Effect of  L -Carnitine and Propionyl- L -Carnitine on Endothelial Function of Small Mesenteric Arteries from SHR

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Abstract

Background:The effect of treatment with either 200 mg·kg–1 of L-carnitine (LC) or propionyl- L-carnitine (PLC) was studied on endothelial dysfunction of small mesenteric arteries (SMA) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Methods: Systolic blood pressure (SBP) was measured and endothelial and vascular functions were assessed by the effect of carbachol (CCh) and phenylephrine (Phe). O2– produced by SMA and eNOS expression were evaluated by chemiluminescence and Western blot, respectively. Results: Although SBP was not affected, endothelial relaxation increased in both LC- and PLC-treated SHR. Nevertheless, the CCh-induced contraction remained sensitive to indomethacin in these rats. On the contrary, NO participation was increased in all the groups except for LC-treated WKY. Furthermore, high concentrations of Phe produced NO-dependent relaxation of SMA from PLC-treated rats. Both compounds decreased basal and NADPH-stimulated O2– in SHR toward values observed in WKY. Only PLC increased eNOS protein expression in SHR. Neither LC nor PLC affected endothelium-derived hyperpolarizing factor-induced relaxation. Conclusions: LC and its propionate improved endothelial responses of SMA from SHR by decreasing O2– production and thus increasing NO availability. PLC also increased NO synthesis by enhancing eNOS expression.

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Most cited references 27

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EDHF: bringing the concepts together

Rudi Busse, Gillian Edwards, Michel Félétou … (2002)

Endothelial cells synthesize and release vasoactive mediators in response to various neurohumoural substances (e.g. bradykinin or acetylcholine) and physical stimuli (e.g. cyclic stretch or fluid shear stress). The best-characterized endothelium-derived relaxing factors are nitric oxide and prostacyclin. However, an additional relaxant pathway associated with smooth muscle hyperpolarization also exists. This hyperpolarization was originally attributed to the release of an endothelium-derived hyperpolarizing factor (EDHF) that diffuses to and activates smooth muscle K(+) channels. More recent evidence suggests that endothelial cell receptor activation by these neurohumoural substances opens endothelial cell K(+) channels. Several mechanisms have been proposed to link this pivotal step to the subsequent smooth muscle hyperpolarization. The main concepts are considered in detail in this review.

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Endothelial dysfunction: from physiology to therapy.

Jean-Vivien Mombouli, Paul M. Vanhoutte (1999)

The endothelium controls the tone of the underlying vascular smooth muscle mainly through the production of vasodilator mediators. In some cases, this function is hampered by the release of constrictor substances. The endothelial mediators are also involved in the regulation by the endothelium of vascular architecture and the blood cell-vascular wall interactions. The endothelium-derived factors comprise nitric oxide (NO), prostacyclin, and a still unknown endothelium-derived hyperpolarizing factor(s) (EDHF). In most vascular diseases, the vasodilator function of the endothelium is attenuated. In advanced atherosclerotic lesions, endothelium-dependent vasodilatation may even be abolished. Various degrees and forms of endothelial dysfunction exist, including (1) the impairment of Galphai proteins, (2) less release of NO, prostacyclin and/or EDHF, (3) increased release of endoperoxides, (4) increased production of reactive oxygen species, (5) increased generation of endothelin-1, and (6) decreased sensitivity of the vascular smooth muscle to NO, prostacyclin and/or EDHF. The levels of bradykinin and angiotensin II within the vascular wall are controlled by angiotensin-converting enzyme (ACE). ACE degrades bradykinin and generates angiotensin II. Bradykinin stimulates endothelial cells to release vasodilators. The actions of the kinin are maintained despite endothelial dysfunction, except in very severe arterial lesions. Angiotensin II may be in part responsible for endothelial dysfunction because it induces resistance to the vasodilator action of NO. Thus, impairment of the generation of angiotensin II blocks the direct and indirect vasoconstrictor effect of the peptide. By potentiating bradykinin, ACE inhibitors promote the release of relaxing vasodilator mediators to restore vasodilator function, and to prevent platelet aggregation as well as the recruitment of leukocytes to the vascular wall.

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NO modulates NADPH oxidase function via heme oxygenase-1 in human endothelial cells.

Beverly L. Roberts, Fan Jiang, Gregory J. Dusting … (2006)

NO is known to induce expression of heme oxygenase-1, an antioxidant enzyme in blood vessels. We tested whether NO might modulate the endothelial NADPH oxidase function via heme oxygenase-1. In human microvascular endothelial cells, the NO donor DETA-NONOate (0.1 to 1 mmol/L) strongly induced expression of heme oxygenase-1 but not Cu/Zn superoxide dismutase. This was associated with a reduction of the superoxide-generating capacity of NADPH oxidase, an effect that depended on de novo gene transcription and heme oxygenase-1 activity. Activation of NADPH oxidase by tumor necrosis factor (TNF) alpha increased generation of reactive oxygen species. DETA-NONOate alone had little effect on TNF-stimulated reactive oxygen species, but it enhanced the TNF response when: (1) heme oxygenase-1 expression was blocked with specific small-interfering RNA; (2) heme oxygenase-1 activity was blocked by zinc-protoporphyrin; or (3) NADPH oxidase activity was blocked by diphenyleneiodonium. Moreover, the heme oxygenase-1 end product bilirubin directly inhibited fully functional NADPH oxidase and seemed to interrupt the assembly and activation of the oxidase. In conclusion, NO may modulate superoxide production by NADPH oxidase in human vascular endothelial cells, at least partly by inducing heme oxygenase-1. Our results indicate that suppression of NADPH oxidase-dependent reactive oxygen species formation may represent a novel mechanism underlying the cardiovascular protective actions of heme oxygenase-1 and bilirubin.

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Author and article information

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: 2007

Publication date (Print): August 2007

Publication date (Electronic): 04 May 2007

Volume: 44

Issue: 5

Pages: 354-364

Affiliations

Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain

Article

Publisher ID: 102303 Other ID: J Vasc Res 2007;44:354–364

DOI: 10.1159/000102303

PubMed ID: 17483601

SO-VID: 80a1b4f3-5175-46e0-a131-c800b327c90b

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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

Date received : 22 May 2006

Date accepted : 02 March 2007

Page count

Figures: 8, Tables: 1, References: 40, Pages: 11

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Effect of L-Carnitine and Propionyl- L-Carnitine on Endothelial Function of Small Mesenteric Arteries from SHR

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Abstract

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Karger: Cardiovascular System

Most cited references 27

EDHF: bringing the concepts together

Endothelial dysfunction: from physiology to therapy.

NO modulates NADPH oxidase function via heme oxygenase-1 in human endothelial cells.

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