Nicorandil has been shown to induce an infarct-limiting effect similar to that induced by the early phase of ischemic preconditioning (PC). The goals of this study were to determine whether nicorandil induces a delayed cardioprotection that is analogous to the late phase of ischemic PC and, if so, whether nicorandil-induced late PC is associated with upregulation of cardioprotective proteins. Chronically-instrumented, conscious rabbits received vehicle (normal saline i.v.; control group, n=10), nicorandil (100 µg/kg bolus + 30 µg/kg/min for 60 min i.v.; nicorandil group, n=10), or ischemic PC (6 cycles of 4-min coronary occlusion/4-min reperfusion; PC group, n=8). Twenty-four hours later, rabbits underwent a 30-min coronary occlusion followed by 3 days of reperfusion. Myocardial infarct size was significantly reduced in rabbits pretreated with nicorandil (27.5 ± 5.3% of the risk region) or with ischemia (30.3 ± 4.2%) vs. controls (59.1 ± 4.7%, P<0.05 vs. both). Furthermore, the expression of cyclooxygenase-2 (COX-2) and Bcl-2 was significantly elevated (+38% and +126%, respectively, P<0.05) in myocardium of rabbits given nicorandil 24 h earlier vs. controls. We conclude that nicorandil induces delayed cardioprotection against myocardial infarction similar to that afforded by the late phase of ischemic PC, possibly by upregulating COX-2 and Bcl-2.