AUGMENTATION OF ENDOGENOUS ADENOSINE ATTENUATES MYOCARDIAL STUNNING INDEPENDENTLY OF CORONARY FLOW OR HEMODYNAMIC-EFFECTS

Background. Mounting evidence suggests a protective effect of exogenou s adenosine in myocardial ischemia and reperfusion. We tested the hypo thesis that augmentation of endogenous adenosine levels, achieved by i nhibiting adenosine catabolism and washout, is beneficial in postische mic myocardial dysfunction (''stunning''). Methods and Results. In pha se I of the study, open-chest dogs undergoing a 15-minute coronary art ery occlusion and 4 hours of reperfusion received an intracoronary inf usion of either saline (controls, n=23) or 6-(4-nitrobenzyl)-mercapto: purine ribonucleoside (NBMPR, a selective nucleoside transport inhibi tor) combined with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, a poten t adenosine deaminase inhibitor) (EHNA+NBMPR, n=15) starting 15 minute s before coronary occlusion and ending 15 minutes after the initiation of reflow. Regional myocardial function (assessed as systolic wall th ickening) was similar in control and treated groups at baseline and du ring ischemia. After reperfusion, however, the dogs treated with EHNANBMPR exhibited a significant improvement in the recovery of function, which was evident as early as 30 minutes after restoration of flow an d was sustained throughout the rest of the reperfusion phase. The enha nced recovery effected by EHNA+NBMPR could not be attributed to nonspe cific factors such as differences in collateral flow during occlusion, coronary flow after reperfusion, arterial pressure, heart rate, or ot her hemodynamic variables. In phase II of the study, the myocardial co ntent of adenine nucleotides and nucleosides was measured by high perf ormance liquid chromatography in myocardial biopsies obtained serially from open-chest dogs undergoing the same protocol used in phase I. Th ere 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 ben eficial effects of EHNA+NBMPR cannot be ascribed to repletion of ATP s tores. 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<.05) and a much smaller increase in inosine (0 .52+/-0.27 vs 3.04+/-0.54 nmol/mg protein, P<.05) at the end of ischem ia, such that the inosine-to-adenosine ratio noted in controls was com pletely reversed (almost-equal-to 6:1 vs almost-equal-to 1:6, respecti vely). In the treated group, adenosine levels remained markedly increa sed compared with controls up to 1 hour after reperfusion. Conclusions . This study demonstrates that (1) administration of an adenosine deam inase inhibitor plus a nucleoside transport blocker is remarkably effe ctive in augmenting myocardial adenosine levels during regional ischem ia and subsequent reperfusion in vivo, (2) this augmentation of adenos ine results in a significant and sustained attenuation of myocardial s tunning, and (3) the attenuation of stunning is not due to ATP repleti on or to nonspecific actions on hemodynamic variables or coronary How. These findings suggest that endogenous adenosine production during is chemia serves as an important pathophysiological mechanism that protec ts against myocardial stunning. The results also suggest that augmenta tion of endogenous adenosine (without exogenous adenosine administrati on) represents an effective therapeutic approach to the alleviation of reversible postischemic dysfunction.