Dipyridamole potentiates the myocardial infarct size-limiting effect of ischemic preconditioning

Abstract

Background. Recent studies implicated a key role for adenosine (ADO) receptor activation in the enhancement of ischemic tolerance by ischemic preconditioning. In this study, we aimed to test the hypothesis that dipyridamole, an ADO transport inhibitor, enhances the preconditioning effect. Methods and Results. Six groups of rabbits underwent 30-minute coronary occlusion and 72-hour reperfusion. Infarct size (IS) and the area-at-risk (AR) were determined by histology and by use of fluorescent particles, respectively. IS expressed as the percentage of AR (%IS/AR) was 46.5±3.4% (n=13) in control rabbits. Preconditioning with 2-minute ischemia tended to limit %IS/AR (%IS/AR, 35.5±3.5%, n=9), and that possible protection was abolished by pretreatment with 10 mg/kg 8-phenyltheophylline (8-PT), an ADO receptor antagonist (%IS/AR, 43.9±5.8%, n=9). Administration of dipyridamole (0.25 mg/kg) before the 2-minute preconditioning markedly limited %IS/AR to 13.8±2.6% (n=12), indicating the potentiation of the preconditioning effect by this agent. Furthermore, this enhancement of preconditioning effect by dipyridamole treatment was significantly attenuated by 8-PT (%IS/AR, 27.6±2.1%, n=11). Dipyridamole given before the 30-minute ischemia, without preconditioning, did not reduce %IS/AR (55.3±5.2%, n=7), and a previous study from this laboratory had demonstrated that the present dose of 8-PT alone did not modify IS in the rabbit. Conclusions. Dipyridamole significantly potentiated the IS-limiting effect of preconditioning. This finding strongly supports the hypothesis that stimulation of ADO receptors by endogenous ADO, which builds up during preconditioning ischemia, mediates the increased ischemic tolerance afforded by preconditioning.