Objective：To observe whether myocardial protective effect of brain natriuretic peptide（BNP） which activate cyclic guano－sine monophosphate/protein kinase G（cGMP/PKG）signaling pathway is associated with the activation of extracellular regulated protein kinase1/2（ERK1/2） and phosphatidylinositol 3 kinase（PI3K） protein kinase. Methods：Totally 84 New Zealand white rabbits were randomly divided into seven groups（n=12）：sham group，control group，BNP group，BNP + LY294002 group（LY294002 is PI3K inhibitor），LY294002 group，BNP + PD98059 group（PD98059 is ERK1/2 inhibitor） and PD98059 group. Occlusion of the left circumflex artery for 45 min followed by 180 min reperfusion was performed on rabbits in all groups except those in sham group. Rabbits in sham group were underwent open thoracotomy without ligating the left circumflex artery. Hemodynamic，electrocardiograph monitor were obtained. At the end of experiment，6 rabbit hearts were stained by Evan’s blue/triphenyltetrazolium chloride methods to test the area of infarction. Expressions of P-Akt/Akt and P-ERK1/2/ERK1/2 proteins in the rest hearts were analyzed by Western blot assay. Results：There was no significant difference in heart rate（HR） and mean arterial blood pressure（MABP） at baseline among seven groups（P >0.05）. Compared with the baseline，HR and MABP were significantly decreased during ischemia and reperfusion（I/R） period（P<0.05），HR and MABP remained relatively stable during the reperfusion period. There was no significant difference in the HR and MABP among seven groups during I/R period（P >0.05）. Rate of arrhythmia was significantly reduced in BNP group than in control group（P<0.003 125）. Rate of arrhythmia was significantly increased in BNP + LY294002 group，LY294002 group，BNP + PD98059 group and PD98059 group than in BNP group（P<0.003 125）. Differences in arrhythmia between BNP + LY294002 group and LY294002 group as well as BNP + PD98059 group and PD98059 group were not statistically significant（P >0.003 125）. Myocardial infarction did not occur in sham group. Myocardial infarction size was significantly smaller in BNP group than in control group（P<0.05）. Myocardial infarction size was significantly increased in BNP + LY294002 group，LY294002 group，BNP + PD98059 group and PD98059 group than in BNP group（P<0.05）. Differences in myocardial infarction size between BNP + LY294002 group and LY294002 group as well as BNP + PD98059 group and PD98059 group were not statistically significant（P >0.05）. Level of Akt and ERK1/2 phosphorylation was increased significantly in BNP group than in control group（P<0.05）. Level of Akt phosphorylation in BNP + LY294002 group and level of ERK1/2 phosphorylation were significantly lower in BNP + PD98059 group than in BNP group（P<0.05）. Difference in Akt phosphorylation between BNP + LY294002 group and LY294002 group was not statistically significant（P >0.05）. There was also no difference in ERK1/2 phosphorylation between BNP + PD98059 group and PD98059 group（P >0.05）. Conclusions：Activation of cGMP/PKG signaling pathway by BNP exerts protective effect on myocardial I/R injury，which is associated with activation of reperfusion injury salvage kinase signaling pathway.