Mitochondrial Damage During Ischemia Determines Post-Ischemic Contractile Dysfunction in Perfused Rat Heart

Iwai, Takeshi; Tanonaka, Kouichi; Inoue, Rie; Kasahara, Sayaka; Kamo, Naoki; Takeo, Satoshi

doi:10.1006/jmcc.2002.2002

Cited by 48 publications

(56 citation statements)

References 27 publications

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“…22 Reduced cytosolic Na ϩ overload may also attenuate mitochondrial injury by limiting Na ϩ -induced membrane depolarization, mitochondrial swelling, cytochrome c release and by preserving oxidative phosphorylation. 23 Less cytosolic Na ϩ overload could also attenuate Na ϩ -induced reverse-mode operation of the Na ϩ -Ca 2ϩ exchanger and the ensuing outward (repolarizing) current, presumably responsible for APD shortening. Less cytosolic Ca 2ϩ overload could also favor postresuscitation electrical stability and myocardial function.…”

Section: Mechanisms Of Protective Actionmentioning

confidence: 99%

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Ayoub

Kolarova

et al. 2003

Circulation

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Background-Inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) is emerging as a promising novel strategy for ameliorating myocardial injury associated with ischemia and reperfusion. We investigated whether NHE-1 inhibition (with cariporide) could minimize mechanical and electrical myocardial abnormalities that develop during ventricular fibrillation (VF) and improve outcome using a porcine model of closed-chest resuscitation. Methods and Results-Two groups of 8 pigs each were subjected to 8 minutes of untreated VF and randomized to receive either a 3-mg/kg bolus of cariporide or 0.9% NaCl immediately before an 8-minute interval of conventional closed-chest resuscitation. Cariporide prevented progressive increases in left ventricular free-wall thickness (from 1.0Ϯ0.2 to 1.5Ϯ0.3 cm with NaCl, PϽ0.001 versus 0.9Ϯ0.1 to 1.1Ϯ0.3 cm with cariporide, PϭNS), maintained the coronary perfusion pressure above resuscitability thresholds (10Ϯ8 versus 19Ϯ3 mm Hg before attempting defibrillation, PϽ0.05), and increased resuscitability (2 of 8 versus 8 of 8, PϽ0.005). In 2 additional groups of 4 pigs each subjected to a briefer interval of untreated VF, cariporide ameliorated postresuscitation shortening of the action potential duration (APD) at 30%, 60%, and 90% repolarization (ie, APD 60 at 2 minutes after resuscitation; 75Ϯ29 versus 226Ϯ16 ms, PϽ0.05), minimized postresuscitation ventricular ectopic activity preventing recurrent VF, and lessened postresuscitation myocardial dysfunction. Conclusions-NHE-1 inhibition may represent a highly potent novel strategy for resuscitation from VF that can ameliorate myocardial manifestations of ischemic injury and improve the effectiveness and outcome of closed-chest resuscitation.

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Section: Mechanisms Of Protective Actionmentioning

confidence: 99%

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Ayoub

Kolarova

et al. 2003

Circulation

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“…1) In the series of previous studies, we showed that myocardial Na + content of the ischemic heart was increased in an ischemic duration-dependent manner. [2][3][4] This abnormal accumulation of myocardial Na + under ischemic conditions eventually resulted in a contractile dysfunction of subsequently reperfused hearts (ischemia/reperfusion injury). Several pharmacological agents that reduce Na + influx through the sarcolemma during ischemia have been shown to attenuate Na + overload during ischemia as well as reperfusion, and thus to lead to a better functional recovery upon reperfusion.…”

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confidence: 99%

Possible Pathway of Na<sup>+</sup> Flux into Mitochondria in Ischemic Heart

Tanonaka

Motegi

Arino

et al. 2012

Biological & Pharmaceutical Bulletin

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Previous studies showed that myocardial Na overload during ischemia directly induced mitochondrial damage. The pathway for Na flux into mitochondria remains unclear. We examined possible routes for Na flux into mitochondria in the ischemic heart. Isolated perfused rat hearts were subjected to 15-to 35-min ischemia followed by 60-min reperfusion and then Na content and respiratory function in mitochondria of the ischemic heart were determined. The mitochondrial Na content of the ischemic heart was ischemic duration-dependently increased, associated with a reduction in mitochondrial respiratory function. To mimic induction of mitochondrial Na overload in vitro, isolated mitochondria were incubated with 6.25 to 50 mM NaCl or sodium lactate, a metabolite of anaerobic glycolysis, in the presence and absence of a mitochondrial Na /Ca 2 exchanger inhibitor CGP37157 and a monocarboxylate transporter (MCT) inhibitor α-cyano-4-hydroxy cinnamic acid (CHCA). Incubation of mitochondria with NaCl or sodium lactate increased the mitochondrial Na concentration. This increase in mitochondrial Na was partially attenuated by the presence of either inhibitor. Combined treatment of mitochondria with both inhibitors attenuated sodium lactate-induced increase in Na content to a greater degree than that treated with either agent. These results suggest that mitochondrial Na /Ca 2 exchanger and MCT inhibitor-sensitive Na transporter are possible pathways for the mitochondrial Na overload in the ischemic myocardium.

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“…They are a principal energy source in these cells (1) and also are responsible for some mechanisms of apoptosis and necrosis (2-6) as well as for ischemic damage of tissues (4,(7)(8)(9)(10). Mitochondrial energy metabolism is very specific for cancer cells, which are characterized by the Crabtree effect (11)(12)(13)(14), by a very high hexokinase activity of mitochondria (15,16), and by high resistance to permeabilization of mitochondrial membranes by various pro-apoptotic proteins (2,(17)(18)(19)(20).…”

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Mitochondria Permeabilization by a Novel Polycation Peptide BTM-P1

Lemeshko

Arias

Ordúz

2005

Journal of Biological Chemistry

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Bacillus thuringiensis subsp. medellin is known to produce the Cry11Bb protein of 94 kDa, which is toxic for mosquito larvae due to permeabilization of the plasma membrane of midgut epithelial cells. Earlier we found that a 2.8-kDa novel peptide BTM-P1, which was artificially synthesized taking into account the primary structure of Cry11Bb endotoxin, is active against several species of bacteria. In this work we show that BTM-P1 induces cyclosporin A-insensitive swelling of rat liver mitochondria in various salt solutions but not in the sucrose medium. Inorganic phosphate and Ca 2؉ significantly increased this effect of the peptide. The uncoupling action of BTM-P1 on oxidative phosphorylation was stronger in the potassiumcontaining media and correlated with a decrease of the inner membrane potential of mitochondria. In isotonic KNO 3 , KCl, or NH 4 NO 3 media, a complete drop of the inner membrane potential was observed at 1-2 g/ml of the peptide. The peptide-induced swelling was increased by energization of mitochondria in the potassium-containing media, but it was inhibited in the NaNO 3 , NH 4 NO 3 , and Tris-NO 3 media. All mitochondrial effects of the peptide were completely prevented by adding a single N-terminal tryptophan residue to the peptide sequence. We suggest a mechanism of membrane permeabilization that includes a transmembrane-and surface potential-dependent insertion of the polycation peptide into the lipid bilayer and its oligomerization leading to formation of ion channels and also to the mitochondrial permeability transition pore opening in a cyclosporin A-insensitive manner.

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Mitochondrial Damage During Ischemia Determines Post-Ischemic Contractile Dysfunction in Perfused Rat Heart

Cited by 48 publications

References 27 publications

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Possible Pathway of Na<sup>+</sup> Flux into Mitochondria in Ischemic Heart

Mitochondria Permeabilization by a Novel Polycation Peptide BTM-P1

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