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

Departments of 1 Physiology II and 2 Thoracic-Cardiovascular Surgery, Nara Medical University, Kashihara, Nara; and 3 Department of Neurology and Neurosurgery, Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan Submitted 8 October 2004 ; accepted in final form 22 December 2004 We have recently reported that exposure of rat hearts to high Ca 2+ produces a Ca 2+ overload-induced contractile failure in rat hearts, which was associated with proteolysis of -fodrin. We hypothesized that contractile failure after ischemia-reperfusion (I/R) is similar to that after high Ca 2+ 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) (PVA mLVV ) 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 (V O 2 ) intercept of (V O 2 -PVA linear relation was significantly decreased from 0.21 ± 0.05 to 0.15 ± 0.03 µl O 2 ·beat –1 ·g –1 without change in its slope. Initial 30-min reperfusion with a Na + /Ca 2+ exchanger (NCX) inhibitor KB-R7943 (KBR; 10 µmol/l) significantly reduced the decrease in mean PVA mLVV and V O 2 intercept ( n = 6). Although V O 2 for the Ca 2+ handling was finally decreased, it transiently but significantly increased from the control for 10–15 min after I/R. This increase in V O 2 for the Ca 2+ handling was completely blocked by KBR, suggesting an inhibition of reverse-mode NCX by KBR. -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 Ca 2+ 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. calcium overload; mechanoenergetics; KB-R7943; -fodrin Address for reprint requests and other correspondence: M. Takaki, Dept. of Physiology II, Nara Medical Univ., 840 Shijo-cho, Kashihara, Nara 634-8521, Japan (E-mail: mtakaki{at}naramed-u.ac.jp )