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Effects of TRA‐418, a novel TP‐receptor antagonist, and IP‐receptor agonist, on human platelet activation and aggregation
Author(s) -
Miyamoto Mitsuko,
Yamada Naohiro,
Ikezawa Shiho,
Ohno Michihiro,
Otake Atsushi,
Umemura Kazuo,
Matsushita Teruo
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705499
Subject(s) - chemistry , platelet activation , thromboxane receptor , agonist , platelet , pharmacology , thromboxane a2 , platelet aggregation inhibitor , receptor antagonist , receptor , platelet membrane glycoprotein , antagonist , medicine , biochemistry , aspirin
{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 α IIb/ β 3 integrin (GPIIb/IIIa) inhibitor. 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). The TP‐receptor antagonist SQ‐29548 inhibited only U‐46619+epinephrine‐induced GPIIb/IIIa activation, P‐selectin expression, and platelet aggregation. 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. The GPIIb/IIIa inhibitor abciximab blocked GPIIb/IIIa activation and platelet aggregation. However, abciximab showed slight inhibitory effects on P‐selectin expression. 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.British Journal of Pharmacology (2003) 140 , 889–894. doi: 10.1038/sj.bjp.0705499