Laropiprant attenuates EP₃and TP prostanoid receptor-mediated thrombus formation

The use of the lipid-lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D₂. Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD₂, which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. Therefore, we investigated the effects of laropiorant on platelet function.

Platelet aggregation assays were performed ex vivo using a platelet aggregation analyser (Aggregometer II). Blood from healthy human donors was used to obtain platelet-rich plasma. The expression of P-selectin and activation of glycoprotein IIb/IIIa was examined using CD62P and PAC1 antibodies, respectively, by direct flow cytometry. In vitro thrombus formation was assessed by flowing whole blood on collagen-coated Cellix biochips at −30 dyn/cm² using the Mirus nanopump.

In vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD₂ on platelet function, i.e. platelet aggregation, P-selectin expression, activation of glycoprotein IIb/IIIa and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations, laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and E-type prostanoid (EP)-3 receptor stimulation, as demonstrated in assays of platelet aggregation, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition of platelet function exerted by EP₄ or I-type prostanoid (IP) receptors was not affected by laropiprant.

These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have a beneficial profile with respect to platelet function and thrombotic events in vascular disease.

S.P. was funded by the PhD Program Molecular Medicine of the Medical University of Graz. This study was supported by the Jubiläumsfonds of the Austrian National Bank (OeNB, grants 13487 and 14263) and the Austrian Science Fund (FWF; grants P22521-B18, P19473-B05, P21004-B02 and P22976-B18).

Affiliations

1. Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010, Graz, Austria

   • Sonia Philipose
   • , Viktória Kónya
   • , Mirjana Lazarević
   • , Lisa M Pasterk
   • , Gunther Marsche
   • , Bernhard A Peskar
   • , Ákos Heinemann
   •  & Rufina Schuligoi

2. Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010, Graz, Austria

   • Sasa Frank

Corresponding author

Correspondence to Ákos Heinemann.

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