The protective effect of brief acidic cardiac reperfusion after ischemia is not mimicked by inhibition of the Na + /H + exchanger NHE1 or of phospholipase A2‐VI (PLA2‐VI)

Abstract

Postconditioning (PC) is a widely studied way to limit cardiac damage after ischemia, but the mechanisms involved are incompletely understood. Here, we investigated the effects of 15 min of acidic pH, or of inhibition of the Na+/H+ exchanger NHE1 or the Ca2+-independent phospholipase A2 (iPLA2-VI) at onset of reperfusion, on ischemia/reperfusion (I/R) damage in Langendorf-perfused rat hearts exposed to 35 min of global no-flow ischemia and 120 min reperfusion. Left ventricular end diastolic pressure (LVeDP) and infarct size were reduced and left ventricular developed pressure (LVDP) recovery improved to a comparable extent by PC (6 × 10 s I/R) or pH 6.0. In contrast, LVeDP and infarct size were increased and LVDP recovery attenuated by the NHE1 inhibitor EIPA and largely unaffected by the iPLA2-VI inhibitor BEL. In cultured HL-1 cardiomyocytes in presence of HCO3− (i.e. presumably capable of efficient pHi regulation) I/R elicited JNK-, Akt- and caspase-3 activation, PARP cleavage and necrotic cell death, neither of which were reduced by 15 min acidic PC or EIPA. In conclusion, PC or pH 6.0 at onset of reperfusion improved myocardial performance after I/R in whole hearts, whereas inhibition of NHE1 or iPLA2-VI were not protective. The protection of intact hearts by acidic pHi could not be mimicked in cultured HL-1 cardiomyocytes; the mechanisms underlying this are under investigation. Funding: Danish Heart Foundation; Danish National Research Council.