Attenuation of postischemic reperfusion injury is related to prevention of [Ca2+]m overload in rat hearts

Abstract

Intracellular calcium overload has been implicated in postischemic reperfusion injury. In myocytes, mitochondrial free calcium concentration ([Ca2+]m), not cytosolic free calcium concentration ([Ca2+]c), overload is related to reoxygenation injury. We tested the hypothesis that [Ca2+]m, not [Ca2+]c, overload is an important mediator of reperfusion injury in whole hearts. [Ca2+]m and [Ca2+]c were assessed using indo 1 fluorescence in isolated rat hearts subjected to 45 min of ischemia and 20 min of reperfusion. Ruthenium red (RR), a selective inhibitor of mitochondrial calcium uptake at 0.025 microM, attenuated the increase of [Ca2+]m (4% RR vs. 57% control) over preischemic levels (230 +/- 10 nM) but did not affect the increase of systolic [Ca2+]c (990 +/- 100 nM RR vs. 1,010 +/- 130 nM control). This was associated with improved recovery of left ventricular developed pressure (61% RR vs. 37% control) and attenuation of the increase of diastolic pressure (34 mmHg RR vs. 47 mmHg control). Contractile recovery was related to the degree of [Ca2+]m overload in both control and RR hearts (r2 = 0.47, P = 0.001). This study is the first to demonstrate that [Ca2+]m, and not [Ca2+]c, overload is related to reperfusion injury in intact beating hearts.

The Role of Myocardial KATP‐Channel Blockade in the Protective Effects of Glibenclamide against Ischaemia in the Rat Heart

“…It has been reported that uncoupling of oxidative phosphorylation in cardiac mitochondria by the classical uncoupling agent dinitrophenol also protects postischaemic cardiac function, which supports the concept that stressful, stimuli to the mitochondrion may result in cardioprotection, in the same way as ischaemic preconditioning (Minners et al 2000). Furthermore, both pinacidil and diazoxide have been shown to uncouple cardiac mitochondria (Garlid 1996;Miyamae et al 1996;Garlid et al 1997;Holmuhamedov et al 1998). The observed preservation of postischaemic cardiac function was similar for pinacidil and diazoxide in the present study.…”

“…In this way, it will be protective for postischaemic cardiac function (D'Alonzo et al 1994). For diazoxide and also for pinacidil, this can be explained by the specific opening of mitochondrial K ATP channels (Miyamae et al 1996;Garlid et al 1997;Holmuhamedov et al 1998). Until now, no consensus has been reached on how exactly this opening of mitochondrial K ATP channels results in protection of postischaemic cardiac function.…”

Reduced Cytosolic Ca 2+ Loading and Improved Cardiac Function After Cardioplegic Cold Storage of Guinea Pig Isolated Hearts

“…We have reported 10 plays a pivotal regulatory role linking cardiac mechanics and energy production. 37,38 Inhibiting mitochondrial Ca 2ϩ uptake was shown to attenuate mechanical dysfunction after warm ischemia and reperfusion without altering cytosolic [Ca 2ϩ ]. 37 Hypothermia helps to preserve mitochondrial function during subsequent ischemia.…”

“…37,38 Inhibiting mitochondrial Ca 2ϩ uptake was shown to attenuate mechanical dysfunction after warm ischemia and reperfusion without altering cytosolic [Ca 2ϩ ]. 37 Hypothermia helps to preserve mitochondrial function during subsequent ischemia. 39 Hypothermia-induced changes in Na ϩ , Ca 2ϩ , K ϩ , and H ϩ homeostasis largely protect the heart.…”

Mitochondrial calcium handling during ischemia-induced cell death in neurons

“…The MCU is therefore a prime target as drugs that inhibit this Ca 2þ uptake system should retain the beneficial effects conferred by PTP inhibition but not its adverse effects. Accordingly, inhibition of the MCU by ruthenium red protects hearts against ischemia injury [125]. Unfortunately ruthenium red is a very unspecific inhibitor that also inhibit several classes of ion channels and that interfere with the binding of Ca 2þ to calmodulin (reviewed in [26]).…”