Effects and metabolism of fumarate in the perfused rat heart. A 13C mass isotopomer study

Laplante, A.; Vincent, Geneviève; Poirier, Myriame; Rosiers, Christine Des

doi:10.1152/ajpendo.1997.272.1.e74

Cited by 47 publications

(74 citation statements)

References 24 publications

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“…Nor do we provide data regarding succinate derived from alternative pathways that remain undefined but contribute substantially to succinate during hypoxia. 32 Limitations and Pitfalls As the techniques used in this study require rapid tissue extraction and freeze clamping, we were able to sample from only one parietal cortex location; therefore, we cannot be certain that these findings occur throughout the brain. However, most previous studies examining CAC metabolism in brain slices indicate uniformity with metabolic perturbations.…”

Section: Discussionmentioning

confidence: 99%

Propofol Compared with Isoflurane Inhibits Mitochondrial Metabolism in Immature Swine Cerebral Cortex

Kajimoto

Atkinson

Ledee

et al. 2014

J Cereb Blood Flow Metab

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Anesthetics used in infants and children are implicated in the development of neurocognitive disorders. Although propofol induces neuroapoptosis in developing brain, the underlying mechanisms require elucidation and may have an energetic basis. We studied substrate utilization in immature swine anesthetized with either propofol or isoflurane for 4 hours. Piglets were infused with 13-Carbon-labeled glucose and leucine in the common carotid artery to assess citric acid cycle (CAC) metabolism in the parietal cortex. The anesthetics produced similar systemic hemodynamics and cerebral oxygen saturation by near-infrared spectroscopy. Compared with isoflurane, propofol depleted ATP and glycogen stores. Propofol decreased pools of the CAC intermediates, citrate, and a-ketoglutarate, while markedly increasing succinate along with decreasing mitochondrial complex II activity. Propofol also inhibited acetyl-CoA entry into the CAC through pyruvate dehydrogenase, while promoting glycolytic flux with marked lactate accumulation. Although oxygen supply appeared similar between the anesthetic groups, propofol yielded a metabolic phenotype that resembled a hypoxic state. Propofol impairs substrate flux through the CAC in the immature cerebral cortex. These impairments occurred without systemic metabolic perturbations that typically accompany propofol infusion syndrome. These metabolic abnormalities may have a role in the neurotoxity observed with propofol in the vulnerable immature brain.

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Section: Discussionmentioning

confidence: 99%

Propofol Compared with Isoflurane Inhibits Mitochondrial Metabolism in Immature Swine Cerebral Cortex

Kajimoto

Atkinson

Ledee

et al. 2014

J Cereb Blood Flow Metab

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“…Heart Perfusions-Procedures for isolation and perfusion of rat hearts were as described in previous publications (35,and Comte et al (67)). Briefly, hearts from fed male Sprague-Dawley rats (Charles River, Quebec) weighing 120 -220 g (heart wet weight, 1.…”

Section: Methodsmentioning

confidence: 99%

“…13 C NMR studies on rat hearts perfused with 13 C-substrates pointed out malate decarboxylation as a cataplerotic reaction (62). How- Table I), and (iii) with 0.4 mM [U- 13 C 4 ]fumarate, tissue pyruvate was unlabeled, although it became significantly enriched in M3 isotopomers when hearts were subjected to lowflow ischemia (35). Although the 13 C labeling of a small pool of mitochondrial pyruvate might not be detected by GCMS assay of pyruvate in whole heart homogenates, our data nevertheless raise some doubt about the occurrence of a cataplerotic efflux at malate at least under our present perfusion conditions.…”

Section: Relative Contributions Of Pyruvate To Carboxylation and Decamentioning

confidence: 99%

“…Thus, the anaplerotic flux at succinate (about 10% of the CAC flux in hearts perfused with 0.2 or 1 mM octanoate) would be similar to that attributed to pyruvate carboxylation (5.4 Ϯ 0.5%, n ϭ 29). However, because of evidence pointing to a heterogenous labeling of the myocardial pool of succinate (35), the possibility and extent of anaplerosis at the level of mitochondrial succinate remain to be investigated in experiments with 13 C-labeled valine or isoleucine.…”

Section: Relative Contributions Of Pyruvate To Carboxylation and Decamentioning

confidence: 99%

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A 13C Mass Isotopomer Study of Anaplerotic Pyruvate Carboxylation in Perfused Rat Hearts

Comte

Vincent

Bouchard

et al. 1997

Journal of Biological Chemistry

113

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Anaplerotic pyruvate carboxylation was examined in hearts perfused with physiological concentrations of glucose, [U-13 C 3 ]lactate, and [U-13 C 3 ]pyruvate. Also, a fatty acid, [1-13 C]octanoate, or ketone bodies were added at concentrations providing acetyl-CoA at a rate resulting in either low or substantial pyruvate decarboxylation. Relative contributions of pyruvate and fatty acids to citrate synthesis were determined from the 13 C labeling pattern of effluent citrate by gas chromatography-mass spectrometry (see companion article, Comte, B., Vincent, G., Bouchard, B., and Des Rosiers, C. (1997) J. Biol. Chem. 272, 26117-26124). Precision on flux measurements of anaplerotic pyruvate carboxylation depended on the mix of substrates supplied to the heart. Anaplerotic fluxes were precisely determined under conditions where acetyl-CoA was predominantly supplied by ␤-oxidation, as it occurred with 0.2 or 1 mM octanoate. Then, anaplerotic pyruvate carboxylation provided 3-8% of the OAA moiety of citrate and was modulated by concentrations of lactate and pyruvate in the physiological range. Also, the contribution of pyruvate to citrate formation through carboxylation was equal to or greater than through decarboxylation. Furthermore, 13 C labeling data on tissue citric acid cycle intermediates and pyruvate suggest that (i) anaplerosis occurs also at succinate and (ii) cataplerotic malate decarboxylation is low. Rather, the presence of citrate in the effluent perfusate of hearts perfused with physiological concentrations of glucose, lactate, and pyruvate and concentrations of octanoate leading to maximal oxidative rates suggests a cataplerotic citrate efflux from mitochondria to cytosol. Taken altogether, our data raise the possibility of a link between pyruvate carboxylation and mitochondrial citrate efflux. In view of the proposed feedback regulation of glycolysis by cytosolic citrate, such a link would support a role of anaplerosis and cataplerosis in metabolic signal transmission between mitochondria and cytosol in the normoxic heart.

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“…The application of fumaric acid in cardoplegia improves myocardial contractility and decreases the concentration of lactate dehydrogenase, which is correlated to increases in the number of dead cells at higher levels of activity. Its protective impact is related to the transformation of fumaric acid into succinic acid via a dehydrogenation reaction in Krebs cycle (28). It has also been shown to positively impact the restoration of proper function in immature myocytes (29).…”

Section: Introductionmentioning

confidence: 99%

Influence of the Selected Antioxidants on the Stability of the Celsior Solution Used for Perfusion and Organ Preservation Purposes

Ostróżka-Cieślik

Dolińska

Ryszka³

2009

AAPS PharmSciTech

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Abstract. The purpose of the following research was to improve the original Celsior solution in order to obtain a higher degree of stability and effectiveness. The solution was modified by the addition of selected antioxidants such as vitamin C, cysteine, and fumaric acid in the following concentrations: 0.1, 0.3, and 0.5 mmol/l. The solution's stability was estimated using an accelerated stability test based on changes in histidine concentrations in the solution using Pauly's method for determining concentrations. Elevated temperatures, the factor accelerating substances' decomposition reaction rate, were used in the tests. The research was conducted at four temperatures at intervals of 10°C: 60±0.2°C, 70±0.2°C, 80±0.2°C, and 90±0.2°C. It was stated that the studied substances' decomposition occurred in accordance with the equation for first-order reactions. The function of the logarithmic concentration (log%C) over time was revealed to be rectilinear. This dependence was used to determine the kinetics of decomposition reaction rate parameters (the rate constant of decomposition k, activation energy E a , and frequency factor A). On the basis of these parameters, the stability of the modified solution was estimated at +5°C. The results obtained show that the proposed antioxidants have a significant effect on lengthening the Celsior solution's stability. The best results were reached when combining two antioxidants: vitamin C and cysteine in 0.5 mmol/l concentrations. As a result, the Celsior solution's stability was lengthened from 22 to 299 days, which is 13.5 times. Vitamin C at a concentration of 0.5 mmol/l increased the solution's stability by 5.2 times (t 90 =115 days), cysteine at a concentration of 0.5 mmol/l caused a 4.4 times stability increase (t 90 =96 days), and fumaric acid at a concentration of 0.5 mmol/l extended the stability by 2.1 times (t 90 =48 days) in relation to the original solution.

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Effects and metabolism of fumarate in the perfused rat heart. A 13C mass isotopomer study

Cited by 47 publications

References 24 publications

Propofol Compared with Isoflurane Inhibits Mitochondrial Metabolism in Immature Swine Cerebral Cortex

Propofol Compared with Isoflurane Inhibits Mitochondrial Metabolism in Immature Swine Cerebral Cortex

A 13C Mass Isotopomer Study of Anaplerotic Pyruvate Carboxylation in Perfused Rat Hearts

Influence of the Selected Antioxidants on the Stability of the Celsior Solution Used for Perfusion and Organ Preservation Purposes

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