Regular dipyridamole therapy produces sustained protection against cardiac ischemia–reperfusion injury: Is it time to revisit PARIS?

Abstract

BackgroundIncreased activated Akt and eNOS expression coincide with this persistent cardioprotection. Emergent coronary reperfusion therapies are rarely carried out before considerable myocardial injury has occurred. Moreover, reperfusion after prolonged ischemia produces paradoxical ischemia–reperfusion injury, attenuating the efficacy of reperfusion therapies. This has provided impetus for identifying chronic therapies to protect against ischemia–reperfusion injury in those at risk. We previously found that regular dipyridamole therapy produces a chronic preconditioning-like effect mediated through adenosine A1 receptors. MethodsTo determine how long this chronic preconditioning effect of dipyridamole remains present after discontinuing therapy, guinea pigs received 4mg/kg/day in their water for 6weeks. Ischemia–reperfusion was performed at 0, 2, 3, and 4days after dipyridamole discontinuation (0day, 2days, 3days and 4days; n=8 per group). Left ventricular developed pressure (LVDP), end-diastolic pressure (LVEDP), coronary flow (CF), infarct size, and western blot analyses for Akt and endothelial nitric oxide synthase (eNOS) were studied. ResultsAfter ischemia–reperfusion, 0day, 2days and 3days, but not 4days, had significantly higher LVDP and lower LVEDP compared to control. Myocardial infarct size was significantly reduced at 0day, 2days and 3days, but not 4days, compared to control. Western blot analyses demonstrated upregulation of phospho-Akt and phospho-eNOS expression at 0day, 2days, and 3days, but not 4days. ConclusionsA chronic preconditioning-like cardioprotection by regular dipyridamole treatment persists for 3days after discontinuing therapy. Increased activated Akt and eNOS expression may play a role in this persistent cardioprotection.