EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin.

SAKARIASSEN KS; FEMIA EA; DARAY FM; PODDA GM; RAZZARI C; PUGLIANO M; ERRASTI AE; ARMESTO AR; NOWAK W; ALBERTS P; MEYER JP; SORENSEN AS; CATTANEO M; ROTHLIN RP

THROMBOSIS RESEARCH

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2012 vol. 130 p. 746 - 752

0049-3848

INTRODUCTION: This study aimed to characterize the in vitro effect of EV-077, acompound that antagonises the binding of prostanoids and isoprostanes to thethromboxane receptor (TP) and inhibits the thromboxane synthase (TS), on plateletaggregation of patients with type-2 diabetes and coronary artery disease (CAD) onchronic aspirin treatment. The effect of EV-077 on 8-iso-PGE(2)-mediated TPreceptor contraction of human arteries was also investigated.MATERIALS AND METHODS: Fifty-two type-2 diabetics with CAD on chronic aspirin(100mg) treatment were studied. Arachidonic acid-induced platelet aggregation wasmeasured by impedance aggregometry in platelet-rich plasma (PRP) and whole blood anticoagulated with hirudin, and by light transmission aggregometry incitrate-anticoagulated PRP following 10-min in vitro exposure to EV-077(100nmol/l) or control. The effect of EV-077 was measured on isometriccontraction of 24 human umbilical arteries induced by isoprostane 8-iso-PGE(2).RESULTS: Arachidonic acid (1mmol/l) induced substantial aggregation inhirudin-anticoagulated whole blood (63±4AU), which was significantly reduced byin vitro exposure to EV-077 (38±3AU, P<0.001). Virtually no arachidonicacid-induced aggregation in citrate-anticoagulated or hirudin-anticoagulated PRP was observed. EV-077 potently, competitively and reversibly inhibited TP mediatedcontraction of umbilical arteries by 8-iso-PGE(2) (P<0.01).CONCLUSIONS: Aspirin did not completely inhibit arachidonic acid-induced plateletaggregation in whole blood from type-2 diabetics with CAD. This aggregation islikely induced by prostanoids and/or isoprostanes produced by leukocytes, becauseit was significantly reduced by EV-077. The TP receptor-mediated contraction ofhuman arteries induced by isoprostane 8-iso-PGE(2) was effectively inhibited byEV-077.