Augmentation of endogenous adenosine attenuates myocardial 'stunning' independently of coronary flow or hemodynamic effects

Abstract

Background. Mounting evidence suggests a protective effect of exogenous adenosine in myocardial ischemia and reperfusion. We tested the hypothesis that augmentation of endogenous adenosine levels, achieved by inhibiting adenosine catabolism and washout, is beneficial in postischemic myocardial dysfunction ("stunning"). Methods and Results. In phase I of the study, open-chest dogs undergoing a 15-minute coronary artery occlusion and 4 hours of reperfusion received an intracoronary infusion of either saline (controls, n=23) or 6-(4-nitrobenzyl)-mercapto: purine ribonucleoside (NBMPR, a selective nucleoside transport inhibitor) combined with eryrtro-9-(2-hydroxy-3-nonyl)adenine (EHNA, a potent adenosine deaminase inhibitor) (EHNA+NBMPR, n=15) starting 15 minutes before coronary occlusion and ending 15 minutes after the initiation of reflow. Regional myocardial function (assessed as systolic wall thickening) was similar in control and treated groups at baseline and during ischemia. After reperfusion, however, the dogs treated with EHNA+NBMPR exhibited a significant improvement in the recovery of function, which was evident as early as 30 minutes after restoration of flow and was sustained throughout the rest of the reperfusion phase. The enhanced recovery effected by EHNA+NBMPR could not be attributed to nonspecific factors such as differences in collateral flow during occlusion, coronary flow after reperfusion, arterial pressure, heart rate, or other hemodynamic variables. In phase II of the study, the myocardial content of adenine nucleotides and nucleosides was measured by high performance liquid chromatography in myocardial biopsies obtained serially from open-chest dogs undergoing the same protocol used in phase I. There were no significant differences between control (n=8) and treated (n=9) dogs with respect to myocardial levels of adenosine triphosphate (ATP) at 30 and 60 minutes after reperfusion, indicating that the beneficial effects of EHNA+NBMPR cannot be ascribed to repletion of ATP stores. Compared with controls, dogs treated with EHNA+NBMPR exhibited a much larger increase in myocardial adenosine (6.07±1.47 vs 1.03±0.16 nmol/mg protein, P