Anaerobic rat heart. Effects of glucose and tricarboxylic acid-cycle metabolites on metabolism and physiological performance

Penney, David G.; Cascarano, Joseph

doi:10.1042/bj1180221

Cited by 96 publications

(31 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The anaerobic metabolic pathways depicted in Fig. 2 are known to function in at least two mammalian tissues that are highly susceptible to ischemic damage, heart and kidney, and benefits from them during injury has been suggested (21)(22)(23)(24)(25)(26)34). The present studies indicate a central, upstream role for these pathways of anaerobic metabolism in modifying mitochondrial susceptibility to damage.…”

Section: Discussionmentioning

confidence: 54%

“…Anaerobic pathways of mitochondrial metabolism as summarized in Fig. 2 contribute to hypoxia resistance in lower species and diving mammals and have the potential to support ATP production during hypoxia in mammalian heart and kidney and to modify injury (21)(22)(23)(24)(25)(26). By virtue of its local generation, ATP formed in the mitochondrial matrix, even in very small amounts, could protect against or repair damage to respiratory components during hypoxia and͞or reoxygenation.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates

Weinberg

Venkatachalam

Roeser

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

292

294

View full text Add to dashboard Cite

Kidney proximal tubule cells developed severe energy deficits during hypoxia͞reoxygenation not attributable to cellular disruption, lack of purine precursors, the mitochondrial permeability transition, or loss of cytochrome c. Reoxygenated cells showed decreased respiration with complex I substrates, but minimal or no impairment with electron donors at complexes II and IV. This was accompanied by diminished mitochondrial membrane potential (⌬⌿ m). The energy deficit, respiratory inhibition, and loss of ⌬⌿m were strongly ameliorated by provision of ␣-ketoglutarate plus aspartate (␣KG͞ASP) supplements during either hypoxia or only during reoxygenation. Measurements of 13 C-labeled metabolites in [3-13 C]aspartate-treated cells indicated the operation of anaerobic pathways of ␣KG͞ASP metabolism to generate ATP, yielding succinate as end product. Anaerobic metabolism of ␣KG͞ASP also mitigated the loss of ⌬⌿ m that occurred during hypoxia before reoxygenation. Rotenone, but not antimycin or oligomycin, prevented this effect, indicating that electron transport in complex I, rather than F 1F0-ATPase activity, had been responsible for maintenance of ⌬⌿ m by the substrates. Thus, tubule cells subjected to hypoxia͞reoxygenation can have persistent energy deficits associated with complex I dysfunction for substantial periods of time before onset of the mitochondrial permeability transition and͞or loss of cytochrome c. The lesion can be prevented or reversed by citric acid cycle metabolites that anaerobically generate ATP by intramitochondrial substrate-level phosphorylation and maintain ⌬⌿ m via electron transport in complex I. Utilization of these anaerobic pathways of mitochondrial energy metabolism known to be present in other mammalian tissues may provide strategies to limit mitochondrial dysfunction and allow cellular repair before the onset of irreversible injury by ischemia or hypoxia. S tructural, biochemical, and functional abnormalities of mitochondria are widely believed to be important pathogenetic factors that underlie ischemic or hypoxic cell injury (1). Two defects recently have gained credence and captured attention. One is characterized by pore formation in the inner mitochondrial membrane, deenergization, and high-amplitude swelling (mitochondrial permeability transition or MPT) (1-4). The second involves leakage of cytochrome c from the intermembrane space into the cytosol (5). Cytochrome c leakage may follow the MPT or occur independently. There is general agreement that these dramatic alterations result in cell death by necrosis and apoptosis in diverse types of cell injury, including those caused by hypoxia and ischemia (1, 3-5). However, the proximate events that lead to the MPT and loss of cytochrome c are unclear and are subjects of ongoing investigation.We have reported that cells in freshly isolated kidney proximal tubules exhibit profound functional deficits of their mitochondria when they are reoxygenated after hypoxic incubation (6). The defect is characterized by failure of oxidative phosphor...

show abstract

Section: Discussionmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates

Weinberg

Venkatachalam

Roeser

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

292

294

View full text Add to dashboard Cite

show abstract

“…The method of estimation of HEP production would need modification if higher collateral flow rates were present. Shuttle mechanisms which could provide substrate level phosphorylation of a-ketoglutarate (aKG) or reduction of fumarate in mitochondria also must be negligible relative to anaerobic glycolysis when no source of exogenous aKG or glutamate is present (Penney and Cascarano, 1970;Hochachka et al, 1975).…”

Section: Comparison Of Hep Production and Utilization In Myocardial Imentioning

confidence: 99%

Total ischemia in dog hearts, in vitro. 1. Comparison of high energy phosphate production, utilization, and depletion, and of adenine nucleotide catabolism in total ischemia in vitro vs. severe ischemia in vivo.

Jennings¹,

Reimer²,

Hill³

et al. 1981

Circulation Research

248

View full text Add to dashboard Cite

SUMMARY This study was done to compare rates of high energy phosphate (HEP) utilization and depletion, as well as the production and distribution of catabolic products of adenine nucleo tides in dog heart during total ischemia in vitro and severe ischemia in vivo. Both HEP production from anaerobic glycolysis and HEP utilization occurred much more quickly during the fir»t 15 mmtuet of severe ischemia in vivo than in total ischemia in vitro. HEP utilization exceeded production in both types of ischemia and tissue HEP decreased progressively. Much of the creatine phosphate (CP) was lost within the first 1-3 minutes; adenosine triphosphate (ATP) depletion occurred more slowly than CP and more slowly in vitro than in vivo. ATP was reduced from control contents of 5-6 /imol/g to 1.0 jirool/g by 75 minutes of total ischemia in vitro, but reached a similar level within only 30 minutes of severe ischemia in vivo. HEP utilization and production during ischemia were estimated from the rate of accumulation of myocardial lactate and essentially ceased when the ATP reached 0.4 jimol/g wet weight. At this time, more than 80% of the HEP that had been utilized in ischemia in vivo or in total ischemia in vitro had been derived from anaerobic glycolysis. ATP depletion was paralleled by dephosphorylation of adenine nucleottdeg. The lost nucleotides were recovered stoichiometrically as adenosine, inosine, hypoxantbine, and xanthine in both models of ischemia, a finding which demonstrates that the low collateral flow of severe ischemia allows little washout of nucleosides, bases, or lactate to the systemic circulation. These results Indicate that total ischemia in vitro can be used as a model of severe ischemia in vivo in that the pathways of energy production and depletion and of adenine nucleotide degradation generally are similar. Moreover, the larger quantities of uniformly ischemic tissue and the slower time course of changes make total ischemia well suited to the study of relationships between the metabolic, ftmctional, and structural consequences of ischemic injury, drc Res 49: 892-900, 1981 WITHIN seconds of the onset of severe ischemia induced by coronary occlusion in vivo, myocardial HEP begins to decrease, and by the time a minute has passed, 80% or more of the creatine phosphate (CP) is lost (Braasch et al., 1968;Dunn and Griggs, 1975). Within 15 minutes, 65% of the tissue adenosine triphosphate (ATP) and 55% of the total adenine nucleotides (£Ad) have disappeared (Jennings et al., 1978). After 40 minutes of ischemia, the HEP supply is approaching zero and most of the severely ischemic cells have become irreversibly injured and do not recover even if blood flow is restored (Jennings et al., 1978).The present report compares the rates of HEP production from anaerobic glycolysis as weD as the rates of utilization and depletion of HEP and the distribution of catabolic products of adenine nu- cleo tides in total ischemia in vitro and severe ischemia in vivo. Both the rate of high energy phosphate production and of ATP deg...

show abstract

“…An additional pathway for anaerobic ATP production in mammalian muscle (including heart) has been reported whereby ATP is gen erated from amino acids involved in anaplerotic reactions of intermediary metabolism [10,13,14,20], Previous studies have fo cused upon aspartate (Asp) and glutamate (Glu), primarily because these amino acids participate in important metabolic shuttling pathways between the cytosol and mitochon dria [3,4,16]. In addition, these amino acids exert prominent effects in vitro on myocar dial metabolism and mechanical recovery during anoxia or ischemia [15].…”

Section: Introductionmentioning

confidence: 99%

Comparative Effects of Aspartate and Glutamate during Myocardial Ischemia

Bush¹,

Warren²,

Mesh³

et al. 1981

Pharmacology

View full text Add to dashboard Cite

The effects of the amino acids aspartate (Asp) and glutamate (Glu) on recovery of contractile function and preservation of compliance were studied in globally ischemic, isolated, blood-perfused cat hearts. Ischemia-induced declines in contractility and compliance were measured with an intraventricular fluid-filled balloon. Asp and Glu were delivered to isolated hearts in physiological salt solution (PSS) containing 10 mM glucose, just prior to, and intermittently during (every 15 min for 1 min) 1 h of normothermic ischemia. Isolated hearts which received Asp and Glu showed recoveries of left ventricular (LV) developed pressure of 79 ± 8 and 50 ± 7% of their preischemic values, respectively, compared to 34 ± 7% in hearts perfused only with PSS. These alterations of contractile function were paralleled by changes in LV compliance. The addition of amino-oxyacetate, an aminotransferase inhibitor, to Asp-containing PSS markedly attenuated the beneficial effects of this amino acid. The results indicate that certain amino acids can protect the ischemic myocardium, presumably through effects on intermediary metabolism.

show abstract

Anaerobic rat heart. Effects of glucose and tricarboxylic acid-cycle metabolites on metabolism and physiological performance

Cited by 96 publications

References 13 publications

Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates

Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates

Total ischemia in dog hearts, in vitro. 1. Comparison of high energy phosphate production, utilization, and depletion, and of adenine nucleotide catabolism in total ischemia in vitro vs. severe ischemia in vivo.

Comparative Effects of Aspartate and Glutamate during Myocardial Ischemia

Contact Info

Product

Resources

About