Blockade of the platelet P2Y12 receptor by AR-C69931MX sustains coronary artery recanalization and improves the myocardial tissue perfusion in a canine thrombosis model.
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.
Wang
Kai
K
Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. wangk@ccf.org
Zhou
Xiaorong
X
Zhou
Zhongmin
Z
Tarakji
Khaldoun
K
Carneiro
Marcelo
M
Penn
Marc S
MS
Murray
Daniel
D
Klein
Allan
A
Humphries
Robert G
RG
Turner
Jonathan
J
Thomas
James D
JD
Topol
Eric J
EJ
Lincoff
A Michael
AM
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
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