Blocking Na+/H+ exchange reduces [Na+](i) and [Ca2+](i) load after ischemia and improves function in intact hearts

We determined in intact hearts whether inhibition of Na+/H+ exchange (NHE) decreases intracellular Na+ and Ca2+ during ischemia and reperfusion, impro ves function during reperfusion, and reduces infarct size. Guinea pig isola ted hearts were perfused with Krebs-Ringer solution at 37 degreesC. Left ve ntricular (LV) free wall intracellular Na+ concentration ([Na+](i)) and int racellular Ca2+ concentration ([Ca2+](i)) were measured using fluorescence dyes. Hearts were exposed to 30 min of ischemia with or without 10 muM of b enzamide (BIIB-513), a selective NHE-1 inhibitor, infused for 10 min just b efore ischemia or for 10 min immediately on reperfusion. At 2 min of reperf usion, BIIB-513 given before ischemia decreased peak increases in [Na+](i) and [Ca2+](i), respectively, from 2.5 and 2.3 times (controls) to 1.6 and 1 .3 times preischemia values. At 30 min of reperfusion, BIIB-513 increased s ystolic-diastolic LV pressure (LVP) from 49 +/-2% (controls) to 80 +/-2% of preischemia values. BIIB-513 reduced ventricular fibrillation by 54% and r educed infarct size from 64 +/-1% to 20 +/-3%. First derivative of the LVP, O-2 consumption, and cardiac efficiency were also improved by BIIB-513. Si milar results were obtained with BIIB-513 given on reperfusion. These data show that Na+ loading is a marker of reperfusion injury in intact hearts in that inhibiting NHE reduces Na+ and Ca2+ loading during reperfusion while improving function. These results clearly implicate the ionic basis by whic h inhibiting NHE protects the guinea pig intact heart from ischemia-reperfu sion injury.