Objective To investigate the protective effects of the specific inhibition of inward rectifier potassium current (IK1) on the ischemic heart in a transgenic mouse model with ischemic preconditioning (IPC). Methods Mice with genetic inhibition of IK1 were divided into 2 groups:observation group with positive expression and control group with negative expression. Arrhythmia was monitored in each group. With the isolated heart, the effects were observed of IPC on the myocardial infarct size and apoptosis following ischemia/reperfusion (IR). Western blot was employed to detect the expressed proteins. SPSS statistics 17.0 was used for statistical analysis, and t-test for comparison between groups. Results Compared with the control group, the observation group had significantly lower arrhythmia score [(3.50±0.67) vs (7.42±0.70)scores], ratio of myocardial infarct size to left ventricular area [(0.25±0.04)% vs (0.38±0.02) %] and cardiomyocyte apoptosis index [(202±93) ‰ vs (822.5±97.5) ‰, P<0.05]. Western blotting revealed significantly greater up-regulation in the observation group than in the control group of phosphorylated glycogen synthase kinase 3 [(1.41±0.16) vs (0.77±0.05)], AKT [(1.84±0.20) vs (0.81±0.14)], and p-AKT [(1.87±0.27) vs (1.08±0.22)]. Conclusion Transgenic inhibition of Kir2.1 can potentially reduce the occurrence of arrhythmia, myocardial cell apoptosis, and myocardial infarct size in myocardial infarction following IPC, and its mechanism may be partially related to the Reperfusion Injury Salvage Kinases (RISK) pathway.