Reduction myocardial I/R injury has become the key in the therapy of ischemic cardiovascular disease. Isoflurane (ISO) preconditioning can mimic the major potent protective mechanisms and attenuate ischemia injury. Nevertheless, the mechanisms involved in the cardioprotective afforded by isoflurane preconditioning have never been valuated systematically. Mice were randomly divided into an ISO preconditioning group and control group. The size of infarcted region was measured, and comparisons between ISO preconditioning and control animals were made. The metabotropic glutamate receptor type 1(GRM1) expression levels in all groups were determined by quantitative PCR. GRM1 protein expression and DNA damage relative protein γ-H2AX were measured by western blot analysis. The oxidative stress was detected by immunofluorescence after staining with the Dihydroethidium (DHE). ISO preconditioning significantly reduced the IR induced infarct volumes and reversed the GRM1 protein expression level in I/R induced myocardial injury. Moreover, ISO preconditioning have the protect effect to reduce the I/R induced DNA damage and oxidative stress. The results of the present study have demonstrated that the expression of GRM1 provides a protective role in ISO preconditioning against I/R-induced myocardial infarction by reduce the oxidative stress and DNA damage. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.