title: Laropiprant attenuates EP3 and TP prostanoid receptor-mediated thrombus formation.
abstract: The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D(2). 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 PGD(2), which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. In fact, we found that in vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD(2) on platelet function, i.e. platelet aggregation, Ca(2+) flux, 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, Ca(2+) flux, 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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Sonia
authors.initials: S
authors.lastname: Philipose
authors.forename: Viktoria
authors.initials: V
authors.lastname: Konya
authors.forename: Mirjana
authors.initials: M
authors.lastname: Lazarevic
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Pasterk
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
authors.forename: Sasa
authors.initials: S
authors.lastname: Frank
authors.forename: Bernhard A
authors.initials: BA
authors.lastname: Peskar
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.forename: Rufina
authors.initials: R
authors.lastname: Schuligoi
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009525:Niacin / Q000627:therapeutic use; D019007:P-Selectin / Q000096:biosynthesis; D010974:Platelet Aggregation / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000096:biosynthesis; D015230:Prostaglandin D2 / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000096:biosynthesis*; D013927:Thrombosis / Q000378:metabolism / Q000517:prevention & control
chemical_list: D000960:Hypolipidemic Agents; D007211:Indoles; C518174:MK-0524; D019007:P-Selectin; C545647:PTGER3 protein, human; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058308:Receptors, Prostaglandin E, EP3 Subtype; D009525:Niacin; D015230:Prostaglandin D2; D002118:Calcium