Effects of TRA-418, a novel TP-receptor antagonist, and IP-receptor agonist, on human platelet activation and aggregation

Abstract

1 {4-[2-(1,1-Diphenylethylsulfanyl)-ethyl]-3,4-dihydro-2H-benzo[1,4] oxazin-8-yloxy}-acetic acid N-Methyl-D-glucamine salt (TRA-418) has both thromboxane A 2 (TP)-receptor antagonist and prostacyclin (IP)-receptor agonist properties. The present study examined the advantageous effects of TRA-418 based on the dual activities, over an agent having either activity alone and also the difference in the effects of TRA-418 and a glycoprotein αIIb/β3 integrin (GPIIb/IIIa) inhibitor. 2 TRA-418 inhibited platelet GPIIb/IIIa activation as well as P-selectin expression induced by adenosine 5′-diphosphate, thrombin receptor agonist peptide 1-6 (Ser-Phe-Leu-Leu-Arg-Asn-NH 2), and U-46619 in the presence of epinephrine (U-46619 + epinephrine). TRA-418 also inhibited platelet aggregation induced by those platelet-stimulants in Ca 2+ chelating anticoagulant, citrate and in nonchelating anticoagulant, D-phenylalanyl-L- prolyl-L-arginyl-chloromethyl ketone (PPACK). 3 The TP-receptor antagonist SQ-29548 inhibited only U-46619 + epinephrine-induced GPIIb/IIIa activation, P-selectin expression, and platelet aggregation. 4 The IP-receptor agonist beraprost sodium inhibited platelet activation. Beraprost also inhibited platelet aggregation induced by platelet stimulants we tested in citrate and in PPACK. 5 The GPIIb/IIIa inhibitor abciximab blocked GPIIb/IIIa activation and platelet aggregation. However, abciximab showed slight inhibitory effects on P-selectin expression. 6 TRA-418 is more advantageous as an antiplatelet agent than TP-receptor antagonists or IP-receptor agonists separately used. TRA-418 showed a different inhibitory profile from abciximab in the effects on P-selectin expression.