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

• Published in: Cardiovascular research 2000-08, Vol.47 (2), p.294-305
• Main Authors: BUDDE, J. M, VELEZ, D. A, ZHAO, Z.-Q, CLARK, K. L, MORRIS, C. D, MURAKI, S, GUYTON, R. A, VINTEN-JOHANSEN, J
• Format: Article
• Language: English
• Subjects: Adenosine - therapeutic use; Analysis of Variance; Animals; Biological and medical sciences; Cardiology. Vascular system; Cell Adhesion; Cells, Cultured; Coronary heart disease; Creatine Kinase - blood; Dogs; Dose-Response Relationship, Drug; Endothelium, Vascular - pathology; Female; Heart; Imidazoles - therapeutic use; Male; Medical sciences; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - physiopathology; Myocardial Reperfusion Injury - prevention & control; Myocardium - enzymology; Myocardium - metabolism; Neutrophils - metabolism; Neutrophils - pathology; Peroxidase - metabolism; Pyridines - therapeutic use; Random Allocation; Receptors, Purinergic P1 - drug effects; Regional Blood Flow - drug effects; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; Reperfusion Injury - prevention & control; Superoxides - metabolism; Time Factors; Water - metabolism
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/s0008-6363(00)00115-2

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. 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 microg/kg i.v. bolus followed by 3 microg/kg/min for 2 h), AMPII (n=7, AMP579, 50 microg/kg i.v. bolus), AMPIII (n=7, AMP579, 3 microg/kg/min i.v. for 2 h), and Ado (n=7, adenosine, 140 microg/kg/min i.v. for 2 h). AMP579 in vitro directly inhibited superoxide radical (O(-)(2)) generation (nM/5x10(6) PMNs) from PMNs dose-dependently (from 17+/-1* at 10 nM to 2+/-0.2* at 10 microM vs. activated 30+/-2). However, inhibition of O(-)(2) generation by Ado at each concentration was significantly less than for AMP579. The IC(50) value for AMP579 (0.09+/-0.02 microM) on O(-)(2) generation was significantly less than that of Ado (3.9+/-1. 1 microM). 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), 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. 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