Objectives: Ischemia/reperfusion (I/R) injury underlies a major part of cardiovascular disease related deaths. Postconditioning (PC) is widely studied as a clinically relevant way to limit infarct size and enhance survival. Classical PC is initialized at the onset of reperfusion as brief repetitive cycles of I/R. The mechanisms behind cardioprotection by PC are incompletely characterized, but roles for pHi and reduced mitochondrial damage/ROS formation are proposed [1]. Here, we tested the effect of acidic pH, and inhibition of the Na⁺/H⁺ exchanger NHE1 and the Ca²⁺-independent phospholipase A2 (iPLA2-VI) at the onset of reperfusion on cardiac damage after I/R. Methods: Langendorf- perfused rat hearts were exposed to 35 min of global no-flow ischemia followed by 120 min reperfusion, and functional parameters and infarct size (TCC staining) determined as in [2]. The first 15 min of reperfusion differed between treatment groups, as follows: (a) control, (b) pH 6.0, (c) NHE1 inhibition (3 mM EIPA), (d) iPLA2-VI inhibition (10 mM BEL), or (e) 6 x 10 s of I/R (PC). Results: Left ventricular end diastolic pressure (LVeDP) and infarct size were reduced and left ventricular developed pressure (LVDP) recovery improved by PC and pH 6.0. In contrast, LVeDP and infarct size were exacerbated and LVDP recovery attenuated by EIPA, and largely unaffected by BEL. In congruence with these findings, 15 min acidic reperfusion was protective against I/R mediated death of cultured HL-1 cardiomyocytes. Conclusions: PC and pH 6.0 at onset of reperfusion improved myocardial performance after I/R. In contrast, NHE1 inhibition modestly exacerbated cardiac damage after I/R, possibly due to roles of NHE1 in survival signaling. Counter to previous reports of its involvement in ROS-mediated lipid peroxidation in I/R, inhibition of iPLA2-VI had little effect on cardiac I/R damage. 1. A.Granfeldt et al. (2009). Cardiovasc.Res. 83, 234-246 2. B.H.Bentzen et al. (2009). Pflugers Arch 457, 979-988