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 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 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).


RESULTS
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.


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.
Budde
J M
JM
Cardiothoracic Research Laboratory, The Carlyle Fraser Heart Center/Crawford Long Hospital, Emory University School of Medicine, Atlanta, GA 30365-2225, USA.
Velez
D A
DA
Zhao
Z
Z
Clark
K L
KL
Morris
C D
CD
Muraki
S
S
Guyton
R A
RA
Vinten-Johansen
J
J
D000241:Adenosine / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D011897:Random Allocation; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014867:Water / Q000378:metabolism
C113971:4-(7-((2-3-chloro-2-thienyl)-1-methyl-propylamino)-3H-imidazo(4,5-b)pyridyl-3-yl)cyclopentane carboxamide; D007093:Imidazoles; D011725:Pyridines; D018047:Receptors, Purinergic P1; D014867:Water; D013481:Superoxides; D009195:Peroxidase; D003402:Creatine Kinase; D000241:Adenosine