ADP Receptor Induced Activation of Guanine Nucleotide Binding Proteins in Rat Platelet Membranes– An Effect Selectively Blocked by the Thienopyridine Clopidogrel

C Gachet; P Savi; P Ohlmann; J-P Maffrand; K H Jakobs; J-P Cazenave

doi:10.1055/s-0038-1656322

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1992; 68(01): 079-083
DOI: 10.1055/s-0038-1656322

Original Article

Schattauer GmbH Stuttgart

ADP Receptor Induced Activation of Guanine Nucleotide Binding Proteins in Rat Platelet Membranes– An Effect Selectively Blocked by the Thienopyridine Clopidogrel

C Gachet

INSERM U.311, Centre Régional de Transfusion Sanguine, Strasbourg, France

,

P Savi

¹Sanofi Recherche, Toulouse, France

,

P Ohlmann

INSERM U.311, Centre Régional de Transfusion Sanguine, Strasbourg, France

,

J-P Maffrand

¹Sanofi Recherche, Toulouse, France

,

K H Jakobs

²Pharmakologisches Institut, Universität Heidelberg, Heidelberg, FRG

,

J-P Cazenave

INSERM U.311, Centre Régional de Transfusion Sanguine, Strasbourg, France

› Institutsangaben

Abstract

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Summary

The thienopyridine clopidogrel, a potent analog of ticlopidine, is a powerful inhibitor of ADP induced platelet aggregation and ADP induced inhibition of cyclic AMP accumulation in intact platelets but not of ADP induced shape change. We have recently demonstrated that ADP stimulates the binding of GTPγS to GTP binding proteins (G proteins) in human platelet membranes. We now studied the effects of clopidogrel, a specific inhibitor of ADP induced platelet aggregation on the stimulation of GTPγS binding to rat platelet membranes by ADP. Using the non hydrolyzable stable analog of ADP, 2MeSADP, we demonstrate that 2MeSADP stimulates the binding of [³⁵S]GTPγS to rat platelet membranes in a concentration dependent manner, that this effect is inhibited by the specific ADP receptor antagonist Sp-ATPαS and that clopidogrel completely and selectively blocks the stimulation by 2MeSADP of [³⁵S]GTPγS binding to platelet membranes of treated rats. We conclude that: i) rat platelet membranes possess an ADP receptor coupled to unidentified G protein(s) and ii) the thienopyridine clopidogrel impairs the interaction of the ADP receptor with its G protein by an irreversible modification the ADP receptor itself or its putative G protein.

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Referenzen

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