Objective To observe the effect of S1PR2/3 on heart during myocardial ischemia-reperfusion (I/R) in rats. Methods Healthy adult male Sprague-Dawley rats were randomly divided into 7 groups: control group, sham operation group, IR group, IR group treated with DMSO, IR group treated with Cym5541( agonist of S1P3), IR group treated with Cay10444 (antagonist of S1P3), IR group treated with Cay10444/Jte-013 (antagonist both S1P3 and S1P2). In vivo model of myocardial ischemia-reperfusion was established. The hemodynamics, infarction area and mortality was recorded. Results Compared with IR, the S1PR3 antagonist group and S1PR2/3 antagonist group showed signiifcantly reduction of heart rate(HR) and increament left ventricular end-diastolic pressure(LVEDP)(P<0.05). In addition, the infarction area was increased in the S1PR3 antagonist group and S1PR2/3 antagonist treated group (55.7%:28.8%, 51.6%:28.8%), respectively. Treatment with S1PR3 agonist reduced the infarct size compared with IR group(18.6%:28.8%). Blocking S1P2/3 receptors increased IR-induced mortality signiifcantly (53%:22%, P<0.05). Conclusion S1PR2/3 have a beneifcial effect on heart. S1PR2 and S1PR3 were involved in the IR-induced SCD.