A Na⁺/Ca²⁺ exchange inhibitor partially protects the rat heart from ischemic-reperfusion injury, linking to complete blockade of more energy-consuming processes

Abstract

We hypothesized that after ischemic-reperfusion (IR) contractile failure similar to that after high Ca²⁺ infusion occurs. To test this hypothesis, we investigated left ventricle (LV) mechanical work and energetics in the cross-circulated rat hearts that underwent 15-min global ischemia and 60-min reperfusion. Mean systolic pressure-volume area (PVA; total mechanical energy per beat) at midrange LV volume (PVA_mLVV) was significantly decreased. Mean myocardial oxygen consumption per beat (VO₂) intercepts (VO₂ for the total Ca²⁺ handling in excitation-contraction coupling and basal metabolism) of VO₂-PVA relation was significantly decreased without change in its slope. After 30-min infusion of a reverse-mode Na⁺/Ca²⁺ exchanger (NCX) inhibitor, KB-R7943 (KBR, 10 µM) during IR, the decrease in mean PVA_mLVV and VO₂ intercept was significantly but partially reduced (n=6). Although VO₂ for the Ca²⁺ handling was finally decreased after 60 min of IR, it was significantly higher than pre IR from 10 to 15 min after IR. This energy-wasting process was completely blocked by KBR. α-fodrin proteolysis significantly increased after IR was significantly reduced by KBR. We clarified the contribution of reverse-mode NCX to the contractile failure after IR due to the impairment of the total Ca²⁺ handling in the excitation-contraction coupling and that NCX inhibitor antagonized this failure by preventing the heart from Ca²⁺ overload. [Jpn J Physiol 55 Suppl:S92 (2005)]