© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Comparative study of AMP579 and adenosine in inhibition of neutrophil-mediated vascular and myocardial injury during 24 h of reperfusion
aCardiothoracic Research Laboratory, The Carlyle Fraser Heart Center/Crawford Long Hospital, Emory University School of Medicine, 550 Peachtree St., NE, Atlanta, GA 30365-2225, USA
bRhône-Poulenc Rorer Research and Development, Collegeville, PA 19426, USA
* Corresponding author. Tel.: +1-404-686-2511; fax: +1-404-686-4888 zzhao{at}emory.edu
Objective: The purpose of this study was to compare protective effects of AMP579 and adenosine (Ado) at reperfusion (R) on inhibition of polymorphonuclear neutrophil (PMN) activation, PMN-mediated injury to coronary artery endothelium, and final infarct size. Methods: In anesthetized dogs, 1 h of left anterior descending coronary artery occlusion was followed by 24 h R and drugs were administered at R. Control (n=8, saline control), AMPI (n=7, AMP579, 50 µg/kg i.v. bolus followed by 3 µg/kg/min for 2 h), AMPII (n=7, AMP579, 50 µg/kg i.v. bolus), AMPIII (n=7, AMP579, 3 µg/kg/min i.v. for 2 h), and Ado (n=7, adenosine, 140 µg/kg/min i.v. for 2 h). Results: AMP579 in vitro directly inhibited superoxide radical (O–2) generation (nM/5x106 PMNs) from PMNs dose-dependently (from 17±1* at 10 nM to 2±0.2* at 10 µM vs. activated 30±2). However, inhibition of O–2 generation by Ado at each concentration was significantly less than for AMP579. The IC50 value for AMP579 (0.09±0.02 µM) on O–2 generation was significantly less than that of Ado (3.9±1.1 µM). Adherence of unstimulated PMN to postischemic coronary artery endothelium (PMNs/mm2) was attenuated in AMPI and AMPIII vs. Control (60±3* and 58±3* vs. Control 110±4), while Ado partially attenuated PMN adherence (98±3*). Accordingly, endothelial-dependent vascular relaxation was significantly greater in AMPI and AMPIII vs. Ado. At 24 h R, myocardial blood flow (MBF, ml/min/g) in the area at risk (AAR), confirmed by colored microspheres, in AMPI and AMPIII was significantly improved (0.8±0.1* and 0.7±0.1* vs. Control 0.3±0.04). Infarct size (IS, TTC staining) in AMPI and AMPIII was significantly reduced from 38±3% in Control to 21±4%* and 22±3%*, respectively, confirmed by lower plasma creatine kinase activity (I.U./g protein) in these two groups (27±6* and 32±2* vs. 49±3). Cardiac myeloperoxidase activity (MPO, Abs/min) in the AAR was significantly reduced in AMPI and AMPIII vs. Control (36±11* and 35±10* vs. 89±10). However, changes in MBF, IS and MPO were not significantly altered by Ado. Conclusions: These data suggest that continuous infusion of AMP579 at R is more potent than adenosine in attenuating R injury, and AMP579-induced cardioprotection involves inhibition of PMN-induced vascular and myocardial tissue injury. *P<0.05 vs. Control.
KEYWORDS Adenosine; Free radicals; Ischemia; Leucocytes
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