Ca²⁺ influx via the Na⁺/Ca ²⁺ exchanger (NCX) may lead to Ca²⁺ overload and myocardial injury in ischemia - reperfusion. Direct evidence that increased cytoplasmic Ca²⁺ concentration ([Ca ²⁺]_i) is mediated by the reverse mode of the NCX is limited, so in the present study the [Ca²⁺] _i dynamics and left ventricular pressure were monitored in perfused beating hearts. The effects of KB-R7943 (KBR), a selective inhibitor of the NCX in the reverse mode, were analyzed during low-Na ⁺ exposure and ischemia - reperfusion. Hearts from Sprague-Dawley rats were retrogradely perfused and loaded with 4 μmol/L fura-2 to measure the fluorescence ratio as an index of [Ca²⁺]_i. To evaluate KBR effects on the reverse mode exchanger, the increase in [Ca²⁺] _i induced by low-Na⁺ exposure (Na⁺: 30 mmol/L, 10 mmol/L caffeine pre-treatment) was measured with and without 10 μmol/L KBR (n=5). In another series, the hearts were subjected to 10 min of low-flow ischemia with pacing, followed by reperfusion in the absence (n=6) or in the presence of 10 μmol/L KBR (n=6). Background autofluorescence was subtracted to estimate the ratio in the ischemia - reperfusion protocol. KBR significantly suppressed the increase in [Ca²⁺] _i induced by low-Na⁺ (40.2±11.2% of control condition, p=0.014), as well as on increase in diastolic [Ca²⁺]_i during ischemia (% increase from pre-ischemia in [Ca²⁺]_i at 10 min: KBR, 17.9±6.4%; no KBR, 44.4±7.7%; p=0.024). After reperfusion, diastolic [Ca²⁺]_i normalized more rapidly in KBR-treated hearts (% increase at 1 min: KBR, 4.5 ±7.0%; no KBR, 39.8±12.2%; p=0.03). Treatment with KBR also accelerated recovery of the rate - pressure product on reperfusion (1 min: KBR, 8,944±1,554 min^-1 · mmHg; no KBR, 4,970±1,325; p<0.05). Thus, inhibition of the reverse mode exchanger by KBR reduced ischemic Ca2+ overload and possibly improved functional myocardial recovery during reperfusion in a whole heart model. (Circ J 2002; 66: 390 - 396)