title: TRA-418, a thromboxane A2 receptor antagonist and prostacyclin receptor agonist, inhibits platelet-leukocyte interaction in human whole blood.
abstract: TRA-418, a compound with both thromboxane A2 receptor (TP receptor) antagonistic and prostacyclin receptor (IP receptor) agonistic activities, was synthesised in our laboratory as a new antithrombotic agent. In this study, we examined the effects of TRA-418 on platelet-leukocyte interactions in human whole blood. Platelet-leukocyte interactions were induced by U-46619 in the presence of epinephrine (U-46619 + epinephrine) or with thrombin receptor agonist peptide 1-6 (TRAP). Platelet-leukocyte interactions were assessed by flow cytometry, with examination of both platelet-neutrophil and platelet-monocyte complexes. In a control experiment, the TP receptor antagonist SQ-29548 significantly inhibited the induction of platelet-leukocyte complexes by the combination of U-46619 and epinephrine, but not TRAP-induced formation of platelet-leukocyte complexes. Conversely, the IP receptor agonist beraprost sodium inhibited platelet-leukocyte complex formation induced by both methods, although the IC50 values of beraprost sodium for U-46619 + epinephrine were at least 10-fold greater than for TRAP. Under such conditions, TRA-418 inhibited both U-46619 + epinephrine-induced and TRAP-induced platelet-leukocyte complex formation in a concentration-dependent manner, in a similar range. These results suggest that TRA-418 exerts its inhibitory effects on platelet-leukocyte interactions by acting as a TP receptor antagonist as well as an IP receptor agonist in an additive or synergistic manner. These inhibitory effects of TRA-418 on formation of platelet-leukocyte complexes suggest the compound is beneficial effects as an antithrombotic agent.
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Kamakura, Japan. Mitsuko_Miyamoto@nts.toray.co.jp
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Michihiro
authors.initials: M
authors.lastname: Ohno
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtake
authors.forename: Teruo
authors.initials: T
authors.lastname: Matsushita
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002450:Cell Communication / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D004837:Epinephrine / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D005434:Flow Cytometry; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D044006:Receptors, Epoprostenol / Q000819:agonists*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010078:Oxazines; D010446:Peptide Fragments; D044006:Receptors, Epoprostenol; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C483402:TRA418; C086309:thrombin receptor peptide SFLLRNP; C048081:beraprost; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D011464:Epoprostenol; D004837:Epinephrine