Consolini A E, Ragone M I, Conforti P, Volonté M G
Cátedra de Farmacología y, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47y 115 (1900) La Plata, Argentina.
Can J Physiol Pharmacol. 2007 May;85(5):483-96. doi: 10.1139/y07-022.
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.
采用机械量热法研究了线粒体钠/钙交换体（mNCX）在接受缺血再灌注（I/R）并经心脏停搏液（CPG）预处理的心脏中的作用。在经10 μmol/L氯硝西泮（CLZP，mNCX抑制剂）和（或）高钾-低钙溶液（CPG）预处理的离体大鼠心脏中制造无血流缺血（ISCH）和再灌注（REP）。连续测量左心室舒张末期压力（LVEDP）、搏动期间的压力上升（P）和稳定的热释放（Ht），并在再灌注结束时分析ATP和磷酸肌酸（PCr）的肌肉含量。在再灌注期间，Ht的增加超过P，降低了肌肉经济性（P/Ht）和ATP含量。与未预处理的心脏（对照组，C组，恢复至64%±10%，p<0.05）相比，CPG使再灌注期间P的恢复增加（至缺血前的90%±10%）。相反，CLZP降低了CPG处理心脏的P恢复（50%±6.4%，p<0.05），并增加了C组心脏的LVEDP。为了评估对肌浆网（SR）功能的影响，用10 mmol/L咖啡因-36 mmol/L钠（C-咖啡因-低钠）对缺血心脏进行再灌注。这增加了LVEDP，随后LVEDP缓慢舒张，而Ht增加（约6.5 mW/g）。CLZP加速了舒张，且ΔHt更高，C-咖啡因-低钠在灌注心脏中产生的挛缩更高，Ht低于缺血心脏。将ΔHt值与报道的钙转运体通量进行比较，表明线粒体可能在C-咖啡因-低钠再灌注期间部分负责ΔHt。结果表明，缺血再灌注降低了SR储存以恢复收缩力，但诱导了Ca2+从线粒体向SR储存的移动。此外，线粒体和SR能够在过载期间（如在咖啡因作用下）通过mNCX和单向转运体清除胞质Ca2+。CPG增加了从线粒体到SR的Ca2+循环，这有助于P的更高恢复。相反，CLZP对缺血再灌注产生有害影响，表现为更高的热释放和高能磷酸盐再合成减少，这表明诱导了线粒体Ca循环和解偶联。
