The role of the mitochondrial Na/Ca-exchanger (mNCX) in hearts exposed to ischemia-reperfusion (I/R) and pretreated with cardioplegia (CPG) was studied from a mechano-calorimetric approach. No-flow ischemia (ISCH) and reperfusion (REP) were developed in isolated rat hearts pretreated with 10 micromol/L clonazepam (CLZP), an inhibitor of the mNCX, and (or) a high K+ - low Ca2+ solution (CPG). Left ventricular end diastolic pressure (LVEDP), pressure development during beats (P), and the steady heat release (Ht) were continuously measured and muscle contents of ATP and PCr were analyzed at the end of REP. During REP, Ht increased more than P, reducing muscle economy (P/Ht) and the ATP content. CPG induced an increase in P recovery during REP (to 90% +/- 10% of preISCH) with respect to nonpretreated hearts (control, C, to 64% +/- 10%, p < 0.05). In contrast, CLZP reduced P recovery of CPG-hearts (50% +/- 6.4%, p < 0.05) and increased LVEDP in C hearts. To evaluate effects on sarcoplasmic reticulum (SR) function, ischemic hearts were reperfused with 10 mmol/L caffeine -36 mmol/L Na (C - caff - low Na). It increased LVEDP, which afterwards slowly relaxed, whereas Ht increased (by about 6.5 mW/g). CLZP sped up the relaxation with higher DeltaHt, C - caff - low Na produced higher contracture and lower Ht in perfused than in ischemic hearts. Values of DeltaHt were compared with reported fluxes of Ca2+-transporters, suggesting that mitochondria may be in part responsible for the DeltaHt during C - caff - low Na REP. Results suggest that ISCH-REP reduced the SR store for the recovery of contractility, but induced Ca2+ movement from the mitochondria to the SR stores. Also, mitochondria and SR are able to remove cytosolic Ca2+ during overloads (as under caffeine), through the mNCX and the uniporter. CPG increases Ca2+ cycling from mitochondria to the SR, which contributes to the higher recovery of P. In contrast, CLZP produces a deleterious effect on ISCH-REP associated with higher heat release and reduced resynthesis of high energy phosphates, which suggests the induction of mitochondrial Ca cycling and uncoupling.

Mitochondria have a precise role for determining cardioprotection or stunning in high-K+ cardioplegic rat hearts under I/R. Known protective drugs, such as Dzx and Ru360, which reduce the mitochondrial Ca2+-uptake, increased the stunning of CPG-rat hearts and reduced muscle economy, whereas 5-hydroxydecanoate and Clzp together increased the stunning by inducing mitochondrial Ca2+ overload.

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Our results demonstrate that increasing SR Ca2+ uptake by PLN ablation can prevent the arrhythmic events triggered by CaMKII-dependent phosphorylation of RyR2-induced-SR Ca2+ leak. These findings underscore the benefits of increasing SERCA2a activity in the face of SR Ca2+ triggered arrhythmias. However, enhanced SERCA2a cannot prevent but rather exacerbates I/R cardiac injury.

CPG, diazoxide and clonazepam improve postischaemic recovery, respectively, by increasing the Ca(2+) cycling and by reducing the mitochondrial Ca(2+) uptake either by uniporter or by mNCX. The mitochondria compete with the leaky sarcoplasmic reticulum (SR) as sink of Ca(2+) in guinea-pig hearts, affecting the postischaemic contractility. CPG also prevented the ouabain-induced dysfunction by avoiding the Ca(2+) overload. Ouabain reduced the synergism between CPG and clonazepam suggesting that [Na(+)]i and SR load influence the mNCX role.