A(3) adenosine receptor activation attenuates neutrophil function and neutrophil-mediated reperfusion injury.

Abstract

This study tested the hypothesis that A(3) adenosine receptors inhibit neutrophil (PMN) function and PMN-mediated reperfusion injury. 2-Chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA), an A(3) 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/mm(2) at 0.1, 1.0, and 10 nM vs. 422 +/- 64 PMNs/mm(2) with platelet-activating factor alone. This inhibition was not blocked by A(1) (5 microM KW-3902) or A(2a) (5 microM KF-21326) antagonists: 44 +/- 3 and 43 +/- 2 PMNs/mm(2), respectively. Endothelial pretreatment with 1 nM Cl-IB-MECA reduced PMN adherence, which was reversed by the A(3) antagonist MRS-1220 (100 nM). PMN-mediated reperfusion injury was initiated in isolated rabbit hearts by infusion of 28 x 10(6) 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 A(3) adenosine receptor may be a novel therapeutic target for treatment of myocardial ischemia and reperfusion.

• Authors: J E Jordan, V H Thourani, J A Auchampach, J A Robinson, N P Wang, J Vinten-Johansen
• Journal: The American journal of physiology (Am J Physiol) Vol. 277 Issue 5 Pg. H1895-905 (11 1999) ISSN: 0002-9513 [Print] United States
• PMID: 10564145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptors, Purinergic P1
• Superoxides
• Peroxidase

Topics

• Animals
• Arteries (metabolism, physiology)
• Binding, Competitive
• COS Cells
• Cell Adhesion
• Cell Degranulation
• Coronary Vessels (metabolism, physiology)
• Dogs
• Hemodynamics
• In Vitro Techniques
• Myocardial Contraction
• Myocardial Reperfusion Injury (metabolism, physiopathology)
• Myocardium (enzymology)
• Neutrophils (physiology)
• Peroxidase (metabolism)
• Rabbits
• Receptors, Purinergic P1 (metabolism, physiology)
• Superoxides (metabolism)
• Ventricular Function, Left