The novel prostaglandin I2 mimetic ONO-1301 escapes desensitization in an antiplatelet effect due to its inhibitory action on thromboxane A2 synthesis in mice.
ONO-1301 [(E)-[5-[2-[1-phenyl-1-(3-pyridyl)methylidene-aminooxy]ethyl]-7,8-dihydronaphthalene-1-yloxy]acetic acid] is a novel prostaglandin (PG) I2 mimetic with inhibitory activity on the thromboxane (TX) A2 synthase. Interestingly, ONO-1301 retains its inhibitory effect on platelet aggregation after repeated administration, while beraprost, a representative agonist for the PGI2 receptor (IP), loses its inhibitory effect after repeated administration. In the present study, we intended to clarify the mechanism by which ONO-1301 escapes desensitization of an antiplatelet effect. In platelets prepared from wild-type mice, ONO-1301 inhibited collagen-induced aggregation and stimulated cAMP production in an IP-dependent manner. In addition, ONO-1301 inhibited arachidonic acid-induced TXA2 production in platelets lacking IP. Despite the decrease in stimulatory action on cAMP production, the antiplatelet effect of ONO-1301 hardly changed after repeated administration for 10 days in wild-type mice. Noteworthy, beraprost could retain its antiplatelet effect after repeated administration in combination with a low dose of ozagrel, a TXA2 synthase inhibitor. Therefore, we hypothesized that chronic IP stimulation by beraprost induces an increase in TXA2 production, leading to reduction in the antiplatelet effect. As expected, repeated administration of beraprost increased the plasma and urinary levels of a TXA2 metabolite, while ONO-1301 did not increase them significantly. In addition, beraprost could retain the ability to inhibit platelet aggregation after repeated administration in mice lacking the TXA2 receptor (TP). These results indicate that TP-mediated signaling participates in platelet desensitization against IP agonists and that simultaneous inhibition of TXA2 production confers resistance against desensitization on IP agonists.
Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan (H.K., K.Y., F.K., S.K., O.T., F.U.); Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan (H.K., K.Y., F.K., S.K., S.N., F.U.); Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan (Y.S.); and Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.N.).
Hitoshi
H
Kashiwagi
Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan (H.K., K.Y., F.K., S.K., O.T., F.U.); Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan (H.K., K.Y., F.K., S.K., S.N., F.U.); Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan (Y.S.); and Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.N.).
Koh-Ichi
K
Yuhki
Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan (H.K., K.Y., F.K., S.K., O.T., F.U.); Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan (H.K., K.Y., F.K., S.K., S.N., F.U.); Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan (Y.S.); and Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.N.).
Fumiaki
F
Kojima
Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan (H.K., K.Y., F.K., S.K., O.T., F.U.); Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan (H.K., K.Y., F.K., S.K., S.N., F.U.); Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan (Y.S.); and Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.N.).
Shima
S
Kumei
Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan (H.K., K.Y., F.K., S.K., O.T., F.U.); Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan (H.K., K.Y., F.K., S.K., S.N., F.U.); Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan (Y.S.); and Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.N.).
Osamu
O
Takahata
Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan (H.K., K.Y., F.K., S.K., O.T., F.U.); Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan (H.K., K.Y., F.K., S.K., S.N., F.U.); Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan (Y.S.); and Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.N.).
Yoshiki
Y
Sakai
Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan (H.K., K.Y., F.K., S.K., O.T., F.U.); Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan (H.K., K.Y., F.K., S.K., S.N., F.U.); Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan (Y.S.); and Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.N.).
Shuh
S
Narumiya
Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan (H.K., K.Y., F.K., S.K., O.T., F.U.); Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan (H.K., K.Y., F.K., S.K., S.N., F.U.); Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan (Y.S.); and Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.N.) ushikubi@asahikawa-med.ac.jp.
Fumitaka
F
Ushikubi
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013928:Thromboxane A2 / Q000096:biosynthesis* / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C105488:ONO 1301; C048081:beraprost; D013928:Thromboxane A2; D011464:Epoprostenol; D000242:Cyclic AMP; D013930:Thromboxane-A Synthase