a metabolite of arachidonic acid formed by cytochrome P₄₅₀ mono-oxygenase or generated by another oxygen-dependent enzyme in this artery.

Journal

Journal ID (publisher-id): JVR

Journal ID (nlm-ta): J Vasc Res

Journal ID (doi): 10.1159/issn.1018-1172

Title: Journal of Vascular Research

Publisher: S. Karger AG

ISSN (Print): 1018-1172

ISSN (Electronic): 1423-0135

Publication date Subscription-year: 1998

Publication date (Print): August 1998

Publication date (Electronic): 07 August 1998

Volume: 35

Issue: 4

Pages: 285-294

Affiliations

Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, Lund, Sweden

Article

Publisher ID: 25595 Other ID: J Vasc Res 1998;35:285–294

DOI: 10.1159/000025595

PubMed ID: 9701713

Copyright statement: © 1998 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

Pages: 10

Product

Self URI (application/pdf): https://www.karger.com/Article/Pdf/25595

Self URI (text/html): https://www.karger.com/Article/FullText/25595

Self URI (journal page): https://www.karger.com/SubjectArea/Cardiovascular-System

Categories

Subject: Research Paper