title: Blockade of the platelet P2Y12 receptor by AR-C69931MX sustains coronary artery recanalization and improves the myocardial tissue perfusion in a canine thrombosis model.
abstract: OBJECTIVE
  Reperfusion therapy for myocardial infarction is limited by a significant reocclusion rate and less optimal myocardial tissue perfusion due to excessive platelet accumulation and recruitment at the sites of vascular injury. We assessed the influence of a selective P2Y(12)-receptor antagonist (AR-C69931MX), in conjunction with thrombolytic therapy, on the prevention of platelet aggregation and thrombus formation.
  
  
  RESULTS
  A canine coronary electrolytic injury thrombosis model was used. Tissue-type plasminogen activator (t-PA; 1 mg/kg in phase I, 0.5 mg/kg in phase II in the AR-C69931MX group, and 1 mg/kg in the placebo group in phase I and II) was administered 30 minutes after thrombus formation; either saline or AR-C69931MX (4 micro g x kg(-1) x min(-1)) was given to all animals intravenously 10 minutes before t-PA administration for a total of 2 hours. All animals received heparin (80 U/kg) as an intravenous bolus followed by a continuous infusion of 17 U x kg(-1) x h(-1). Myocardial tissue perfusion was evaluated by use of the colored microsphere technique and real-time myocardial contrast echocardiography. The incidences of reocclusion and cyclic flow variation were significantly decreased in the AR-C69931MX group (P<0.05). Myocardial tissue flow with AR-C69931MX treatment improved significantly at 20 and 120 minutes after reflow, whereas tissue flow with placebo remained at a level similar to that during occlusion (P<0.05).
  
  
  CONCLUSIONS
  The adjunctive administration of AR-C69931MX blocked ADP-mediated platelet aggregation and recruitment and prevented platelet-mediated thrombosis, resulting in prolongation of reperfusion time and a decrease in reocclusion and cyclic flow variations. Importantly, myocardial tissue perfusion was significantly improved in the P2Y(12) antagonist group.
authors.affiliation: Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. wangk@ccf.org
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhou
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Zhou
authors.forename: Khaldoun
authors.initials: K
authors.lastname: Tarakji
authors.forename: Marcelo
authors.initials: M
authors.lastname: Carneiro
authors.forename: Marc S
authors.initials: MS
authors.lastname: Penn
authors.forename: Daniel
authors.initials: D
authors.lastname: Murray
authors.forename: Allan
authors.initials: A
authors.lastname: Klein
authors.forename: Robert G
authors.initials: RG
authors.lastname: Humphries
authors.forename: Jonathan
authors.initials: J
authors.lastname: Turner
authors.forename: James D
authors.initials: JD
authors.lastname: Thomas
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
authors.forename: A Michael
authors.initials: AM
authors.lastname: Lincoff
mesh_terms: D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D015906:Angioplasty, Balloon, Coronary / Q000379:methods; D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D003326:Coronary Circulation / Q000187:drug effects; D023903:Coronary Restenosis / Q000517:prevention & control; D023921:Coronary Stenosis / Q000188:drug therapy* / Q000628:therapy*; D004195:Disease Models, Animal; D004285:Dogs; D004338:Drug Combinations; D004452:Echocardiography; D005260:Female; D006493:Heparin / Q000008:administration & dosage / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008297:Male; D008565:Membrane Proteins; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D015425:Myocardial Reperfusion; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058925:Receptors, Purinergic P2Y12; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D004338:Drug Combinations; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; C117446:cangrelor; D006493:Heparin; D010959:Tissue Plasminogen Activator