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1 Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Crawford Long Hospital of Emory University, Atlanta, Georgia 30365; and 2 Division of Cardiology, University of Louisville, Louisville, Kentucky 40292
This study tested the hypothesis that A3 adenosine receptors inhibit neutrophil (PMN) function and PMN-mediated reperfusion injury. 2-Chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA), an A3 agonist, did not attenuate superoxide production or myeloperoxidase release from stimulated PMNs. However, Cl-IB-MECA reduced platelet-activating factor-stimulated PMN adherence to coronary endothelium at low concentrations: 52 ± 27, 45 ± 10, and 87 ± 23 PMNs/mm2 at 0.1, 1.0, and 10 nM vs. 422 ± 64 PMNs/mm2 with platelet-activating factor alone. This inhibition was not blocked by A1 (5 µM KW-3902) or A2a (5 µM KF-21326) antagonists: 44 ± 3 and 43 ± 2 PMNs/mm2, respectively. Endothelial pretreatment with 1 nM Cl-IB-MECA reduced PMN adherence, which was reversed by the A3 antagonist MRS-1220 (100 nM). PMN-mediated reperfusion injury was initiated in isolated rabbit hearts by infusion of 28 × 106 PMNs/min for 10 min early in reperfusion. PMNs caused a significant decrease in recovery of left ventricular developed pressure and positive and negative time derivatives of pressure (23 ± 3, 25 ± 3, and 23 ± 3% of baseline, respectively) vs. buffer-perfused hearts (43 ± 7, 44 ± 7, and 45 ± 6%, respectively). Cl-IB-MECA (10 nM) given at reperfusion attenuated the PMN-mediated loss of contractile recovery (40 ± 3, 46 ± 5, and 42 ± 4% of baseline). Cl-IB-MECA reduced myeloperoxidase release activity (5.3 ± 0.6 absorbance units/min) and CD18-positive cells (54 ± 9 cells/slide) compared with the untreated PMN group (17.9 ± 1.7 absorbance units/min and 183 ± 68 cells/slide). We conclude that Cl-IB-MECA attenuates reperfusion injury by decreasing PMN-endothelial cell interactions. These results suggest that the A3 adenosine receptor may be a novel therapeutic target for treatment of myocardial ischemia and reperfusion.
endothelial adherence; superoxide; myeloperoxidase; CD18
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