Conditions Of Limited Oxygen Availability Research Articles

Fumarate is a terminal electron acceptor in the mammalian electron transport chain.

For electrons to continuously enter and flow through the mitochondrial electron transport chain (ETC), they must ultimately land on a terminal electron acceptor (TEA), which is known to be oxygen in mammals. Paradoxically, we find that complex I and dihydroorotate dehydrogenase (DHODH) can still deposit electrons into the ETC when oxygen reduction is impeded. Cells lacking oxygen reduction accumulate ubiquinol, driving the succinate dehydrogenase (SDH) complex in reverse to enable electron deposition onto fumarate. Upon inhibition of oxygen reduction, fumarate reduction sustains DHODH and complex I activities. Mouse tissues display varying capacities to use fumarate as a TEA, most of which net reverse the SDH complex under hypoxia. Thus, we delineate a circuit of electron flow in the mammalian ETC that maintains mitochondrial functions under oxygen limitation.

Heritable variation in swimming performance in Nile tilapia (Oreochromis niloticus) and negative genetic correlations with growth and harvest weight

Nile tilapia is predominantly produced in smallholder ponds without aeration. We hypothesize that Nile tilapia with high oxygen uptake efficiency (O2UE) may perform better under these conditions than Nile tilapia with low O2UE. Critical swimming speed (Ucrit, in cm s−1) is a potential indicator for O2UE. Our objectives were to estimate variance components for Ucrit and fish size at swim testing early in life, and genetic correlations (rg) between Ucrit with harvest weight (HW) and daily growth coefficient (DGC) later after grow-out in a non-aerated pond. Substantial heritability was found for absolute Ucrit (0.48). The estimated rg between absolute Ucrit and fish size at testing were all strong and positive (range 0.72–0.83). The estimated rg between absolute Ucrit and HW, and absolute Ucrit and DGC were − 0.21 and − 0.63 respectively, indicating that fish with higher absolute Ucrit had lower growth in the non-aerated pond as compared to fish with lower absolute Ucrit. These results suggest a juvenile trade-off between swimming and growth performance where fish with high Ucrit early in life show slower growth later under conditions of limited oxygen availability. We conclude that Ucrit in Nile tilapia is heritable and can be used to predict growth performance.

Abstract 16722: L-2-Hydroxyglutarate Protects Against Myocardial Ischemia-Reperfusion Injury

Background: L-2-hydroxyglutarate (L2HG) couples mitochondrial (Mito) and cytoplasmic energy metabolism in a model of cellular redox regulation. Under conditions of limited oxygen availability, mammalian cells generate L2HG to counteract the adverse effects of Mito reductive stress induced by hypoxia. L2HG is oxidized to α-ketoglutarate by L2HG dehydrogenase (L2HGDH) in a variety of mammalian tissues, including the heart. Myocardial ischemia/reperfusion injury (MIRI) is a consequence of coronary vascular disease and vascular procedures. Mito oxidative stress plays a critical role in MIRI. Here we hypothesized that L2HG protects against MIRI. Methods and Results: We induced accumulation of L2HG by heterozygous (HET) and homozygous (KO) deletion of L2HGDH gene in mice. The hearts isolated from HET, KO, and wild-type (WT) littermate mice were subjected to 30 min global thermal ischemia followed by 60 min reperfusion. Cardiac function and energy metabolism were simultaneously measured using a Langendorff heart perfusion model and 31 P-NMR spectroscopy. We found that female HET and KO exhibited better recovery of cardiac function post-MIRI in consistent with better preservation of intracellular ATP and phosphocreatine (Table). Using HPLC, we measured compounds representative of cellular redox state (GSG, GSSG, NAD, NADH, NADP, NADPH, coenzyme A and ascorbate), cellular energy state (ATP, ADP, AMP, GTP, GDP, GMP, UTP, UDP, UMP, CTP, CDP, CMP, IMP, malonyl-CoA and acetyl-CoA), and nucleotide catabolism (adenosine, hypoxanthine, xanthine and inosine) in freeze-clamped hearts. We found that ratios of GSH/GSSG and ATP/ADP increased in HET and KO hearts (Table). Interestingly, the ratios of NADH/NAD and NADPH/NADP increased only in KO but not in HET hearts. Consistent with the increased ratio of ATP/AMP, hypoxanthine and xanthine decreased only in KO hearts but not in HET hearts (Table). Conclusion: The accumulation of L2HG in a genetic mouse model protects against MIRI though increasing cellular antioxidative capacity and preserving high energy phosphates. The underlying mechanism of these beneficial adaptive phenomena warrants further study. Targeting L2HG levels and L2HGDH expression may serve as new therapeutic strategies for MIRI protection.

Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR.

Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. However, tumour cells are capable of counteracting these signals through mechanisms that are largely unknown. Here we show that the prolyl hydroxylase PHD3 restrains tumour growth in response to microenvironmental cues through the control of EGFR. PHD3 silencing in human gliomas or genetic deletion in a murine high-grade astrocytoma model markedly promotes tumour growth and the ability of tumours to continue growing under unfavourable conditions. The growth-suppressive function of PHD3 is independent of the established PHD3 targets HIF and NF-κB and its hydroxylase activity. Instead, loss of PHD3 results in hyperphosphorylation of epidermal growth factor receptor (EGFR). Importantly, epigenetic/genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification. Our findings reveal that PHD3 inactivation provides an alternative route of EGFR activation through which tumour cells sustain proliferative signalling even under conditions of limited oxygen availability.

The hypoxia–inflammation link and potential drug targets

Hypoxia represents one of the strongest transcriptional stimuli known to us. In most cases, hypoxia-induced changes in gene expression are directed towards adapting tissues to conditions of limited oxygen availability. As a well known example, physical exercise at high altitude results in the transcriptional induction of erythropoietin that functions to increase oxygen carrying capacity and red cell volume. Studies of the transcriptional pathway responsible for the induction of erythropoietin during conditions of hypoxia led to the discovery of the transcription factor hypoxia-inducible factor (HIF) that is known today as the key transcription factor for hypoxia adaptation. Surgical patients are frequently at risk for experiencing detrimental effects of hypoxia or ischemia, for example, in the context of acute kidney injury, myocardial, intestinal or hepatic ischemia, acute lung injury, or during organ transplantation. In the present review, we discuss the mechanisms of transcriptional adaptation to hypoxia and provide evidence supporting the hypothesis that targeting hypoxia-induced inflammation can represent novel pharmacologic strategies to improve perioperative outcomes. Currently, such strategies are being explored at an experimental level, but we hope that some of these targets can be translated into perioperative patient care within the next decade.

Extracellular Adenosine: A Safety Signal That Dampens Hypoxia-Induced Inflammation During Ischemia

Traditionally, the single most unique feature of the immune system has been attributed to its capability to discriminate between self (e.g., host proteins) and nonself (e.g., pathogens). More recently, an emerging immunologic concept involves the notion that the immune system responds via a complex system for sensing signals of danger, such as pathogens or host-derived signals of cellular distress (e.g., ischemia), while remaining unresponsive to nondangerous motifs. Experimental studies have provided strong evidence that the production and signaling effects of extracellular adenosine are dramatically enhanced during conditions of limited oxygen availability as occurs during ischemia. As such, adenosine would fit the bill of signaling molecules that are enhanced during situations of cellular distress. In contrast to a danger signal, we propose here that extracellular adenosine operates as a countermeasure, in fact as a safety signal, to both restrain potentially harmful immune responses and to maintain and promote general tissue integrity during conditions of limited oxygen availability.

Targeting the A2B adenosine receptor during gastrointestinal ischemia and inflammation

Extracellular adenosine functions as an endogenous distress signal via activation of four distinct adenosine receptors (A1, A2A, A2B and A3). Conditions of limited oxygen availability or acute inflammation lead to elevated levels of extracellular adenosine and enhanced signaling events. This relates to a combination of four mechanisms: i) increased production of adenosine via extracellular phosphohydrolysis of precursor molecules (particularly ATP and ADP); ii) increased expression and signaling via hypoxia-induced adenosine receptors, particularly the A2B adenosine receptor; iii) attenuated uptake from the extracellular towards the intracellular compartment; and iv) attenuated intracellular metabolism. Due to their large surface area, mucosal organs are particularly prone to hypoxia and ischemia associated inflammation. Therefore, it is not surprising that adenosine production and signaling plays a central role in attenuating tissue inflammation and injury during intestinal ischemia or inflammation. In fact, recent studies combining pharmacological and genetic approaches demonstrated that adenosine signaling via the A2B adenosine receptor dampens mucosal inflammation and tissue injury during intestinal ischemia or experimental colitis. This review outlines basic principles of extracellular adenosine production, signaling, uptake and metabolism. In addition, we discuss the role of this pathway in dampening hypoxia-elicited inflammation, specifically in the setting of intestinal ischemia and inflammation.

Physiological Roles of Vascular Nucleoside Transporters

Nucleoside transporters (NTs) comprise 2 widely expressed families, the equilibrative nucleoside transporters (diffusion-limited channels) and concentrative nucleoside transporters (sodium-dependent transporters). Because of their anatomic position at the blood-tissue interface, vascular NTs are in an ideal position to influence vascular nucleoside levels, particularly adenosine, which among others plays an important role in tissue protection during acute injury. For example, endothelial NTs contribute to preserving the vascular integrity during conditions of limited oxygen availability (hypoxia). Indeed, hypoxia-inducible factor-1-dependent repression of NTs results in enhanced extracellular adenosine signaling and thus attenuates hypoxia-associated increases in vascular leakage. In addition, vascular NTs also contribute to cardiac ischemic preconditioning, coronary vasodilation, and inhibition of platelet aggregation. Moreover, vascular nucleoside uptake via NTs is important for nucleoside recovery, particularly in cells lacking de novo nucleotide synthesis pathways (erythrocytes, leukocytes). Taken together, vascular NTs are critical in modulating adenosine-mediated responses during conditions such as inflammation or hypoxia.

Protective Role of Ecto-5′-Nucleotidase (CD73) in Renal Ischemia

Acute renal failure from ischemia significantly contributes to cardiovascular morbidity and mortality. Extracellular adenosine has been implicated as an anti-inflammatory metabolite particularly during conditions of limited oxygen availability (e.g., ischemia). Because ecto-5'-nucleotidase (CD73) is rate limiting for extracellular adenosine generation, this study examined the contribution of CD73-dependent adenosine production to ischemic preconditioning (IP) of the kidneys. After the initial observation that murine CD73 transcript, protein, and function are induced by renal IP, its role in IP-mediated kidney protection was studied. In fact, increases in renal adenosine concentration with IP are attenuated in cd73(-/-) mice. Moreover, pharmacologic inhibition of CD73 or its targeted gene deletion abolished renal protection by IP as measured by clearance studies, plasma electrolytes, and renal tubular destruction, and reconstitution of cd73(-/-) mice with soluble 5'-nucleotidase resulted in complete restoration of renal protection by IP. Finally, renal injury after ischemia was attenuated by intraperitoneal treatment of wild-type mice with soluble 5'-nucleotidase to a similar degree as by IP. Taken together, these data reveal what is believed to be a previously unrecognized role of CD73 in renal protection from ischemia and suggest treatment with soluble 5'-nucleotidase as a novel therapeutic approach in the treatment of renal diseases that are precipitated by limited oxygen availability.

HIF-1–dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

Extracellular adenosine (Ado) has been implicated as central signaling molecule during conditions of limited oxygen availability (hypoxia), regulating physiologic outcomes as diverse as vascular leak, leukocyte activation, and accumulation. Presently, the molecular mechanisms that elevate extracellular Ado during hypoxia are unclear. In the present study, we pursued the hypothesis that diminished uptake of Ado effectively enhances extracellular Ado signaling. Initial studies indicated that the half-life of Ado was increased by as much as fivefold after exposure of endothelia to hypoxia. Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia. Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)–dependent repression of ENT1 during hypoxia. Using in vitro and in vivo models of Ado signaling, we revealed that decreased Ado uptake promotes vascular barrier and dampens neutrophil tissue accumulation during hypoxia. Moreover, epithelial Hif1 α mutant animals displayed increased epithelial ENT1 expression. Together, these results identify transcriptional repression of ENT as an innate mechanism to elevate extracellular Ado during hypoxia.

Hypoxia-dependent activation of HIF into a transcriptional regulator

Adaptation to conditions of limited oxygen availability (hypoxia) is a critical determinant of cell and tissue viability in several physiological and pathophysiological conditions. The hypoxia-inducible factor (HIF) is an oxygen-sensitive transcriptional activator that, under hypoxia, upregulates the expression of genes involved in the control of glucose metabolism, angiogenesis and cellular proliferation, among others. Activation of HIF to a fully competent transcriptional regulatory protein complex is a multi-step process that involves control of protein stability, subcellular localization, DNA-binding and interaction with transcriptional coregulators. The identity, regulation and hierarchy of interactions between several components of the HIF signal transduction pathway has been the object of intense study over the past decade and will be the subject of this review. Particular emphasis is given to the process of coordinated coactivator recruitment within the cell nucleus. The implications for future development of angiogenic/antiangiogenic therapeutic strategies of HIF activation/inactivation are discussed.

Low Extracellular Po2 Decreases Ca2+ Sensitivity During Fatigue In Single Xenopus Skeletal Muscle Fibers

PURPOSE We examined whether reduced O2 availability in working skeletal muscle, compared to conditions when O availability is greater, involves an alteration in myofilament Ca2+ sensitivity during fatigue. METHODS Relative force (P) and cytosolic Ca2+ concentration ([Ca2+]c) were measured simultaneously in isolated single Xenopusskeletal muscle fibers (n=8) stimulated at sequentially increasing frequencies (0.25, 0.33, 0.5 and 1 contraction/sec), at an extracellular PO2 of either 21 or 159 mm Hg. Stimulation was terminated when P<50% of initial peak tension values (Po). RESULTS No significant difference (p<0.05) in P was observed between treatments during the first 2 min of contractions. At 2 min, however, a significant difference (p<0.05) in P was observed between the low PO2 treatment (P/Po=0.81±0.03) and the high (P/PO=0.89±0.02), which continued until the end of stimulation. The fatigue end-point (P/P =0.5) occurred significantly sooner during the low PO treatment (4.6±0.4 min) than the high (5.3±0.4 min). Myofilament Ca2+ sensitivity was determined by examining the ratio of relative peak [Ca2+]c to relative force (i.e, [Ca2+]c /P). No difference in [Ca2+]c /P was observed between the two treatments during the initial 2 min. However, beyond this two-minute time point, a significant difference in [Ca2+] /P was observed between the low PO2 condition (1.16±0.03) and the high (1.09±0.03), showing a diminished force development for a given [Ca2+]c in the low extracellular PO2condition. CONCLUSIONS These results suggest that in contracting, single Xenopusskeletal muscle fibers, the development of fatigue during conditions of limited oxygen availability is associated with a decrease in myofilament Ca2+ sensitivity when compared to conditions of greater oxygen availability. Supported by NIH Grant AR40155

Low Extracellular Po2 Decreases Ca2+ Sensitivity During Fatigue In Single Xenopus Skeletal Muscle Fibers

PURPOSE We examined whether reduced O2 availability in working skeletal muscle, compared to conditions when O availability is greater, involves an alteration in myofilament Ca2+ sensitivity during fatigue. METHODS Relative force (P) and cytosolic Ca2+ concentration ([Ca2+]c) were measured simultaneously in isolated single Xenopusskeletal muscle fibers (n=8) stimulated at sequentially increasing frequencies (0.25, 0.33, 0.5 and 1 contraction/sec), at an extracellular PO2 of either 21 or 159 mm Hg. Stimulation was terminated when P<50% of initial peak tension values (Po). RESULTS No significant difference (p<0.05) in P was observed between treatments during the first 2 min of contractions. At 2 min, however, a significant difference (p<0.05) in P was observed between the low PO2 treatment (P/Po=0.81±0.03) and the high (P/PO=0.89±0.02), which continued until the end of stimulation. The fatigue end-point (P/P =0.5) occurred significantly sooner during the low PO treatment (4.6±0.4 min) than the high (5.3±0.4 min). Myofilament Ca2+ sensitivity was determined by examining the ratio of relative peak [Ca2+]c to relative force (i.e, [Ca2+]c /P). No difference in [Ca2+]c /P was observed between the two treatments during the initial 2 min. However, beyond this two-minute time point, a significant difference in [Ca2+] /P was observed between the low PO2 condition (1.16±0.03) and the high (1.09±0.03), showing a diminished force development for a given [Ca2+]c in the low extracellular PO2condition. CONCLUSIONS These results suggest that in contracting, single Xenopusskeletal muscle fibers, the development of fatigue during conditions of limited oxygen availability is associated with a decrease in myofilament Ca2+ sensitivity when compared to conditions of greater oxygen availability. Supported by NIH Grant AR40155

Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia

Under conditions of limited oxygen availability (hypoxia), multiple cell types release adenine nucleotides in the form of ATP, ADP, and AMP. Extracellular AMP is metabolized to adenosine by surface-expressed ecto-5′-nucleotidase (CD73) and subsequently activates surface adenosine receptors regulating endothelial and epithelial barrier function. Therefore, we hypothesized that hypoxia transcriptionally regulates CD73 expression. Microarray RNA analysis revealed an increase in CD73 and ecto-apyrase CD39 in hypoxic epithelial cells. Metabolic studies of CD39/CD73 function in intact epithelia revealed that hypoxia enhances CD39/CD73 function as much as 6 ± 0.5–fold over normoxia. Examination of the CD73 gene promoter identified at least one binding site for hypoxia-inducible factor-1 (HIF-1) and inhibition of HIF-1α expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 expression. Studies using luciferase reporter constructs revealed a significant increase in activity in cells subjected to hypoxia, which was lost in truncated constructs lacking the HIF-1 site. Mutagenesis of the HIF-1α binding site resulted in a nearly complete loss of hypoxia-inducibility. In vivo studies in a murine hypoxia model revealed that hypoxia-induced CD73 may serve to protect the epithelial barrier, since the CD73 inhibitor α,β-methylene ADP promotes increased intestinal permeability. These results identify an HIF-1–dependent regulatory pathway for CD73 and indicate the likelihood that CD39/CD73 protects the epithelial barrier during hypoxia.

Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia.

Under conditions of limited oxygen availability (hypoxia), multiple cell types release adenine nucleotides in the form of ATP, ADP, and AMP. Extracellular AMP is metabolized to adenosine by surface-expressed ecto-5'-nucleotidase (CD73) and subsequently activates surface adenosine receptors regulating endothelial and epithelial barrier function. Therefore, we hypothesized that hypoxia transcriptionally regulates CD73 expression. Microarray RNA analysis revealed an increase in CD73 and ecto-apyrase CD39 in hypoxic epithelial cells. Metabolic studies of CD39/CD73 function in intact epithelia revealed that hypoxia enhances CD39/CD73 function as much as 6 +/- 0.5-fold over normoxia. Examination of the CD73 gene promoter identified at least one binding site for hypoxia-inducible factor-1 (HIF-1) and inhibition of HIF-1alpha expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 expression. Studies using luciferase reporter constructs revealed a significant increase in activity in cells subjected to hypoxia, which was lost in truncated constructs lacking the HIF-1 site. Mutagenesis of the HIF-1alpha binding site resulted in a nearly complete loss of hypoxia-inducibility. In vivo studies in a murine hypoxia model revealed that hypoxia-induced CD73 may serve to protect the epithelial barrier, since the CD73 inhibitor alpha,beta-methylene ADP promotes increased intestinal permeability. These results identify an HIF-1-dependent regulatory pathway for CD73 and indicate the likelihood that CD39/CD73 protects the epithelial barrier during hypoxia.

A cooperative oxygen-binding hemoglobin from Mycobacterium tuberculosis.

Two putative hemoglobin genes, glbN and glbO, were recently discovered in the complete genome sequence of Mycobacterium tuberculosis H37Rv. Here, we show that the glbN gene encodes a dimeric hemoglobin (HbN) that binds oxygen cooperatively with very high affinity (P(50) = 0.013 mmHg at 20 degrees C) because of a fast combination (25 microM(-1).s(-1)) and a slow dissociation (0.2 s(-1)) rate. Resonance Raman spectroscopy and ligand association/dissociation kinetic measurements, along with mutagenesis studies, reveal that the stabilization of the bound oxygen is achieved through a tyrosine at the B10 position in the distal pocket of the heme with a conformation that is unique among the globins. Physiological studies performed with Mycobacterium bovis bacillus Calmette-Guérin demonstrate that the expression of HbN is greatly enhanced during the stationary phase in aerobic cultures but not under conditions of limited oxygen availability. The results suggest that, physiologically, the primary role of HbN may be to protect the bacilli against reactive nitrogen species produced by the host macrophage.

Carbon- and Oxygen-Isotopic Behavior of Carbonate Rocks of the Phosphatic Gramame Formation, Pernambuco-Paraíba Coastal Basin, Northeastern Brazil

In the basal section of the carbonates of the Maastrichtian Gramame Formation in the Pernambuco-Paraiba coastal basin of northeastern Brazil, major phosphate concentrations (P2O5 > 10%) were deposited in shallow-marine environments (inner shelf). In contrast, dolomite-associated phosphates are characterized by low P2O5 concentrations (<10%) and were deposited in the relatively deep water of a platform ramp, under conditions of limited oxygen availability. Calcite is the main carbonate phase remaining after the diagenesis that affected the phosphorite. A positive δ13C (up to +2%PDB), coupled with a positive MgO-δ180 correlation in the phosphate-enriched carbonates, suggests that upwelling currents were the early phosphogenic vectors during marine transgression, in contrast to warm superficial seawater that prevailed during the Maastrichtian elsewhere. The major phosphate concentrations are related to reworking and diagenesis in a shallow shelf environment during a regression pulse of sea level, followed by a dramatic drop of δ13C to negative values (down to −6%PDB). This study suggests that carbon and oxygen isotopes can be used as potential tools for phosphorite prospecting elsewhere.

Use of EPR and ENDOR spectroscopy in conjunction with the spin trapping technique to study the high-temperature oxidative degradation of fatty acid methyl esters †

Free radicals produced during the autoxidation of unsaturated edible oils are extremely short-lived, but are able to react with spin traps to produce adducts with sufficient stability for spectroscopic characterisation at (near) cooking temperatures (353–443 K). EPR spectra have shown that the model esters methyl oleate, linoleate and linolenate each formed three distinct radical adducts with N-tert-butyl-α-phenylnitrone (PBN). These adducts have been further characterised by obtaining spectra under conditions of limited oxygen availability and in the presence of α-tocopherol; two of these adducts corresponded to peroxyl and alkyl radical adducts of PBN, whereas the other was an alkyl adduct of 2-methyl-2-nitrosopropane (MNP), which was formed as a result of decomposition of the PBN peroxyl radical adduct. The origins of the various 1H hyperfine splittings have been determined by using selectively and fully deuterated PBN and selectively deuterated oleate and some of their magnitudes have been confirmed by ENDOR spectroscopy. The results obtained clearly confirm the high temperature oxidation of fatty acid esters to proceed via a different mechanism from that observed at low temperature, and point to significant differences in oxidation mechanisms of monounsaturated fatty acid esters relative to polyunsaturated.

Dichloroacetate as metabolic therapy for myocardial ischemia and failure

This article critically reviews the pharmacologic effects of the investigational drug dichloroacetate (DCA), which activates the mitochondrial pyruvate dehydrogenase enzyme complex in cardiac tissue and thus preferentially facilitates aerobic oxidation of carbohydrate over fatty acids. The pharmacologic effects of DCA are compared with other interventions, such as glucose plus insulin, inhibitors of long chain fatty acid oxidation and adenosine, that are also thought to exert their therapeutic effects by altering myocardial energy metabolism. Short-term clinical and laboratory experiments demonstrate that intravenous DCA rapidly stimulates pyruvate dehydrogenase enzyme complex activity and, therefore, aerobic glucose oxidation in myocardial cells. Typically these effects are associated with suppression of myocardial long chain fatty acid metabolism and increased left ventricular stroke work and cardiac output without changes in coronary blood flow or myocardial oxygen consumption. Although long-term studies are lacking, short-term parenteral administration of DCA appears to be safe and capable of significantly improving myocardial function in conditions of limited oxygen availability by increasing the efficient conversion of myocardial substrate fuels into energy.

Mobilization of Endosperm Reserves in Cereal Seeds under Anoxia

The great majority of seeds from higher plants fail to germinate under anoxic conditions. While the metabolic pathways operating during the aerobic process of seed germination are well described, there is only limited evidence concerning metabolic pathways operating under conditions of limited oxygen availability. This is despite the importance of carbohydrate availability for plant tolerance to anaerobic conditions. We review and discuss carbohydrate metabolism in cereal seeds and seedlings subjected to anaerobic conditions. Analysis of recent results reveals that, among cereal seeds, only rice is able to degrade the starchy endosperm. This is achieved by the concerted action of the complete set of amylolytic enzymes. In anoxic wheat and barley seeds, the enzymes involved in starch degradation are either absent or present as inactive forms. Differences are also observed in the metabolism of soluble carbohydrates and in status of related enzymes, with rice showing anoxia-enhanced activities of sucrose synthase, fructokinase, glucose-6P dehydrogenase, and nucleoside diphosphate kinase. The possible occurrence of a sucrose synthase pathway for sucrose utilization under anoxia is discussed. © 1997 Annals of Botany Company