Comparative study of AMP579 and adenosine in inhibition of neutrophil-mediated vascular and myocardial injury during 24 h of reperfusion

Objective: The purpose of this study was to compare protective effects of A MP579 and adenosine (Ado) at reperfusion (R) on inhibition of polymorphonuc lear neutrophil (PMN) activation, PMN-mediated injury to coronary artery en dothelium, and final infarct size. Methods: In anesthetized dogs, 1 h of le ft 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, AM P579, 50 mu g/kg i.v. bolus followed by 3 mu g/kg/min for 2 h), AMPII (n=7, AMP579, 50 mu g/kg i.v. bolus), AMPIII (n=7, AMP579, 3 mu g/kg/min i.v. fo r 3, h), and Ado (n=7, adenosine, 140 mu g/kg/min i.v. for 2 h). Results: A MP579 in vitro directly inhibited superoxide radical (O-2(-)) generation (n M/5x10(6) PMNs) from PMNs dose-dependently (from 17+/-1* at 10 nM to 2+/-0. 2* at 10 mu M vs. activated 30+/-2). However, inhibition of O-2(-) generati on by Ado at each concentration was significantly less than for AMP579. The IC50 value for AMP579 (0.09+/-0.02 mu M) on O-2(-) generation was signific antly less than that of Ado (3.9+/-1.1 mu M) Adherence of unstimulated PMN to postischemic coronary artery endothelium (PMNs/mm(2)) was attenuated in AMPI and AMPIII vs. Control (60+/-3* and 58+/-3* vs. Control 110+/-4), whil e Ado partially attenuated PMN adherence (98+/-3*). Accordingly, endothelia l-dependent vascular relaxation was significantly greater in AMPI and AMPII I 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 signi ficantly improved (0.8+/-0.1* and 0.7+/-0.1* vs. Control 0.3+/-0.04). Infar ct size (IS, TTC staining) in AMPI and AMPIII was significantly reduced fro m 38+/-3% in Control to 21+/-4%* and 22+/-3%*, respectively, confirmed by l ower 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 wer e not significantly altered by Ado. Conclusions: These data suggest that co ntinuous infusion of AMP579 at R is more potent than adenosine in attenuati ng R injury, and AMP579-induced cardioprotection involves inhibition of PMN -induced vascular and myocardial tissue injury. *P<0.05 vs. Control. (C) 20 00 Elsevier Science B.V. All rights reserved.