Abstract
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.
Footnotes
- Received January 5, 2015.
- Accepted March 4, 2015.
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and by a grant from Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (JST). This work was also supported by Grants-in-Aid for Regional R&D Proposal-Based Program from Northern Advancement Center for Science & Technology (NOASTEC); Ono Pharmaceutical Co., Ltd.; and the Smoking Research Foundation.
Primary laboratory of origin: Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|