Impaired Oxidative Metabolism Research Articles

Cerebral Blood Flow and Oxygen Metabolism in Rett Syndrome

Positron emission tomography was performed on six patients with Rett syndrome to investigate cerebral blood flow and oxygen metabolism, and the results were compared with the concurrent clinical status of the patients. The cerebral metabolic rate of oxygen (CMRO2) was low in five patients, and oxygen extraction fraction was low in four patients; both had a tendency to decline with advancing age. Although the cause is unknown, it is suggested that impaired oxidative metabolism exists in Rett syndrome. An analysis of the distribution among brain regions showed that the ratios of values for the frontal cortex to those for the temporal cortex for both cerebral blood flow and CMRO2 were lower than those for the controls, which may indicate the loss of hyperfrontality in Rett syndrome.

Neutrophil dysfunction in glycogen storage disease Ib: Association with Crohn's-like colitis

Two cases of patients with Crohn's-like colitis and glycogen storage disease Ib have been reported previously. In the current report, chronic inflammatory bowel disease that developed in another adolescent with this glycogenosis is described, thereby corroborating the association. The neutrophil dysfunction observed in glycogen storage disease Ib is the most likely predisposing factor. Neutrophil function was investigated in our patient in an attempt to shed light on the pathogenesis of his intestinal inflammation. The patient displayed reduced neutrophil chemotaxis to zymosan-activated serum, N-formyl-methionine-phenylalanine, and Escherichia coli bacteria-derived factor and reduced intracellular killing of Staphylococcus aureus 502A. Others have found this defective bacteriocidal activity to be caused by impaired oxidative metabolism. The recent recognition of chronic inflammatory bowel disease in glycogen storage disease Ib, as well as in chronic granulomatous disease, suggests that further study of respiratory burst activity of neutrophils in Crohn's disease is warranted.

Impaired oxidative metabolism increases adenine nucleotide breakdown in McArdle's disease

Two patients with muscle phosphorylase deficiency [McArdle's disease (McA)] were studied during bicycle exercise at 40 (n = 2) and 60 W (n = 1). Peak heart rate was 170 and 162 beats/min, corresponding to approximately 90% of estimated maximal heart rate. Muscle samples were taken at rest and immediately after exercise from the quadriceps femoris. Lactate content remained low in both muscle and blood. Acetylcarnitine, which constitutes a readily available form of acetyl units and thus a substrate for the tricarboxylic acid cycle, was very low in McA patients both at rest and during exercise, corresponding to approximately 17 and 11%, respectively, of that in healthy subjects. Muscle NADH was unchanged during exercise in McA patients in contrast to healthy subjects, in whom NADH increases markedly at high exercise intensities. Despite low lactate levels, arterial plasma NH3 and muscle inosine 5'-monophosphate increased more steeply relative to work load in McA patients than in healthy subjects. The low postexercise levels of lactate, acetylcarnitine, and NADH in McA patients support the idea that exercise performance is limited by the availability of oxidative fuels. Increases in muscle inosine 5'-monophosphate and plasma NH3 indicate that lack of glycogen as an oxidative fuel is associated with adenine nucleotide breakdown and increased deamination of AMP. It is suggested that the early onset of fatigue in McA patients is caused by an insufficient rate of ADP phosphorylation, resulting in transient increases in ADP.

Impaired Oxidative Metabolism of Salicylate in Reye’s Syndrome

Administration of salicylates during prodromal viral illness has been associated with the development of Reye's syndrome (RS). We studied salicylate biotransformation in RS patients and compared it with those on chronic salicylate therapy for juvenile rheumatoid arthritis (JRA). Urine of RS patients contained significantly more salicylic acid and less gentisic acid than that of JRA patients while the conjugated metabolites were not different between the two groups. These results suggest decreased salicylate microsomal oxidation in RS. The role of altered salicylate metabolism in the pathogenesis of RS is unclear.

Human interleukin-1 beta induced stimulation of insulin release from rat pancreatic islets is accompanied by an increase in mitochondrial oxidative events.

Acute exposure of pancreatic islets to interleukin-1 beta results in an increase in insulin release, while an extension of the exposure time induces a functional suppression and eventually, destruction of the B-cells. We have recently suggested that the interleukin-1 beta induced inhibition of islet function is mediated through an impairment in oxidative metabolism. The aim of the current study was to investigate if the acute, stimulatory effects of interleukin-1 beta on islet function could also be related to changes in the substrate metabolism. For this purpose, rat islets were exposed for 90-120 min to 30 pmol/l human recombinant interleukin-1 beta (biological activity of 2.5 U/ml) and their function and metabolism characterized during this period. The cytokine did not increase insulin release in the presence of 1.7 or 5.5 mmol/l glucose but in both the presence of 16.7 mmol/l glucose or 10 mmol/l leucine + 2 mmol/l glutamine there was a 50% increase in insulin release. Interleukin-1 beta exposure increased the oxidation of D-[U-14C]glucose at 5.5 mmol/l glucose by 25% and at 16.7 mmol/l glucose by 60%. Carbohydrate and amino acid metabolism were further examined in the presence of D-[5-3H]glucose, D-[6-14C]glucose, [1-14C]pyruvate, L-[U-14C]glutamine, L-[U-14C]leucine and L-[1-14C]leucine. There was no difference between control islets and interleukin-1 beta exposed islets in terms of D-[5-3H]glucose utilization or [1-14C]pyruvate decarboxylation, but the oxidation of D-[6-14C]glucose was increased by 64% in the interleukin-1 beta exposed islets.(ABSTRACT TRUNCATED AT 250 WORDS)

Long‐term coenzyme Q 10 therapy for a mitochondrial encephalomyopathy with cytochrome c oxidase deficiency

For 2 years we administered high doses of coenzyme Q10 (CoQ) to a patient having mitochondrial encephalomyopathy with cytochrome c oxidase deficiency. Abnormal elevation of the serum lactate per pyruvate ratio and the increased concentration of serum lactate plus pyruvate induced by exercise decreased with CoQ treatment. This therapeutic effect continued for 2 years. 31P nuclear magnetic resonance spectroscopy showed acceleration of the postexercise recovery of the ratio of phosphocreatine to inorganic phosphate in muscle during CoQ treatment. These observations support the beneficial effect of CoQ on the impaired mitochondrial oxidative metabolism in muscle. Also, impaired central and peripheral nerve conductivities consistently improved during CoQ treatment. These results indicate that CoQ has clinical value in the long-term management of patients with mitochondrial encephalomyopathies, even though there are clinical limitations to the effects of this therapy.

Intracellular activity of cefamandole and aztreonam against phagocytosed Escherichia coli and Staphylococcus aureus.

The intracellular activity of cefamandole and aztreonam against phagocytosed Escherichia coli and cefamandole against phagocytosed Staphylococcus aureus was studied using a sensitive and standardized method of murine peritoneal macrophages. Cefamandole and aztreonam exerted an intracellular antibacterial activity against E. coli which was greater than their extracellular one. With concentrations of both antibiotics up to 16 x MBC a dose-dependent decrease of the initial number of intracellular E. coli which ranged from 32% to 90% was observed. However, similar antibiotic concentrations above the MBC affected the viability of extracellular E. coli by only 20% to 30%. The intracellular antibacterial activity of both antibiotics against E. coli was further enhanced by immune serum. Cefamandole at 4 x the MBC did not affect the survival of intracellular S. aureus, but killed 41% of extracellular bacteria by 1 h and 99% after 3 h. The intracellular activity of both antibiotics against E. coli was also maintained in NaF-pulsed macrophages which have an impaired oxidative metabolism. The data suggest that both cefamandole and aztreonam possess an intracellular antibacterial activity against E. coli that seems at least in part due to a positive cooperation of antibiotics with the O2-independent microbicidal system of macrophages.

Impaired mitochondrial oxidative energy metabolism following paracetamol‐induced hepatotoxicity in the rat

1. Effects of paracetamol treatment in vivo at subtoxic (375 mg kg-1 body weight) and toxic (750 mg kg-1 body weight) doses on energy metabolism in rat liver mitochondria were examined. 2. Paracetamol treatment resulted in a significant loss in body weights without affecting the liver protein contents. Toxic doses, however, resulted in 21% decrease in the yield of mitochondrial proteins. 3. Subtoxic doses of paracetamol did not, in general, affect the respiratory parameters in the liver mitochondria except in the case of succinate where both the state 3 respiration and the ADP-phosphorylation rates increased by 28%. 4. Toxic doses of paracetamol caused 25 to 47% decrease in the state 3 respiration rates depending on the substrate used. ADP/O ratios also decreased significantly with pyruvate + malate and succinate as the substrates. Consequently, ADP-phosphorylation was impaired significantly from 20 to 63%. 5. Subtoxic doses of paracetamol resulted in increased contents of cytochrome c + c1 while the toxic doses caused lowering of the cytochromes aa3 and b contents. 6. Glutamate and succinate dehydrogenase activities decreased in both the experimental groups while Mg2+-ATPase activity was impaired only after toxic dose-treatment. 7. The results show that toxic doses of paracetamol result in impaired energy coupling in the liver mitochondria. Effects of subtoxic doses were also demonstrable in terms of impaired dehydrogenases activities.

Pharmacokinetics of diltiazem in patients with liver cirrhosis.

The pharmacokinetics of diltiazem (DTZ) was investigated in seven control subjects with normal liver function and in seven patients with liver cirrhosis. After long-term oral administration of diltiazem, 30 or 60 mg thrice daily, serum levels of DTZ and its active metabolites, deacetyl DTZ (DAD) and N-demethyl DTZ (DMD), were determined by high performance liquid chromatography. The mean peak serum concentrations (nmol/L) in control patients were 280 for DTZ, 58 for DAD and 101 for DMD. In cirrhotic patients, the serum DTZ tended to increase and the DAD increased (p less than 0.05), while the DMD decreased (p less than 0.05) compared with that of the control (335 for DTZ, 133 for DAD and 77 for DMD, nmol/L). Pharmacokinetic analysis using a one-compartment model revealed no change in the absorption, but a decrease in the elimination for cirrhotic patients (t 1/2; 5.3 to 7.2 h, p less than 0.1). The elimination rate constant correlated with some biochemical indices for hepatocyte function. These results may be explained by the impaired oxidative metabolism of diltiazem in liver cirrhosis.

Interleukin-1 induced impairment in pancreatic islet oxidative metabolism of glucose is potentiated by tumor necrosis factor.

Recent observations suggest that human interleukin-1 (IL-1) causes functional impairment and death of pancreatic B-cells. This action seems to be potentiated by another cytokine, tumor necrosis factor (TNF). In the present investigation, the effects of recombinant human (r)IL-1 (10, 30 and 150 pmol/l), and a combination of rIL-1 and human rTNF (25 micrograms/l), on islet glucose metabolism were examined in the presence of D-[5-3H] and D-[6-14C) glucose. The utilization of glucose was not affected by rIL-1 or rIL-1 plus rTNF. However, rIL-1 induced a 40% decrease in glucose oxidation, which was further potentiated by the addition of rTNF. rTNF alone did not impair islet glucose utilization or oxidation. It is concluded that rIL-1 induces a perturbation of islet glucose handling, mainly at the mitochondrial level. This impairment in the oxidative metabolism of glucose is further increased by the addition of rTNF.

Carnitine metabolism during exercise in patients with peripheral vascular disease.

The distribution between carnitine and the acyl derivatives of carnitine reflects changes in the metabolic state of a variety of tissues. Patients with peripheral vascular disease (PVD) develop skeletal muscle ischemia with exertion. This impairment in oxidative metabolism during exercise may result in the generation of acylcarnitines. To test this hypothesis, 11 patients with PVD and 7 age-matched control subjects were evaluated with graded treadmill exercise. Subjects with PVD walked to maximal claudication pain at a peak O2 consumption (VO2) of 19.9 +/- 1.3 ml X kg-1 X min-1 (mean +/- SE). Control subjects were taken to a near-maximal work load at a VO2 of 31.3 +/- 1.0 ml X kg-1 X min-1. In patients with PVD, the plasma concentration of total acid-soluble, long-chain acylcarnitine and total carnitine was increased at peak exercise compared with resting values. Four minutes postexercise, the plasma short-chain acylcarnitine concentration was also increased. In control subjects taken to the higher work load, only the long-chain acylcarnitine concentration was increased at peak exercise. In patients with PVD, plasma short-chain acylcarnitine concentration at rest was negatively correlated with subsequent maximal walking time (r = -0.51, P less than 0.05). In conclusion, acylcarnitines increased in patients with PVD who walked to maximal claudication pain, whereas control subjects did not show equivalent changes even when taken to a higher work load. The relationship between short-chain acylcarnitine concentration at rest and subsequent exercise performance suggests that repeated episodes of ischemia may cause chronic accumulation of short-chain acylcarnitine in plasma in proportion to the severity of disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Motility and oxidative metabolism of normal polymorphonuclear leukocytes in acute non-lymphoid leukemia in complete remission

Polymorphonuclear leukocytes (PMN) from 11 patients with acute non-lymphoid leukemia (ANLL) in complete remission and off therapy for at least 22 months were studied for their oxidative metabolism and motility. In all patients, PMN motility tests revealed no consistent abnormality, whereas cells from 2 patients showed a selective impairment of oxidative metabolism, as assessed by the low capacity to reduce nitroblue tetrazolium and/or to generate chemiluminescence when stimulated with phorbol myristate acetate. No morphological change was detectable in PMN from these patients. However, the functional alterations appeared related to an early tendency to relapse, as both patients developed an acute phase after 5 and 9 months from testing, respectively. This suggests that abnormal PMN may circulate in ANLL patients in complete remission in spite of a normal differential count and that functional studies may be useful for detecting such a population.

The pathophysiology of McArdle's disease: clues to regulation in exercise and fatigue.

Muscle phosphorylase deficiency (McArdle's disease) has conventionally been considered a disorder of glycogenolysis, and the associated impairment in oxidative metabolism has been largely overlooked. Muscle glycogen normally is the primary oxidative fuel at exercise work loads requiring more than 75-80% of maximal O2 uptake (VO2max). Evidence is presented to support the hypothesis that a limited flux through the Embden-Myerhof pathway in McArdle's disease reduces the capacity to generate NADH required to support a normal VO2max. The extent of the oxidative defect is substrate dependent; i.e., it can be partially corrected by increasing the availability of alternative oxidative substrates (e.g., glucose, free fatty acids) to working muscle. Experiments employing modification of substrate availability closely link the hyperkinetic circulatory response to exercise (i.e., an abnormally large increase in O2 transport to skeletal muscle) and the premature muscle fatigue and cramping of McArdle patients with their oxidative impairment and suggest that a metabolic common denominator in these abnormal responses may be a pronounced decline in the muscle phosphorylation potential ([ATP]/[ADP][Pi]). The hyperkinetic circulation likely is mediated by the local effects on metabolically sensitive skeletal muscle afferents and vascular smooth muscle of K+, Pi, or adenosine or a combination of these substances released excessively from working skeletal muscle. The premature muscle fatigue and cramping of McArdle patients does not appear to be due to depletion of ATP but is associated with an increased accumulation of Pi and probably ADP in skeletal muscle. Accumulations of Pi and ADP are known to inhibit the myofibrillar, Ca2+, and Na+-K+-ATPase reactions.

Evidence for induction of hepatic microsomal cytochrome P-450 by cimetidine: Binding and kinetic studies

The interaction of cimetidine with liver microsomes has been examined by spectral and equilibrium partition studies. First, difference spectroscopy has been used to evaluate the proportion of cytochrome P-450 in rat liver microsomes that exhibits an affinity for cimetidine in the pharmacologically relevant, low micromolar range of drug concentration. The value of 0.45 so obtained has confirmed that a substantial proportion of rat liver cytochrome P-450 has a high binding affinity for this drug. Second, a study of the binding of cimetidine to human liver microsomes by difference spectroscopy and partition equilibrium has detected a similar interaction, thus providing direct support for the postulate that the clinically observed impairment of oxidative drug metabolism may be due in part to inhibition of cytochrome P-450 monooxygenase by cimetidine. Hepatic microsomes from cimetidine-pretreated rats have been shown to exhibit elevated cytochrome P-450 specific content but a decreased proportion of sites with high affinity for the drug; this finding has been shown not to be the consequence of cimetidine-mediated, time-dependent, irreversible monooxygenase inhibition. Although cimetidine pretreatment caused enhanced specific activity of 7-ethoxyresorufin O-dealkylation, the specific activities for O-dealkylation of 7-ethoxycoumarin and 4-nitroanisole were decreased, as were those for the N-dealkylation of morphine, ethylmorphine, aminopyrine, and dimethylnitrosamine. Since cimetidine pretreatment was shown to cause no change in the Michaelis constants for oxidation of morphine or 7-ethoxyresorufin, it is argued that these results provide strong presumptive evidence for changes in the relative abundance of isoenzymes catalyzing these various oxidations. Thus, a dual role of cimetidine, acting both as inhibitor and inducer of the cytochrome P-450 system, is proposed to account for the impaired oxidative metabolism of some drugs that occurs during coadministration with this H 2-receptor antagonist.

P NMR evaluation of hypoxic stress in brain of animal models.

Quantification by NMR of hypoxic stress is best afforded by the ratio of phosphocreatine (PCr) to inorganic phosphate (Pi). The thin cranium and sternum of neonates affords ideal conditions for NMR evaluation of impaired oxidative metabolism. Brains of animal models (dog and cat) are best studied with muscles retracted with the rf coil placed on the bare skull. 31P and 1H (lactate) signals are time shared with a doubly tuned coil. Servo-stabilized hypoxia gives simplified steady state analysis. Hypoxic insults of the brain are evaluated by the integral of the deviation of the PCr/Pi ratio from the normoxic values. Generally, a deviation of 1 unit of PCr/Pi for an interval of 3 hr will lead to a severe metabolic damage and recovery from hypoxia is often 30-fold delayed. Comprehensive monitoring of energy metabolism (PCr/Pi), respiratory chain redox states, intracellular pH and lactate accumulation allow the calculation of integrated pH and lactate "insults" and thus offer new insights on the effects of hypoxia on brain oxidative metabolism.

Pyridoxine neuropathy in rats: specific degeneration of sensory axons.

When rats received pyridoxine in doses large enough to cause neuropathy in humans, the animals developed gait ataxia that subsided after the toxin was withdrawn. By using quantitative histologic techniques, we found axonal degeneration of sensory system fibers and that the fibers derived from the ventral root were spared. Although the degeneration approached the dorsal root ganglion, neurons in the ganglion did not degenerate. We found no early decrease in oxygen consumption of nerve, suggesting that impaired oxidative metabolism was not the primary event.

Phosphate loading attenuates renal tubular dysfunction induced by maleic acid in the dog.

The metabolic pathogenesis of the complex renal tubular dysfunction of type II renal tubular acidosis and Fanconi's syndrome (RTA II/FS) acutely induced by maleic acid could depend on the occurrence of a positive feedback loop in cells of the proximal renal tubule: impaired mitochondrial oxidation----increased glucose uptake----increased formation and concentration of phosphorylated glycolytic intermediates----limitation on availability of cellular inorganic phosphate----more severely impaired mitochondrial oxidative metabolism. To test this hypothesis we intravenously administered maleic acid both alone and after initiating intravenously administered neutral sodium phosphate, sodium sulfate, or sodium chloride to 10 unanesthetized trained female dogs undergoing water diuresis. We made the following observations: 1) Administration of maleic acid alone predictably induced dose-dependent increments in urine flow (V) and in renal clearance of HCO3-, Na+, K+, and alpha-aminonitrogen and a pronounced increase in the renal clearance and excretion of citrate. 2) Prior phosphate loading, which increased the plasma concentration of phosphate from 2.5 +/- 0.20 to 11.3 +/- 2 mg/dl: a) attenuated the increment in renal clearance of HCO3- by one-half even though the filtered load of bicarbonate was higher by 37%, owing to the higher values of both GFR and plasma bicarbonate concentration that obtained with phosphate loading; b) prevented the increment in renal clearance and excretion of alpha-aminonitrogen; c) significantly attenuated the increments in V and renal clearance of K+; but d) did not affect the increment in renal clearance and excretion of citrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Proximal tubule function in chronic serum sickness glomerulonephritis of rats.

Fatal immune complex glomerulonephritis can be induced in rats by chronic intravenous administration of bovine serum albumin. There are three distinct stages, mild, moderate, and severe, in the development of renal immunopathology and pathophysiology in this model of chronic serum sickness. The work described here was undertaken to evaluate aspects of proximal tubule function in those different stages. Tissue water distribution, oxidative metabolism, and transport of representative organic anions and cations were measured in renal cortical slices. In mild chronic serum sickness all functions were normal except the transport of p-aminohippurate (PAH, organic anion), which was significantly decreased. This decrease appeared to be attributable to immunization with Freund's adjuvant. In the moderate stage of chronic serum sickness, proximal tubule functions and morphology appeared essentially normal. Only Na-K-ATPase activity was somewhat lower than in controls. However, proximal tubule dysfunction was a feature of severe chronic serum sickness. A significant inhibition of anion and cation transport was observed. Reduction in transport functions occurred together with impaired oxidative metabolism and severe reduction in Na-K-ATPase activity. Abnormalities of mitochondrial structure, a decrease in number of mitochondria, and a significant increase in intracellular H2O content provided additional evidence of degenerative changes in proximal tubule cells during the severe stage of chronic serum sickness. It was concluded that decreased transport of organic ions by the basolateral membrane in proximal tubules of rats with severe chronic serum sickness resulted from a breakdown in the metabolic machinery of the tubule epithelium rather than a specific injury to organic ion transport systems.

Respiratory quotient and patterns of substrate utilization in human sepsis and trauma.

Three hundred measurements of indirect calorimetric and hemodynamic variables were performed in 99 critically ill septic and nonseptic surgical patients. Septics manifested, with respect to nonseptics, higher O2 consumption, metabolic rate and cardiac index, and lower respiratory quotient in the presence of higher glucose infusion rates and glucose infusion rate/metabolic rate ratios. Among septics there was a group of more severely ill patients with signs of multiple organ failure who manifested a dissociated pattern characterized by a tendency to decreased O2 consumption in the presence of increasing cardiac index and central venous O2 partial pressure: they had higher respiratory quotients, with respect to the other septics, for a given glucose infusion rate/metabolic rate ratio. The lower mean respiratory quotient of septics indicates that they depend generally more than nonseptic trauma patients on fat as an energy substrate and confirms a previously obtained evidence of limited hepatic lipogenesis in sepsis. At the same time, however, it is suggested that fat utilization becomes impaired (and hepatic lipogenesis becomes prominent) in sepsis at a stage in which signs of impaired oxidative metabolism and major metabolic abnormalities also develop.

Monocyte Function in Patients With Chronic Granulomatous Disease of Childhood

AbstractAdults with chronic granulomatous disease of childhood (CGD) have been described who remain relatively free of infection despite markedly abnormal neutrophil function. Monocyte function in four adults with this mild or atypical CGD syndrome was examined and compared to that of normal controls and to that of two patients with the more severe or classic CGD syndrome. Monocytes from patients with atypical CGD killed 75.7% ± 2.6% (mean ± SEM) of ingested organisms at 30 min, while monocytes from the patients with classic CGD killed only 50.3% ± 4.2% of bacteria (p < 0.001). The difference in bactericidal activity between atypical CGD monocytes and normal monocytes was relatively small (75.7% ± 2.6% versus 88.1% ± 3.7%, respectively) but was statistically significant (p = 0.007). Monocytes from both atypical and classic CGD patients showed markedly impaired oxidative metabolism. Differences in monocyte bactericidal activity may explain why atypical CGD patients have fewer infections than classic CGD patients. The presence of nonoxidative bactericidal mechanisms in atypical CGD monocytes is suggested by the demonstration of bactericidal activity despite severe oxidative metabolic defects.