Na + /H + Exchange Inhibition With HOE642 Improves Postischemic Recovery due to Attenuation of Ca 2+ Overload and Prolonged Acidosis on Reperfusion

Abstract

Background —Na + /H + exchange inhibition with HOE642 (cariporide) improves postischemic recovery of cardiac function, but the mechanisms of action remain speculative. Because Na + /H + exchange is activated on reperfusion, it was hypothesized that its inhibition delays realkalinization and decreases intracellular Na + and, via Na + /Ca 2+ exchange, Ca 2+ overload. Attenuated Ca 2+ overload and prolonged acidosis are known to be cardioprotective. Methods and Results —Left ventricular developed and end-diastolic pressures were measured in isolated buffer-perfused rat hearts subjected to 30 minutes of no-flow ischemia and 30 minutes of reperfusion (37°C) with or without 1 μmol/L HOE642 added to the perfusate 15 minutes before ischemia. Intracellular Ca 2+ concentration ([Ca 2+ ] i ) and pH i were measured with aequorin (n=10 per group) and 31 P NMR spectroscopy (n=6 per group), respectively. HOE642 did not affect preischemic mechanical function, [Ca 2+ ] i , or pH i . Mechanical recovery after 30 minutes of reperfusion was substantially improved with HOE642: left ventricular developed pressure (in percent of preischemic values) was 92±3 versus 49±7 and left ventricular end-diastolic pressure was 16±3 versus 46±5 mm Hg ( P <0.05 for HOE642-treated versus untreated hearts). End-ischemic [Ca 2+ ] i was significantly lower in HOE642-treated than in untreated hearts (1.04±0.06 versus 1.84±0.02 μmol/L, P <0.05). Maximal intracellular Ca 2+ overload during the first 60 seconds of reperfusion was attenuated with HOE642 compared with untreated hearts: 2.0±0.3 versus 3.2±0.3 μmol/L ( P <0.05). pH i was not different at end ischemia (≈5.9±0.05). Realkalinization was similar in the first 90 seconds of reperfusion and significantly delayed in the next 3 minutes (eg, 6.8±0.07 in HOE642-treated hearts compared with 7.2±0.07 in untreated hearts; P <0.05). Conclusions —HOE642 improves postischemic recovery by reducing Ca 2+ overload during ischemia and early reperfusion and by prolonging postischemic acidosis.