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      Platelet-Activating Factor Antagonist, SM-12502, Attenuates Experimental Glomerular Thrombosis in Rats

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          Abstract

          Platelet-activating factor (PAF) is involved in many pathologic conditions through its potent proinflammatory and vasoactive effects. Using a specific PAF antagonist, SM-12502, we investigated the role of PAF in rat experimental glomerular thrombosis. In this model, sequential injections of nephrotoxic serum (NTS) and lipopolysaccharide (LPS) selectively induce glomerular fibrin deposition accompanied by neutrophil accumulation. SM-12502, when injected simultaneously with either NTS or LPS, strongly inhibited glomerular fibrin deposition in a dose-dependent manner. In contrast, neutrophil invasion was similar in both SM-12502-injected and uninjected rats, suggesting that the antithrombotic effect was not mediated by inhibition of neutrophil migration. However, serum myeloperoxidase activity, a marker of neutrophil activation, was significantly suppressed by treatment with SM-12502. From a previous finding supporting the indispensable role of neutrophils in this model and the current observations, SM-12502 is suggested to attenuate glomerular thrombosis by inhibiting neutrophil activation. Thus, the present findings suggest an involvement of PAF in this glomerular thrombosis model.

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          Inhibition by CV-3988 of the binding of [3H]-platelet activating factor (PAF) to the platelet.

          The inhibitory effects of CV-3988, a specific antagonist of PAF, on the binding of [3H]-PAF to washed platelets of various species including human were examined. The dissociation constant (Kd), binding capacity (Bmax), and the number of receptor/platelet for the specific binding site of rabbit platelets were 2.2 +/- 0.2 nM, 93.7 +/- 8.3 fmoles/10(8) platelets, and 568 +/- 50, respectively. CV-3988 selectively inhibited the specific binding of [3H]-PAF to rabbit platelets with an IC50 of 7.9 X 10(-8) M, and it slightly increased the Kd value (2.5 +/- 0.8 nM) and decreased the binding capacity for PAF (Bmax: 54.3 +/- 16.3 fmoles/10(8) platelets). The Ki value of CV-3988 for the specific binding of [3H]-PAF to rabbit platelets was 1.2 X 10(-7) M. CV-3988 had no effects on the binding of [3H]-5-hydroxytryptamine (5-HT) to rabbit platelets and on the shape change of the platelet induced by 5-HT. CV-3988 also inhibited the specific binding of [3H]-PAF to human and guinea-pig platelets with IC50 values of 1.6 X 10(-7) and 1.8 X 10(-7) M, respectively. CV-3988 inhibited the PAF-induced aggregation in rabbit, guinea-pig, and human platelets. These findings show that CV-3988 is a specific antagonist of PAF at the receptor site(s) of platelets and, in these species, inhibits PAF-induced platelet aggregation by inhibiting the binding of PAF to the "PAF receptor". No specific binding of [3H]-PAF to the platelet of rats and mice was observed, indicating that these species lack a PAF receptor.
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            Author and article information

            Journal
            NEF
            Nephron
            10.1159/issn.1660-8151
            Nephron
            S. Karger AG
            1660-8151
            2235-3186
            2001
            2001
            16 March 2001
            : 87
            : 3
            : 274-278
            Affiliations
            Third Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma, Japan
            Article
            45926 Nephron 2001;87:274–278
            10.1159/000045926
            11287764
            © 2001 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
            Figures: 5, References: 17, Pages: 5
            Product
            Self URI (application/pdf): https://www.karger.com/Article/Pdf/45926
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            Original Paper

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