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

Background-Na+/H+ exchange inhibition with HOE642 (cariporide) improves pos tischemic recovery of cardiac function, but the mechanisms of action remain speculative. Because Na+/H+ exchange is activated on reperfusion, it was h ypothesized that its inhibition delays realkalinization and decreases intra cellular Na+ and, via Na+/Ca2+ exchange, Ca2+ overload. Attenuated Ca2+ ove rload 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 minute s of no-flow ischemia and 30 minutes of reperfusion (37 degrees C) with or without 1 mu mol/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 P-31 NMR spectroscopy (n=6 per group), respe ctively. HOE642 did not affect preischemic mechanical function, [Ca2+](i), or pH(i). Mechanical recovery after 30 minutes of reperfusion was substanti ally improved with HOE642: left ventricular developed pressure (in percent of preischemic values) was 92+/-3 versus 49+/-7 and left ventricular end-di astolic 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 i n HOE642-treated than in untreated hearts (1.04+/-0.06 versus 1.84+/-0.02 m u mol/L, P<0.05). Maximal intracellular Ca2+ overload during the first 60 s econds of reperfusion was attenuated with HOE642 compared with untreated he arts: 2.0+/-0.3 versus 3.2+/-0.3 mu mol/L (P<0.05), pH(i) was not different at end ischemia (approximate to 5.9+/-0.05). Realkalinization was similar in the first 90 seconds of reperfusion and significantly delayed in the nex t 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 acido sis.