Potassium 2-(1-hydroxypentyl)-benzoate inhibits ADP-induced rat platelet aggregation through P2Y1-PLC signaling pathways.

Abstract

Potassium 2-(1-hydroxypenty1)-benzoate (dl-PHPB) is a new drug candidate for treatment of ischemic stroke with antiplatelet effect. In this study, we investigated the mechanisms of dl-PHPB in inhibiting platelet aggregation. The ADP-activated P2Y1-Gq-PLC and P2Y12-Gi-AC pathways were observed, respectively. Intravenous injection of dl-PHPB (1.3, 3.9, 12.9 mg/kg) significantly inhibited ADP-, collagen-, and arachidonic acid-induced rat platelet aggregation in a dose-dependent manner, and dl-PHPB had a relatively more potent inhibitory effect on ADP-induced rat platelet aggregation than other agonists. Dl-PHPB also showed a decreased expression of CD62P (a marker for platelet activation) mediated by ADP. Both dl-PHPB and ticlopidine (P2Y12 receptor antagonist) decreased cytoplasmic Ca(2+) concentration. But, dl-PHPB did not reverse the inhibition of PGE1-induced platelet cAMP formation by ADP, which was different from ticlopidine. Further, dl-PHPB instead of ticlopidine showed increasing phospholipase C-β phosphorylation (ser(1105)). The m-3M3FBS, a phospholipase C activator, attenuated the inhibitory effect of dl-PHPB on ADP-induced platelet aggregation and enhanced IP1 accumulation in rat platelets. Dl-PHPB decreased IP1 accumulation induced by ADP but had no effect on IP1 level enhanced by m-3M3FBS. Our results suggest that dl-PHPB has a potent antiplatelet effect, which is mainly through blockade of P2Y1 receptor-PLC-IP3 pathway and decreasing cytoplasmic calcium.

• Authors: Hongyan Yang, Shaofeng Xu, Jiang Li, Ling Wang, Xiaoliang Wang
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 388 Issue 9 Pg. 983-90 (Sep 2015) ISSN: 1432-1912 [Electronic] Germany
• PMID: 25787305 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(1-hydroxypentyl)-benzoate
• Benzoates
• Pentanes
• Platelet Aggregation Inhibitors
• Purinergic P2Y Receptor Antagonists
• Adenosine Diphosphate
• Type C Phospholipases
• Ticlopidine
• Calcium

Topics

• Adenosine Diphosphate (metabolism)
• Animals
• Benzoates (administration & dosage, pharmacology)
• Calcium (metabolism)
• Cytoplasm (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Injections, Intravenous
• Male
• Pentanes (administration & dosage, pharmacology)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (administration & dosage, pharmacology)
• Purinergic P2Y Receptor Antagonists (administration & dosage, pharmacology)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)
• Ticlopidine (pharmacology)
• Type C Phospholipases (metabolism)