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

Abstract

We determined in intact hearts whether inhibition of Na+/H+ exchange (NHE) decreases intracellular Na+ and Ca2+ during ischemia and reperfusion, improves function during reperfusion, and reduces infarct size. Guinea pig isolated hearts were perfused with Krebs-Ringer solution at 37°C. Left ventricular (LV) free wall intracellular Na+ concentration ([Na+]i) and intracellular Ca2+ concentration ([Ca2+]i) were measured using fluorescence dyes. Hearts were exposed to 30 min of ischemia with or without 10 μM of benzamide (BIIB-513), a selective NHE-1 inhibitor, infused for 10 min just before ischemia or for 10 min immediately on reperfusion. At 2 min of reperfusion, 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 systolic-diastolic LV pressure (LVP) from 49 ± 2% (controls) to 80 ± 2% of preischemia values. BIIB-513 reduced ventricular fibrillation by 54% and reduced infarct size from 64 ± 1% to 20 ± 3%. First derivative of the LVP, O2 consumption, and cardiac efficiency were also improved by BIIB-513. Similar 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 which inhibiting NHE protects the guinea pig intact heart from ischemia-reperfusion injury.