Objective:To examine whether activation of calcium-sensing receptor(CaSR) is associated with apoptosis and inflammatory reaction of cardiomyocytes stimulated by ischemia/reperfusion(I/R). Methods:Primary neonatal rat ventricular cardiomyocytes were incubated in anoxia/reoxygenation method to establish a model of simulated I/R. And neonatal rat ventricular cardiomyocytes were randomly divided into control group,I/R group,GdCl3 (CaSR agonist) group and GdCl3+SB203058 (a specific inhibitor of p38MAPK) group. Cardiomyocyte apoptosis was detected by TUNEL assay. The expressions of CaSR,tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were detected by real reverse transcriptase polymerase chain reaction(RT-PCR). The expressions of Caspase-3,Bcl-2 and p38MAPK were detected by Western blot. Results:The simulated I/R enhances cardiomyocyte apoptosis and the expression of CaSR,TNF-α,IL-6 and p38MAPK. GdCl3 can further increase cardiomyocyte apoptosis and expression of above proteins,along with up-regulation of Caspase-3 and down-regulation of Bcl-2. Compared with GdCl3 group,the mRNA expression of TNF-α and IL-6 were markedly decreased with no significant changes of cardiomyocytes apoptosis and CaSR mRNA in GdCl3+SB203058 group. Conclusion:Activation of CaSR is not only associated with increased cardiomyocytes apoptosis after I/R injury via suppressing Bcl-2 and promoting Caspase-3 expression,but also induces inflammatory reaction via p38MAPK signaling pathway at I/R area.