title: Selective blockade of P2Y12 receptors by prasugrel inhibits myocardial infarction induced by thrombotic coronary artery occlusion in rats.
abstract: We evaluated the effects of prasugrel, a third-generation thienopyridyl prodrug, on P2Y12 receptors, adenosine 5'-diphosphate (ADP)-induced platelet aggregation, and myocardial infarction (MI) in rats. Oral administration of prasugrel (0.3-3 mg/kg) resulted in the dose-related inhibition of washed platelet aggregation induced by ADP (1-10 μM). Ex vivo [H]-2-MeS-ADP binding to platelet P2Y12 receptors was also inhibited by prasugrel in a similar dose range. The antiaggregatory effects of prasugrel correlated strongly with P2Y12 blockade with correlation coefficients of 0.85-0.92, suggesting that the antiaggregatory activity of prasugrel largely reflected P2Y12 blockade achieved in vivo. We further examined the effects of the in vivo P2Y12 inhibition by prasugrel (1-10 mg/kg, po) on MI induced by thrombotic coronary artery occlusion in rats. In surviving rats, infarct size at 24 hours after photoirradiation was evaluated. In the vehicle group, necrosis area/total left ventricular area was 37.9% ± 6.8% (mean ± SE, n = 7). At all prasugrel doses tested (n = 7 for each dose), necrosis area/total left ventricular area was significantly smaller than that in the vehicle group: 14.4% ± 4.0% for 1 mg/kg (P < 0.01), 19.8% ± 4.5% for 3 mg/kg (P < 0.05), and 14.8% ± 3.6% for 10 mg/kg (P < 0.01). At the highest administered dose of prasugrel (10 mg/kg), blood pressure and heart rate were unchanged. Arrhythmia was observed in 5 of 7 animals in the vehicle group at 24 hours after irradiation; in contrast, no arrhythmia was found in the group treated with prasugrel (10 mg/kg). Taken together, these results demonstrate that prasugrel is a selective P2Y12 inhibitor in vivo, providing effective inhibition of platelet aggregation and MI in rats.
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo, Co, Ltd, Tokyo, Japan. sugidachi.atsuhiro.r7@daiichisankyo.co.jp
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Kosaku
authors.initials: K
authors.lastname: Ohno
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Tomizawa
authors.forename: Masami
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Niitsu
mesh_terms: D000818:Animals; D001792:Blood Platelets; D001794:Blood Pressure; D054059:Coronary Occlusion / Q000188:drug therapy / Q000473:pathology; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D006339:Heart Rate; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010879:Piperazines / Q000494:pharmacology*; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D011485:Protein Binding; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D000068799:Prasugrel Hydrochloride