Na+/Ca2+ exchange inhibition protects the rat heart from ischemia-reperfusion injury by blocking energy-wasting processes

Abstract

We have recently reported that exposure of rat hearts to high Ca2+ produces a Ca2+ overload-induced contractile failure in rat hearts, which was associated with proteolysis of α-fodrin. We hypothesized that contractile failure after ischemia-reperfusion (I/R) is similar to that after high Ca2+ infusion. To test this hypothesis, we investigated left ventricular (LV) mechanical work and energetics in the cross-circulated rat hearts, which were subjected to 15 min global ischemia and 60 min reperfusion. Sixty minutes after I/R, mean systolic pressure-volume area (PVA; a total mechanical energy per beat) at midrange LV volume (mLVV) (PVAmLVV) was significantly decreased from 5.89 ± 1.55 to 3.83 ± 1.16 mmHg·ml·beat−1·g−1 ( n = 6). Mean myocardial oxygen consumption per beat (Vo2) intercept of (Vo2-PVA linear relation was significantly decreased from 0.21 ± 0.05 to 0.15 ± 0.03 μl O2·beat−1·g−1 without change in its slope. Initial 30-min reperfusion with a Na+/Ca2+ exchanger (NCX) inhibitor KB-R7943 (KBR; 10 μmol/l) significantly reduced the decrease in mean PVAmLVV and Vo2 intercept ( n = 6). Although Vo2 for the Ca2+ handling was finally decreased, it transiently but significantly increased from the control for 10–15 min after I/R. This increase in Vo2 for the Ca2+ handling was completely blocked by KBR, suggesting an inhibition of reverse-mode NCX by KBR. α-Fodrin proteolysis, which was significantly increased after I/R, was also significantly reduced by KBR. Our study shows that the contractile failure after I/R is similar to that after high Ca2+ infusion, although the contribution of reverse-mode NCX to the contractile failure is different. An inhibition of reverse-mode NCX during initial reperfusion protects the heart against reperfusion injury.