Adenosine Triphosphate Utilization Research Articles

The Warburg Effect Reinterpreted 100 yr on: A First-Principles Stoichiometric Analysis and Interpretation from the Perspective of ATP Metabolism in Cancer Cells.

The Warburg Effect is a longstanding enigma in cancer biology. Despite the passage of 100 yr since its discovery, and the accumulation of a vast body of research on the subject, no convincing biochemical explanation has been given for the original observations of aerobic glycolysis in cancer cell metabolism. Here, we have worked out a first-principles quantitative analysis of the problem from the principles of stoichiometry and available electron balance. The results have been interpreted using Nath's unified theory of energy coupling and adenosine triphosphate (ATP) synthesis, and the original data of Warburg and colleagues have been analyzed from this new perspective. Use of the biomass yield based on ATP per unit substrate consumed, [Formula: see text], or the Nath-Warburg number, NaWa has been shown to excellently model the original data on the Warburg Effect with very small standard deviation values, and without employing additional fitted or adjustable parameters. Based on the results of the quantitative analysis, a novel conservative mechanism of synthesis, utilization, and recycling of ATP and other key metabolites (eg, lactate) is proposed. The mechanism offers fresh insights into metabolic symbiosis and coupling within and/or among proliferating cells. The fundamental understanding gained using our approach should help in catalyzing the development of more efficient metabolism-targeting anticancer drugs.

Evidence for inefficient contraction and abnormal mitochondrial activity in sarcopenia using magnetic resonance spectroscopy.

Mitochondrial dysfunction has been implicated in sarcopenia. 31 P magnetic resonance spectroscopy (MRS) enables non-invasive measurement of adenosine triphosphate (ATP) synthesis rates to probe mitochondrial function. Here, we assessed muscle energetics in older sarcopenic and non-sarcopenic men and compared with muscle biopsy-derived markers of mitochondrial function. Twenty Chinese men with sarcopenia (SARC, age=73.1±4.1years) and 19 healthy aged and sex-matched controls (CON, age=70.3±4.2years) underwent assessment of strength, physical performance, and magnetic resonance imaging. Concentrations of phosphocreatine (PCr), ATP and inorganic phosphate (Pi) as well as muscle pH were measured at rest and during an interleaved rest-exercise protocol to probe muscle mitochondrial function. Results were compared to biopsy-derived mitochondrial complex activity and expression to understand underlying metabolic perturbations. Despite matched muscle contractile power (strength/cross-sectional area), the ATP contractile cost was higher in SARC compared with CON (low-intensity exercise: 1.06±0.59 vs. 0.57±0.22, moderate: 0.93±0.43 vs. 0.58±0.68, high: 0.70±0.57 vs. 0.43±0.51mmolL-1 min-1 bar-1 cm-2 , P=0.003, <0.0001 and <0.0001, respectively). Post-exercise mitochondrial oxidative synthesis rates (a marker of mitochondrial function) tended to be longer in SARC but did not reach significance (17.3±6.4 vs. 14.6±6.5mmolL-1 min-1 , P=0.2). However, relative increases in end-exercise ADP in SARC (31.8±9.9 vs. 24.0±7.3mmolL-1 , P=0.008) may have been a compensatory mechanism. Mitochondrial complex activity was found to be associated with exercise-induced drops in PCr [citrate synthetase activity (CS), Spearman correlation rho=-0.42, P=0.03] and end-exercise ADP (complex III, rho=-0.52, P=0.01; CS rho=-0.45, P=0.02; SDH rho=-0.45, P=0.03), with CS also being strongly associated with the PCr recovery rate following low intensity exercise (rho=-0.47, P=0.02), and the cost of contraction at high intensity (rho=-0.54, P=0.02). Interestingly, at high intensity, the fractional contribution of oxidative phosphorylation to exercise was correlated with activity in complex II (rho=0.5, P=0.03), CS (rho=0.47, P=0.02) and SDH (rho=0.46, P=0.03), linking increased mitochondrial complex activity with increased ability to generate energy through oxidative pathways. This study used 31 P MRS to assess ATP utilization and resynthesis in sarcopenic muscle and demonstrated abnormal increases in the energy cost during exercise and perturbed mitochondrial energetics in recovery. Associations between mitochondrial complex activity and the fractional contribution to energy requirement during exercise indicate increased ability to generate energy oxidatively in those with better mitochondrial complex activity.

Effects of sex and APOE ε4 genotype on brain mitochondrial high-energy phosphates in midlife individuals at risk for Alzheimer's disease: A 31Phosphorus MR spectroscopy study.

Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer's disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40-65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men's brains to a similar metabolic range as women's brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.

Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load

Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer’s disease (AD) in women. We conducted 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aβ) 11C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aβ load were not significant, individuals with the highest Aβ load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging.

Study on community structure and metabolic mechanism of dominant polyphosphate-accumulating organisms (PAOs) and glycogen-accumulating organisms (GAOs) in suspended biofilm based on phosphate recovery

Biofilm sequencing batch reactor (BSBR) can achieve efficient phosphate (P) removal and enrichment, but its process performance and metabolic mechanisms for P removal and enrichment of municipal wastewater remain largely unclear. In the present study, we assessed the P removal and enrichment of municipal wastewater at influent P concentrations of 2.5 mg/L and 10 mg/L. The efficiency of P removal and enzyme activity in polyphosphate-accumulating organisms (PAOs) and glycogen-accumulating organisms (GAOs) were compared, and the growth and metabolic characteristics of dominant PAOs and GAOs at different influent P concentrations were studied with the macro-sequencing technology. The results showed that the P recovery efficiencies were 70.03% and 76.19% when the influent P concentration was 2.5 mg/L and 10 mg/L in BSBR, respectively, and the maximum P concentration of recovery liquid was 81.29 mg/L and 173.12 mg/L, respectively. There were no phosphate kinase (PPK) and phosphate hydrolase (PPX) in extracellular polymeric substances (EPS). The dominant PAOs were Candidatus_Contendobacter, Dechloromonas, and Flavobacterium, and the dominant GAO was Candidatus_Competibacter. The abundance of Candidatus_Contendobacter was the highest with the most potential contribution to P removal. PAOs had competitive advantages in carbon (C) source uptake, glycogen metabolism, P metabolism, and adenosine triphosphate (ATP) metabolism. HMP was unique to PAOs, EMP had the highest abundance in glycogen metabolism, and ED was contained in PAOs of BSBR. These results indicated that BSBR provided sufficient reducing power and ATP for PAOs through different glycogen decomposition pathways to promote P uptake and obtained competitive advantages in P metabolism, C source uptake, and ATP utilization to achieve efficient P removal and enrichment. Collectively, our current findings provided valuable insights into the P removal and enrichment mechanism of BSBR in municipal sewage.

Oral dextrose reduced procedural pain without altering cellular ATP metabolism in preterm neonates: a prospective randomized trial

ObjectiveTo examine the effects of 30% oral dextrose on biochemical markers of pain, adenosine triphosphate (ATP) degradation, and oxidative stress in preterm neonates experiencing a clinically required heel lance.Study designUtilizing a prospective study design, preterm neonates that met study criteria (n = 169) were randomized to receive either (1) 30% oral dextrose, (2) facilitated tucking, or (3) 30% oral dextrose and facilitated tucking 2 min before heel lance. Plasma markers of ATP degradation (hypoxanthine, uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the premature infant pain profile-revised (PIPP-R).ResultsOral dextrose, administered alone or with facilitated tucking, did not alter plasma markers of ATP utilization and oxidative stress.ConclusionA single dose of 30% oral dextrose, given before a clinically required heel lance, decreased signs of pain without increasing ATP utilization and oxidative stress in premature neonates.

The role of thyroid hormone in metabolism and metabolic syndrome.

Metabolic syndrome (MetS) and thyroid dysfunction are common in clinical practice. The objectives of this review are to discuss some proposed mechanisms by which thyroid dysfunctions may lead to MetS, to describe the bidirectional relationship between thyroid hormones (THs) and adiposity and finally, to resume a list of recent studies in humans that evaluated possible associations between thyroid hormone status and MetS or its clinical components. Not solely THs, but also its metabolites regulate metabolic rate, influencing adiposity. The mechanisms enrolled are related to its direct effect on adenosine triphosphate (ATP) utilization, uncoupling synthesis of ATP, mitochondrial biogenesis, and its inotropic and chronotropic effects. THs also act controlling core body temperature, appetite, and sympathetic activity. In a bidirectional way, thyroid function is affected by adiposity. Leptin is one of the hallmarks, but the pro-inflammatory cytokines and also insulin resistance impact thyroid function and perhaps its structure. MetS development and weight gain have been positively associated with thyroid-stimulating hormone (TSH) in several studies. Adverse glucose metabolism may be related to hyperthyroidism, but also to reduction of thyroid function or higher serum TSH, as do abnormal serum triglyceride levels. Hypo- and hyperthyroidism have been related to higher blood pressure (BP), that may be consequence of genomic or nongenomic action of THs on the vasculature and in the heart. In summary, the interaction between THs and components of MetS is complex and not fully understood. More longitudinal studies controlling each of all confounding variables that interact with endpoints or exposure factors are still necessary.

Involvement of the phosphoryl transfer network in gill bioenergetic imbalance of pacamã (Lophiosilurus alexandri) subjected to hypoxia: notable participation of creatine kinase.

Hypoxia is among the most critical environmental stressors for fish in aquatic environments, and several energetic alterations have been associated with it. The aim of the present study was to evaluate the involvement of the phosphoryl transfer network and its effects on adenosine triphosphate (ATP)-dependent enzymes during hypoxia, as well as the role of oxidative stress in the activity of the phosphoryl transfer network in pacamã (Lophiosilurus alexandri) subjected to severe hypoxia. Branchial creatine kinase (CK; cytosolic and mitochondrial fractions), adenylate kinase (AK), and pyruvate kinase (PK) activities were inhibited after 72h of exposure to hypoxia compared to their respective normoxia groups, and remained low (except for AK) after 24 and 72h of re-oxygenation. Activities of the branchial sodium-potassium pump (Na+, K+-ATPase) and proton pump (H+-ATPase) were inhibited in fish exposed to 72h of hypoxia compared to the normoxia group, remained inhibited after 24h of re-oxygenation, and were restored to physiological levels after 72h of re-oxygenation. Levels of branchial reactive oxygen species (ROS) were higher in fish exposed to hypoxia for 72h compared to the normoxia group, and increased during re-oxygenation. Lipid peroxidation (LOOH) levels were higher in fish subjected to 72h of hypoxia compared to the normoxia group, and remained higher during re-oxygenation. On the other hand, protein sulfhydryl (PSH) levels were lower in fish exposed to hypoxia for 72h compared to the normoxia group, and remained low during re-oxygenation. Based on this evidence, inhibition of the activities of enzymes belonging to phosphoryl transfer network contributed to impairing energetic homeostasis linked to ATP production and ATP utilization in gills of pacamã subjected to hypoxia, and remained inhibited during re-oxygenation (except AK activity). Moreover, inhibition of the phosphoryl transfer network impaired activity of ATP-dependent enzymes, which can be mediated by ROS overproduction, lipid peroxidation, and oxidation of SH groups.

Tissue oxidative damage mediates impairment on phosphotransfer network during thymol intake: Effects on hepatic and renal bioenergetics

Recent evidences demonstrated that ingestion of several monoterpenes cause hepatic and renal damage due to impairment on mitochondrial energy production, eliciting a collapse on adenosine triphosphate (ATP) synthesis and consequently impairment on bioenergetic homeostasis. Thus, the aim of this study was to evaluate whether phosphotransfer network, catalyzed by creatine kinase (CK), adenylate kinase (AK), and pyruvate kinase (PK), can be a pathway to explain hepatic and renal bioenergetics homeostasis impairment due to thymol ingestion. Daily intake of thymol (40 mg/kg) significantly cause a decreased kidney weight and relative kidney weight compared to control group. The same dose of thymol inhibited renal cytosolic and mitochondrial CK activity as well as renal PK activity compared to control group. Finally, thymol (40 mg/kg) elicited a significant increase on renal reactive oxygen species and lipid damage levels, as well as an inhibition on antioxidant capacity against peroxyl radicals and non-protein thiol levels, which did not occur liver. Doses of 10 and 20 mg/kg of thymol administered orally for 30 consecutive days non-changed these variables. Based on these evidence, the data supported that intake of a high dose of thymol severely inhibits cytosolic and mitochondrial CK activity, a crucial enzyme to maintain cellular energy homeostasis. Moreover, high dietary thymol intake impaired communication between CK isoenzymes, which inhibits the attempts to regenerate ATP or to facilitate the CK/PCr shuttle to improve the intracellular ATP utilization and consumption. Moreover, the inhibition of renal CK and PK activities appears to be mediated by the renal oxidation of lipids and thiol groups, as well as by the reduction of the renal antioxidant capacity.

Changes in the cerebral phosphotransfer network impair energetic homeostasis in an aflatoxin B1-contaminated diet.

The phosphotransfer network system, through the enzymes creatine kinase (CK), adenylate kinase (AK), and pyruvate kinase (PK), contributes to efficient intracellular energetic communication between cellular adenosine triphosphate (ATP) consumption and production in tissues with high energetic demand, such as cerebral tissue. Thus, the aim of this study was to evaluate whether aflatoxin B1 (AFB1) intoxication in diet negatively affects the cerebral phosphotransfer network related to impairment of cerebral ATP levels in silver catfish (Rhamdia quelen). Brain cytosolic CK activity decreased in animals fed with a diet contaminated with AFB1 on days 14 and 21 post-feeding, while mitochondrial CK activity increased, when compared to the control group (basal diet). Also, cerebral AK and PK activity decreased in animals fed with a diet contaminated with AFB1 on days 14 and 21 post-feeding, similarly to the results observed for cerebral ATP levels. Based on this evidence, inhibition of cerebral cytosolic CK activity is compensated by stimulation of mitochondrial CK activity in an attempt to prevent impairment of communication between sites of ATP generation and ATP utilization. The inhibition of cerebral AK and PK activity leads to impairment of cerebral energy homeostasis, decreasing the brain's ATP availability. Moreover, the absence of a reciprocal compensatory mechanism between these enzymes contributes to cerebral energetic imbalance, which may contribute to disease pathophysiology.

Streptococcus agalactiae alters cerebral enzymes of phosphoryl transfer network in experimentally infected silver catfish: Impairment on brain energy homeostasis

It is recognized that phosphoryl transfer network, through the activities of creatine kinase (cytosolic and mitochondrial CK), adenylate kinase (AK) and pyruvate kinase (PK), provides new perspectives to understand the disturbances of energetic metabolism between sites of generation and utilization of adenosine triphosphate (ATP). Thus, the aim of this study was to evaluate the involvement of phosphoryl transfer network in the pathophysiology of Streptococcus agalactiae linked with central nervous system (CNS). Cerebral cytosolic and mitochondrial CK activities decreased in infected animals compared to uninfected animals, similarly to observed by cerebral AK and PK activities. Moreover, the cerebral ATP levels decreased in infected animals compared to uninfected animals. Based on these evidences, the inhibition and absence of efficient nucleocytoplasmic communication between CK isoenzymes caused an impairment on cerebral energetics. Moreover, the inhibition on hepatic AK and PK caused an impairment of communication between sites of ATP generation and ATP utilization, which is corroborated by cerebral ATP depletion. In summary, these alterations contribute to disease pathogenesis linked to CNS during fish streptococcosis.

Ichthyophthirius multifiliis impairs splenic enzymes of the phosphoryl transfer network in naturally infected Rhamdia quelen: effects on energetic homeostasis.

Its integrated energetic and metabolic signaling roles place the phosphoryl transfer network, through the enzymes creatine kinase (CK), adenylate kinase (AK), and pyruvate kinase (PK), as a regulatory system coordinating components of the cellular bioenergetics network. Analysis of these enzymes provides new information and perspectives with which to understand disturbances in energetic metabolism between sites of adenosine triphosphate (ATP) generation and utilization. Thus, the aim of this study was to evaluate the involvement of the phosphoryl transfer network in splenic tissue linked with the pathogenesis of silver catfish naturally infected with Ichthyophthirius multifiliis. Splenic cytosolic and mitochondrial CK activities decreased in infected animals compared to uninfected animals, as was also observed for splenic PK activity and splenic ATP levels. In contrast, splenic AK activity increased in infected animals compared to uninfected animals. Based on this evidence, the inhibition and absence of efficient communication between CK isoenzymes cause the impairment of splenic bioenergetics, which is in turn compensated by the augmentation of splenic AK activity in an attempt to restore energy homeostasis. The inhibition of splenic PK activity impairs communication between sites of ATP generation and ATP utilization, as corroborated by splenic ATP depletion. In summary, these alterations contribute to disease pathogenesis linked to spleen tissue in animals infected with white spot disease.

Aeromonas caviae inhibits hepatic enzymes of the phosphotransfer network in experimentally infected silver catfish: Impairment on bioenergetics.

Several studies have been demonstrated that phosphotransfer network, through the adenylate kinase (AK) and pyruvate kinase (PK) activities, allows for new perspectives leading to understanding of disease conditions associated with disturbances in energy metabolism, metabolic monitoring and signalling. In this sense, the aim of this study was to evaluate whether experimental infection by Aeromonas caviae alters hepatic AK and PK activities of silver catfish Rhamdia quelen. Hepatic AK and PK activities decreased in infected animals compared to uninfected animals, as well as the hepatic adenosine triphosphate (ATP) levels. Also, a severe hepatic damage was observed in the infected animals due to the presence of dilation and congestion of vessels, degeneration of hepatocytes and loss of liver parenchyma architecture and sinusoidal structure. Therefore, we have demonstrated, for the first time, that experimental infection by A.caviae inhibits key enzymes linked to the communication between sites of ATP generation and ATP utilization. Moreover, the absence of a reciprocal compensatory mechanism between these enzymes contributes directly to hepatic damage and for a severe energetic imbalance, which may contribute to disease pathophysiology.

Human Cardiac 31P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise.

Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is a unique non-invasive imaging modality for probing in vivo high-energy phosphate metabolism in the human heart. We investigated whether current 31P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized 31P-MRS methods [3D image-selected in vivo spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans (n = 8) at rest were determined on a clinical 3 Tesla MR system. Numerical simulations of myocardial energy homeostasis in response to increased cardiac work rates were performed using a biophysical model of myocardial oxidative metabolism. Hypertrophic cardiomyopathy was modeled by either inefficient sarcomere ATP utilization or decreased mitochondrial ATP synthesis. The effect of creatine depletion on myocardial energy homeostasis was explored for both conditions. The mean in vivo myocardial PCr/ATP ratio measured with 3D ISIS was 1.57 ± 0.17 with a large repeatability coefficient of 40.4%. For 1D CSI in a 1D ISIS-selected slice perpendicular to the surface coil, the PCr/ATP ratio was 2.78 ± 0.50 (repeatability 42.5%). With 1D CSI in a 1D ISIS-selected slice parallel to the surface coil, the PCr/ATP ratio was 1.70 ± 0.56 (repeatability 43.7%). The model predicted a PCr/ATP ratio reduction of only 10% at the maximal cardiac work rate in normal myocardium. Hypertrophic cardiomyopathy led to lower PCr/ATP ratios for high cardiac work rates, which was exacerbated by creatine depletion. Simulations illustrated that when conducting cardiac 31P-MRS exercise stress testing with large measurement error margins, results obtained under pathophysiologic conditions may still lie well within the 95% confidence interval of normal myocardial PCr/ATP dynamics. Current measurement precision of localized 31P-MRS for quantification of the myocardial PCr/ATP ratio precludes the detection of the changes predicted by computational modeling. This hampers clinical employment of 31P-MRS for diagnostic testing and risk stratification, and warrants developments in cardiac 31P-MRS exercise stress testing methodology.

Oral sucrose for heel lance enhances adenosine triphosphate use in preterm neonates with respiratory distress

Objective:To examine the effects of oral sucrose on procedural pain, and on biochemical markers of adenosine triphosphate utilization and oxidative stress in preterm neonates with mild to moderate respiratory distress.Study design:Preterm neonates with a clinically required heel lance that met study criteria (n = 49) were randomized into three groups: (1) control (n = 24), (2) heel lance treated with placebo and non-nutritive sucking (n = 15) and (3) heel lance treated with sucrose and non-nutritive sucking (n = 10). Plasma markers of adenosine triphosphate degradation (hypoxanthine, xanthine and uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the Premature Infant Pain Profile. Data were analyzed using repeated measures analysis of variance, chi-square and one-way analysis of variance.Results:We found that in preterm neonates who were intubated and/or were receiving ⩾30% FiO2, a single dose of oral sucrose given before a heel lance significantly increased markers of adenosine triphosphate use.Conclusion:We found that oral sucrose enhanced adenosine triphosphate use in neonates who were intubated and/or were receiving ⩾30% FiO2. Although oral sucrose decreased pain scores, our data suggest that it also increased energy use as evidenced by increased plasma markers of adenosine triphosphate utilization. These effects of sucrose, specifically the fructose component, on adenosine triphosphate metabolism warrant further investigation.

Inhaled Beta2-Agonist Increases Power Output and Glycolysis during Sprinting in Men.

The aim of the present study was to investigate the effects of the beta2-agonist terbutaline (TER) on power output and muscle metabolism during maximal sprint cycling. In a randomized double-blind cross-over design, nine moderately trained men (VO2max = 4.6 ± 0.2 L · min(-1)) conducted a 10-s cycle sprint after inhalation of either 15 mg of TER or placebo (PLA). A muscle biopsy sample was collected before and <10 s after the sprint and was analyzed for metabolites. The mean power and peak power during the sprint were 8.3% ± 1.1% and 7.8% ± 2.5% higher (P < 0.05) with TER than with PLA, respectively. Moreover, the net rates of glycogenolysis (6.5 ± 0.8 vs 3.1 ± 0.7 mmol glucosyl units · kg dry weight(-1) · s(-1)) and glycolysis (2.4 ± 0.2 vs 1.6 ± 0.2 mmol glucosyl units · kg dry weight(-1) · s(-1)) were higher (P < 0.05) with TER than with PLA. After the sprint, adenosine triphosphate (ATP) was reduced with PLA (P < 0.05) but not with TER. During the sprint, there was no difference in the breakdown of phosphocreatine (PCr) between treatments. Estimated anaerobic ATP utilization was 9.2% ± 4.0% higher (P < 0.05) with TER than with PLA. After the sprint, ATP in Type II fibers was lowered (P < 0.05) by 25.7% ± 7.3% with PLA but was not reduced with TER. Before the sprint, PCr in Type II fibers was 24.5% ± 7.2% lower (P < 0.05) with TER than with PLA. With PLA, breakdown of PCr was 50.2% ± 24.8% higher (P < 0.05) in Type II fibers (vs Type I fibers), whereas no difference was observed between fiber types with TER. The present study shows that a TER-induced increase in power output is associated with increased rates of glycogenolysis and glycolysis in skeletal muscles. Furthermore, as TER counteracts a reduction in ATP in Type II fibers, TER may postpone fatigue development in these fibers.

Adenosine’s Autacoid Function in the Central Nervous System and the Behavioral State of Conservation-Withdrawal

The purine nucleoside adenosine has the critical autacoid function of directly linking cellular excitability to energy availability. The mechanism is activated whenever the rate of adenosine triphosphate (ATP) utilization exceeds the rate of synthesis. In CNS neurons, adenosine is produced by the rapid intracellular hydrolysis of purine nucleotides during neural excitation and then is extruded into extracellular space. The nucleoside is also produced by the extracellular hydrolysis of ATP by ectonucleotidases. Extracellular adenosine interacts with G-protein linked stereospecific receptors to reestablish metabolic homeostasis by exerting extraordinarily potent inhibition of neural excitation via a number of mechanisms. This autacoid mechanism is directly linked to the production of a depression like behavioral state termed conservation-withdrawal during times of physical stress or severe emotional distress. We review evidence here that adenosine produces a transition to conservation-withdrawal by activation of A2A receptors in the ventral-medial striatum.

The Electrophysiological Properties of Ranolazine: A Metabolic Anti-Ischemic Drug or an Energy-Efficient Antiarrhythmic Agent?

Ranolazine, a newer anti-ischemic agent that appears to induce a more efficient utilization of adenosine triphosphate at the cellular level, has been shown to be clinically beneficial in patients with chronic stable angina. More recently, the antiarrhythmic effects of the drug have been described in patients with acute coronary syndromes, as well as in those with atrial fibrillation, when combined with other agents. Experimentally, the predominant inhibitory effects on late I(Na), I(Ca), I(Na-Ca), and I(Ks), with little or no effect on I(to) or I(K1), have been demonstrated. Different experimental models have shown the potential beneficial effect of the drug in both supraventricular and ventricular arrhythmias. Interestingly, despite its potential prolongation of the QT interval, ranolazine does not appear to induce ventricular arrhythmias in animal models. Whether the antiarrhythmic effect is secondary to a more efficient energy production by the cardiac cell or by its direct effect on ion channels is still unclear. The effect of ranolazine on other ionic currents, as well as its potential as a clinically relevant antiarrhythmic agent, still needs to be studied.

An Animal Model for Measuring the Effect of Common NICU Procedures on ATP Metabolism

Neonates exposed to common neonatal intensive care unit (NICU) procedures show alterations in heart rate, blood pressure, and oxygen saturation. However, it is unclear if these physiologic changes increase adenosine triphosphate (ATP) utilization, thus potentially increasing the risk for tissue hypoxia in medically fragile neonates. Plasma uric acid is a commonly used marker of increased ATP utilization because uric acid levels increase when ATP consumption is enhanced. To examine the effect of a common NICU procedure on plasma uric acid concentration, we developed a model that allows for acute monitoring of this biochemical marker in plasma in 7- to 9-day-old rabbits. In our pilot study, we exposed neonatal rabbits to a single heel lance 2.5 hr after catheter placement. We measured uric acid concentration before and 30 min after the heel lance and compared findings to levels in control animals not exposed to the heel lance. Our pilot data shows a significant difference in uric acid concentration over time between the control and heel lance groups (46.2 ± 7.1 μM vs. 54.7 ± 5.8 μM, respectively, p = .027). Calculation of percentage change from baseline showed uric acid concentration increasing in rabbits exposed to heel lance and decreasing in control rabbits (1.5 ± 4.7% vs. -16.1 ± 4.2%, respectively, p = .03). These data suggest that this animal model can be successfully used to examine the biochemical effect of common NICU procedures, such as heel lance, on markers of ATP breakdown and purine metabolism.

Adenosine Receptor-Mediated Cardioprotection

Adenosine is a purine nucleoside, which is produced primarily through the metabolism of adenosine triphosphate (ATP), therefore its levels increase during stressful situations when ATP utilization increases. Adenosine exerts potent cardioprotective effects on the ischemic/reperfused heart, reducing reversible and irreversible myocardial injury. Adenosine receptors (ARs) are G-protein-coupled receptors, and 4 subtypes exist--A(1), A(2A), A(2B), and A(3), all of which have been shown to be cardioprotective. Adenosine receptors are expressed on multiple cardiac cells, including fibroblasts, endothelial cells, smooth muscle cells, and myocytes. Activation of both A(1) and A(3) receptors prior to ischemia has been shown in multiple experimental models to reduce ischemia/reperfusion-induced cardiac injury. Additionally, activation of the A(2A) receptor at the onset of reperfusion has been shown to reduce injury. Most recently, there is evidence that the A(2B) receptor has cardioprotective effects upon its activation. However, controversy remains regarding the precise timing of activation of these receptors required to induce cardioprotection, as well as their involvement in ischemic preconditioning and postconditioning. Adenosine receptors have been suggested to reduce cell death through actions at the mitochondrial ATP-dependent potassium (K(ATP)) channel, as well as protein kinase C and mitogen-activated protein kinase (MAPK) signaling. Additionally, the ability of ARs to interact has been documented, and several recent reports suggest that these interactions play a role in AR-mediated cardioprotection. This review summarizes the current knowledge of the cardioprotective effects of each AR subtype, as well as the proposed mechanisms of AR cardioprotection. Additionally, the role of AR interactions in cardioprotection is discussed.