on December 19, 2002
Published online before print December 19, 2002, doi: 10.1161/01.ATV.0000052669.50791.0B
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Submitted on October 16, 2002
Accepted on December 4, 2002
Blockade of the Platelet P2Y12 Receptor by AR-C69931 MX Sustains Coronary Artery Recanalization and Improves Myocardial Tissue Perfusion in a Canine Thrombosis Model
Kai Wang *;
From the Department of Cardiovascular Medicine (K.W., X.Z., Z.Z., K.T., M.C., M.S.P., D.M., A.K., J.D.T., E.J.T., A.M.L.), The Cleveland Clinic Foundation, Cleveland, Ohio, and Astra-Zeneca (R.G.H., J.T.), R & D, Charnwood, England.
* To whom correspondence should be addressed. E-mail: wangk{at}ccf.org.
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-C69931 MX), 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 the AR-C69931 MX group, and 1 mg/kg in the placebo group in phase II) was administered 30 minutes after thrombus formation; either saline or AR-C69931 MX (4 µg·kg-1·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·kg-1·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-C69931 MX group (P<0.05). Myocardial tissue flow with AR-C69931 MX 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-C69931 MX 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.
Key words: P2Y12 receptor • thrombosis • myocardial tissue perfusion • myocardial contrast echocardiography
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