Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle.

Yan, Gan‐Xin; Kléber, André G.

doi:10.1161/01.res.71.2.460

Cited by 124 publications

(78 citation statements)

References 62 publications

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“…1a) including an increased NADH/NAD + ratio 18,22 , an increased intracellular concentration of αKG 18,23 , and acidification of the extracellular and intracellular environments 24,25 . Prior reports implicated lactate dehydrogenase A (LDH) and malate dehydrogenase 1 and 2 (MDH) as contributing to hypoxia-induced L-2HG in cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1a) 18,23–25 , but it is unclear to what extent these conditions might be sufficient to induce production of L-2HG. Therefore, we tested the effects of acidified medium and/or exogenous αKG on cells cultured in normoxia (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The relative contributions of LDHA and MDH2 to hypoxia-induced L-2HG appear to vary depending on the type of cell, which may be related to enzyme levels and subcellular pools of substrate. Hypoxic cells undergo a variety of metabolic changes that might favor L-2HG production 18,22–25,45 . Here we identify acidification and increased αKG concentration as factors that are sufficient to induce cellular production of L-2HG in normoxia.…”

Section: Discussionmentioning

confidence: 99%

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L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via ‘promiscuous’ reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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“…No-flow global ischemia was then induced by stopping flow in the aortic cannula and quickly replacing the oxygenated HEPES-Tyrode solution in the chamber with HEPESTyrode solution saturated with 100% N 2 and having a pH of 6.8. 16 Optical mapping data and corresponding ECG recordings were obtained at 1, 3, 5, and 10 minutes of ischemia. At this time, reperfusion was started by opening flow in the aortic cannula and replacing the HEPES-Tyrode solution in the chamber with HEPESTyrode solution saturated with 100% O 2 at pH 7.4.…”

Section: Effects Of Global Ischemia On Activation Patterns Of Vfmentioning

confidence: 99%

Quantification of Effects of Global Ischemia on Dynamics of Ventricular Fibrillation in Isolated Rabbit Heart

et al. 1998

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Background-Ventricular fibrillation (VF) leads to global ischemia of the heart. After 1 to 2 minutes of onset, the VF rate decreases and appears more organized. The objectives of this study were to determine the effects of no-flow global ischemia on nonlinear wave dynamics and establish the mechanism of ischemia-induced slowing of the VF rate. Methods and Results-Activation patterns of VF in the Langendorff-perfused rabbit heart were studied with the use of 2 protocols: (1) 15 minutes of no-flow global ischemia followed by reperfusion (nϭ7) and (2) decreased excitability induced by perfusion with 5 mol/L of tetrodotoxin (TTX) followed by washout (nϭ3). Video imaging (Ϸ7500 pixels per frame; 240 frames per second) with a voltage-sensitive dye, ECG, and signal processing (fast Fourier transform) were used for analysis. The dominant frequency of VF decreased from 13.5Ϯ1.3 during control to 9.3Ϯ1.4 Hz at 5 minutes of global ischemia (PϽ0.02). The dominant frequency decreased from 13.9Ϯ1.1 during control to 7.0Ϯ0.3 Hz at 2 minutes of TTX infusion (PϽ0.001). The rotation period of rotors on the epicardial surface (nϭ27) strongly correlated with the inverse dominant frequency of the corresponding episode of VF (R 2 ϭ0.93). The core area, measured for 27 transiently appearing rotors, was 5.3Ϯ0.7 mm 2 during control. A remarkable increase in core area was observed both during global ischemia (13.6Ϯ1.7 mm 2 ; PϽ0.001) and TTX perfusion (16.8Ϯ3.6 mm 2 ; PϽ0.001). Density of wave fronts decreased during both global ischemia (PϽ0.002) and TTX perfusion (PϽ0.002) compared with control. Conclusions-This study suggests that rotating spiral waves are most likely the underlying mechanism of VF and contribute to its frequency content. Ischemia-induced decrease in the VF rate results from an increase in the rotation period of spiral waves that occurs secondary to an increase in their core area. Remarkably, similar findings in the TTX protocol suggest that reduced excitability during ischemia is an important underlying mechanism for the changes seen.

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“…22) Moreover, isch- emia-induced intracellular acidification decreases gap junctional conductance. 23) Decreased intracellular pH also renders gap junctions more sensitive to increased intracellular Ca 2+ . In this study, phlorizin is likely to inhibit Ca 2+ overload during the ischemia.…”

Section: Discussionmentioning

confidence: 99%

Phlorizin Prevents Electrically-Induced Ventricular Tachyarrhythmia during Ischemia in Langendorff-Perfused Guinea-Pig Hearts

Hirose

Shibazaki

Nakada

et al. 2014

Biological & Pharmaceutical Bulletin

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Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle.

Cited by 124 publications

References 62 publications

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

Quantification of Effects of Global Ischemia on Dynamics of Ventricular Fibrillation in Isolated Rabbit Heart

Phlorizin Prevents Electrically-Induced Ventricular Tachyarrhythmia during Ischemia in Langendorff-Perfused Guinea-Pig Hearts

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