Protein kinase C (PKC) plays a role in cardioprotection through reduction of intracellular Ca2+ concentration [Ca2+](i) during ischemic preconditioning (IPC). Cardioprotection against ischemic post-conditioning (PC) could be associated with reduced [Ca2+](i) through PKC. The calcium-sensing receptor (CaR), G protein-coupled receptor, causes accumulation of inositol phosphate (IP) to increase the release of intracellular Ca2+. However, this phenomenon can be negatively regulated by PKC through phosphorylation of Thr-888 of the CaR. This study tested the hypothesis that the prevention of cardiomyocyte damage by PC is associated with [Ca2+](i) reduction through an interaction of PKC with the CaR. Isolated rat hearts were subjected to 40 min of ischemia followed by 90 min of reperfusion. The hearts were post-conditioned after the 40 min of ischemia by three cycles of 30 s of reperfusion and 30 s of re-ischemia applied before the 90 min of reperfusion. Immunolocalization of PKC epsilon in the cell membrane was observed with IPC and PC, and in hearts exposed to GdCl3 during PC. CaR was expressed in cardiac cell membrane and interacted with PKC in IPC, PC, and exposure to GdCl3 during PC groups. On laser confocal microscopy, intracellular Ca2+ was significantly decreased with IPC, PC, and exposure to GdCl3 during PC compared with the I/R and PKC inhibitor groups, and cell structure was better preserved and promoted the recovery of cardiac function after reperfusion in the same groups. These results Suggested that PKC is involved in cardioprotection against PC through negative feedback of a CaR-mediated reduction in [Ca2+](i). (c) 2007 Elsevier Inc. All rights reserved.