Blockade of the Platelet P2Y12 Receptor by AR-C69931MX Sustains Coronary Artery Recanalization and Improves the Myocardial Tissue Perfusion in a Canine Thrombosis Model

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 23; no. 2; pp. 357 - 362
• Main Authors: Wang, Kai, Zhou, Xiaorong, Zhou, Zhongmin, Tarakji, Khaldoun, Carneiro, Marcelo, Penn, Marc S, Murray, Daniel, Klein, Allan, Humphries, Robert G, Turner, Jonathan, Thomas, James D, Topol, Eric J, Lincoff, A Michael
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-02-2003; Hagerstown, MD Lippincott
• Subjects: Adenosine Monophosphate - administration & dosage; Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - pharmacology; Adenosine Monophosphate - therapeutic use; Angioplasty, Balloon, Coronary - methods; Animals; Biological and medical sciences; Bleeding Time; Blood Coagulation - drug effects; Blood Coagulation - physiology; Blood. Blood coagulation. Reticuloendothelial system; Coronary Circulation - drug effects; Coronary Restenosis - prevention & control; Coronary Stenosis - drug therapy; Coronary Stenosis - therapy; Disease Models, Animal; Dogs; Drug Combinations; Echocardiography; Female; Heparin - administration & dosage; Heparin - therapeutic use; Infusions, Intravenous; Male; Medical sciences; Membrane Proteins; Myocardial Infarction - drug therapy; Myocardial Infarction - pathology; Myocardial Reperfusion; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2 - physiology; Receptors, Purinergic P2Y12; Space life sciences; Thrombosis - drug therapy; Thrombosis - pathology; Tissue Plasminogen Activator - administration & dosage; Tissue Plasminogen Activator - pharmacology; Relapse; myocardial tissue perfusion; Cardiovascular disease; t-Plasminogen activator; Arterial disease; Vascular disease; Prevention; Complication; Antagonist; Inhibition; Dog; Contrast media; Sonography; P2Y12 receptor; Fissipedia; P2Y12 purinergic receptor; Carnivora; Echocardiography; Serine endopeptidases; Enzyme; Treatment efficiency; Coronary artery; Coronary heart disease; Thrombosis; Peptidases; Vertebrata; Chemotherapy; Platelet; Mammalia; Treatment; Animal; Hydrolases; myocardial contrast echocardiography; Hemodynamics; Fibrinolytic; Non-programmatic
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000052669.50791.0B

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 P2Y12-receptor antagonist (AR-C69931MX), in conjunction with thrombolytic therapy, on the prevention of platelet aggregation and thrombus formation.
METHODS AND 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 μg · kg · min) 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 · kg · h. 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 P2Y12 antagonist group.