title: The thienopyridine ticlopidine selectively prevents the inhibitory effects of ADP but not of adrenaline on cAMP levels raised by stimulation of the adenylate cyclase of human platelets by PGE1.
abstract: After oral administration, ticlopidine specifically inhibits ADP-induced platelet aggregation, prolongs the bleeding time and prevents thrombosis in man. Its mechanism of action is not well known. Ticlopidine inhibits ADP-induced binding of fibrinogen to platelet glycoprotein GP IIb-IIIa but not shape change and increases deaggregation. Ticlopidine has no direct effect on the GP IIb-IIIa complex. We studied the effects of ticlopidine (500 mg/day for 8 days) in four healthy male volunteers on washed platelet aggregation induced by 5 microM ADP or thrombin (0.1 units/mL) and potentiated by 1 microM adrenaline (Adr), on basal and 1 microM PGE1-stimulated cAMP levels and on elevation of cytosolic free Ca2+ concentration ([Ca2+]i). We found that: (i) ticlopidine inhibits aggregation by ADP but not the potentiation by Adr of ADP-induced aggregation; (ii) ADP, Adr or thrombin decreases cAMP levels raised by PGE1, an effect inhibited by ticlopidine only for ADP and not for Adr or thrombin; and (iii) Ca2+ influx and Ca2+ mobilization from internal stores were not affected. These results suggested that ticlopidine or a metabolite impairs the coupling mechanism of the ADP aggregation pathway at an unknown level.
authors.affiliation: INSERM U.311, Biologie et Pharmacologie des Interactions du Sang avec les Vaisseaux et les Biomatériaux, Centre Régional de Transfusion Sanguine, Strasbourg, France.
authors.forename: C
authors.initials: C
authors.lastname: Gachet
authors.forename: J P
authors.initials: JP
authors.lastname: Cazenave
authors.forename: P
authors.initials: P
authors.lastname: Ohlmann
authors.forename: C
authors.initials: C
authors.lastname: Bouloux
authors.forename: G
authors.initials: G
authors.lastname: Defreyn
authors.forename: F
authors.initials: F
authors.lastname: Driot
authors.forename: J P
authors.initials: JP
authors.lastname: Maffrand
mesh_terms: D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000527:Alprostadil / Q000494:pharmacology*; D001760:Bleeding Time; D001792:Blood Platelets / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013988:Ticlopidine / Q000494:pharmacology*
chemical_list: D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000527:Alprostadil; D013988:Ticlopidine; D002118:Calcium; D004837:Epinephrine