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

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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 Ca2+ 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 (ser1105). 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.

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Abbreviations

dl-PHPB:

Potassium 2-(1-hydroxypentyl)-benzoate

ADP:

Adenosine diphosphate

AA:

Arachidonic acid

PRP:

Platelet-rich plasma

PPP:

Platelet-poor plasma

PLC:

Phospholipase C

PGE1 :

Prostaglandin E1

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Acknowledgments

The study was supported by National Major Special Project on New Drug Innovation of China (2012ZX09301002-004) and the National Nature Science Foundation of China (No. 81373387).

Conflicts of interest

The authors declare no conflict of interest.

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Author notes

  1. Hongyan Yang

    Present address: Department of Pharmacology, Qiqihar Medical University, Qiqihar, China

Authors and Affiliations

  1. State Key laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Xiannongtan Street, Beijing, 100050, China

    Hongyan Yang, Shaofeng Xu, Jiang Li, Ling Wang & Xiaoliang Wang

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  1. Hongyan Yang
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  2. Shaofeng Xu
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  3. Jiang Li
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Correspondence to Xiaoliang Wang.

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Yang, H., Xu, S., Li, J. et al. Potassium 2-(1-hydroxypentyl)-benzoate inhibits ADP-induced rat platelet aggregation through P2Y1-PLC signaling pathways. Naunyn-Schmiedeberg's Arch Pharmacol 388, 983–990 (2015). https://doi.org/10.1007/s00210-015-1113-6

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  • DOI: https://doi.org/10.1007/s00210-015-1113-6

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