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OBJECTIVE The aim of this study was to explore whether the mechanism of Irbesartan (IRB) in the treatment of rats with myocardial ischemia-reperfusion injury (MIRI) was related to the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway. MATERIALS AND METHODS The rat model of MIRI was first successfully established. All rats were randomly divided into 5 groups, including the Sham group (sham operation control group, ligation only), Model group (MIRI rat model group), IRB12.5 group [low-dose IRB (12.5 mg/kg/d) group], IRB50.0 group [medium-dose IRB (50.0 mg/kg/d) group] and IRB200.0 group [high-dose IRB (200.0 mg/kg/d) group]. After treatment of IRB in MIRI rats, the activities of four myocardial enzyme indexes, including creatine kinase-MB (CK-MB), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT), were detected via enzyme-linked immunosorbent assay (ELISA). The effect of IRB on myocardial apoptosis in MIRI rats was detected via Annexin V-fluorescein isothiocyanate/Propidium Iodide (FITC/PI) double staining. Meanwhile, the messenger ribonucleic acid (mRNA) levels of ERK, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in myocardial cells after treatment of IRB were detected via Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Furthermore, the protein levels of ERK and p-ERK were detected via Western blotting. RESULTS Different concentrations of IRB could protect myocardium from MIRI. IRB at doses of 50.0 mg/kg/d and 200.0 mg/kg/d could significantly downregulate myocardial enzyme indexes in MIRI (p<0.01). Meanwhile, both the doses could markedly inhibit myocardial apoptosis in MIRI rat model by regulating the expressions of apoptosis-related genes (Bcl-2 and Bax) (p<0.01), eventually improving myocardial pathological damage. At the same time, it could also significantly decrease the mRNA and protein levels of ERK in the MAPK-ERK signaling pathway (p<0.05). CONCLUSIONS The cardioprotective mechanism of IRB in MIRI rats may be related to the inhibition of the activation of the MAPK-ERK signaling pathway.