Sustained reduction in myocardial reperfusion injury with an adenosine receptor antagonist: Possible role of the neutrophil chemoattractant response

Recent studies have demonstrated that three membrane-permeant A(1) receptor antagonists reduced infarct size in a model of ischemia followed by brief reperfusion. However, it was not determined whether cardioprotection was me diated by non-specific intracellular effects of these highly lipophilic dru gs and whether the antagonists only delayed myocardial necrosis without aff ecting the ultimate infarct size. In the present study, closed-chest dogs w ere subjected to 90 min of left anterior descending coronary artery occlusi on and 72 h of reperfusion and received either a nonmembrane-permeant adeno sine receptor blocker that is devoid of direct intracellular effects and is 6-fold selective for the A(1) receptor [1,3-dipropyl-8-p-sulfophenylxanthi ne (DPSPX); n = 11] or vehicle (n = 12). DPSPX was administered as three 20 0-mg boluses 60 min before and 30 and 120 min after reperfusion. The area o f necrosis was determined histologically and expressed as a percentage of t he area at risk. Baseline predictors of infarct size were similar in the tw o groups. The ratio of the area of necrosis to the area at risk was less in the DPSPX group (17.8 +/- 4.3% versus 35.0 +/- 1.9%; P = .012), and DPSPX improved regional ventricular function. Under both basal and stimulated (fo rmyl-Met-Leu-Phe) conditions, suspensions of human neutrophils generated ex tracellular adenosine levels (approximately 50 nM) sufficient to activate A (1) receptors. Moreover, both DPSPX and 1,3-dipropyl-8-cyclopentylxanthine, a selective A1 receptor antagonist, significantly reduced the chemoattract ant response of neutrophils to formyl-Met-Leu-Phe. We conclude that blockad e of A1 adenosine receptors attenuates myocardial ischemic/reperfusion inju ry, possibly in part by decreasing the chemoattractant response of neutroph ils.