Na+/H+ exchange inhibition with HOE642 improves postischemic recovery due to attenuation of Ca2+ overload and prolonged acidosis on reperfusion

Abstract

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+/Ca2+ exchange, Ca2+ overload. Attenuated Ca2+ 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 Ca2+ concentration ([Ca2+](i)) and pH(i) were measured with aequorin (n = 10 per group) and 31P NMR spectroscopy (n = 6 per group), respectively. HOE642 did not affect preischemic mechanical function, [Ca2+](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 [Ca2+](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 Ca2+ 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 Ca2+ overload during ischemia and early reperfusion and by prolonging postischemic acidosis.