Reduction Of Oxidative Metabolism Research Articles

Hypoxia alters posterior cingulate cortex metabolism during a memory task: A 1H fMRS study

Environmental hypoxia (fraction of inspired oxygen (FIO2) ∼ 0.120) is known to trigger a global increase in cerebral blood flow (CBF). However, regionally, a heterogeneous response is reported, particularly within the posterior cingulate cortex (PCC) where decreased CBF is found after two hours of hypoxic exposure. Furthermore, hypoxia reverses task-evoked BOLD signals within the PCC, and other regions of the default mode network, suggesting a reversal of neurovascular coupling. An alternative explanation is that the neural architecture supporting cognitive tasks is reorganised. Therefore, to confirm if this previous result is neural or vascular in origin, a measure of neural activity that is not haemodynamic-dependant is required.To achieve this, we utilised functional magnetic resonance spectroscopy to probe the glutamate response to memory recall in the PCC during normoxia (FIO2 = 0.209) and after two hours of poikilocapnic hypoxia (FIO2 = 0.120). We also acquired ASL-based measures of CBF to confirm previous findings of reduced CBF within the PCC in hypoxia.Consistent with previous findings, hypoxia induced a reduction in CBF within the PCC and other regions of the default mode network. Under normoxic conditions, memory recall was associated with an 8% increase in PCC glutamate compared to rest (P = 0.019); a change which was not observed during hypoxia. However, exploratory analysis of other neurometabolites showed that PCC glucose was reduced during hypoxia compared to normoxia both at rest (P = 0.039) and during the task (P = 0.046).We conclude that hypoxia alters the activity-induced increase in glutamate, which may reflect a reduction in oxidative metabolism within the PCC. The reduction in glucose in hypoxia reflects continued metabolism, presumably by non-oxidative means, without replacement of glucose due to reduced CBF.

Myocardium Metabolism in Physiological and Pathophysiological States: Implications of Epicardial Adipose Tissue and Potential Therapeutic Targets.

The main energy substrate of adult cardiomyocytes for their contractility are the fatty acids. Its metabolism generates high ATP levels at the expense of high oxygen consumption in the mitochondria. Under low oxygen supply, they can get energy from other substrates, mainly glucose, lactate, ketone bodies, etc., but the mitochondrial dysfunction, in pathological conditions, reduces the oxidative metabolism. In consequence, fatty acids are stored into epicardial fat and its accumulation provokes inflammation, insulin resistance, and oxidative stress, which enhance the myocardium dysfunction. Some therapies focused on improvement the fatty acids entry into mitochondria have failed to demonstrate benefits on cardiovascular disorders. Oppositely, those therapies with effects on epicardial fat volume and inflammation might improve the oxidative metabolism of myocardium and might reduce the cardiovascular disease progression. This review aims at explain (a) the energy substrate adaptation of myocardium in physiological conditions, (b) the reduction of oxidative metabolism in pathological conditions and consequences on epicardial fat accumulation and insulin resistance, and (c) the reduction of cardiovascular outcomes after regulation by some therapies.

Perturbations in myocardial energy metabolism in the ischemic heart

As an organ that must continuously pump oxygenated blood throughout the body, the heart has an enormous metabolic demand, which is primarily met via oxidative metabolism of fatty acids and carbohydrates. Because of its high metabolic demand, during times of reduced oxygen supply such as ischemia, the heart becomes highly susceptible to injury, and if flow is not re-established, myocardial tissue is lost and can result in death (myocardial infarction). Of interest, both myocardial ischemia and reperfusion are associated with a number of perturbations in energy metabolism that contribute to the pathology of ischemic heart disease. This includes marked elevations in glycolysis to counteract the reduction in oxidative metabolism, whereas fatty acids predominate as the primary fuel source for residual oxidative metabolism. During the early stages of cardiac recovery after successful reperfusion of the ischemic heart, fatty acid oxidation rates also rapidly recover at the expense of low glucose oxidation rates. These metabolic perturbations increase myocardial acidosis due to glycolysis being uncoupled from glucose oxidation, which impairs cardiac efficiency. As such, therapeutic approaches to stimulate glucose oxidation or inhibit fatty acid oxidation have the potential to correct dysregulated myocardial energy metabolism during ischemia and reperfusion, which improves cardiac efficiency and may lead to improved clinical outcomes in people with ischemic heart disease. L

MiR-133a function in the pathogenesis of dedifferentiated liposarcoma

BackgroundSarcomas are malignant heterogeneous tumors of mesenchymal derivation. Dedifferentiated liposarcoma (DDLPS) is aggressive with recurrence in 80% and metastasis in 20% of patients. We previously found that miR-133a was significantly underexpressed in liposarcoma tissues. As this miRNA has recently been shown to be a tumor suppressor in many cancers, the objective of this study was to characterize the biological and molecular consequences of miR-133a underexpression in DDLPS.MethodsReal-time PCR was used to evaluate expression levels of miR-133a in human DDLPS tissue, normal fat tissue, and human DDLPS cell lines. DDLPS cells were stably transduced with miR-133a vector to assess the effects in vitro on proliferation, cell cycle, cell death, migration, and metabolism. A Seahorse Bioanalyzer system was also used to assess metabolism in vivo by measuring glycolysis and oxidative phosphorylation (OXPHOS) in subcutaneous xenograft tumors from immunocompromised mice.ResultsmiR-133a expression was significantly decreased in human DDLPS tissue and cell lines. Enforced expression of miR-133a decreased cell proliferation, impacted cell cycle progression kinetics, decreased glycolysis, and increased OXPHOS. There was no significant effect on cell death or migration. Using an in vivo xenograft mouse study, we showed that tumors with increased miR-133a expression had no difference in tumor growth compared to control, but did exhibit an increase in OXPHOS metabolic respiration.ConclusionsBased on our collective findings, we propose that in DDPLS, loss of miR-133a induces a metabolic shift due to a reduction in oxidative metabolism favoring a Warburg effect in DDLPS tumors, but this regulation on metabolism was not sufficient to affect DDPLS.

The impact of hibernation and arousal on energy metabolism and antioxidant defenses in leech (Whitmania pigra)

Whitmania pigra is an important medicinal resource that is widely farmed in aquaculture in Asia, and a decrease in body weight occurring during hibernation and hibernation lasting long time has serious impacts on production efficiency in aquaculture system. We examined energy metabolic and antioxidant enzymes of intestine from a hibernator (W. pigra) over cycles of hibernation-arousal. Results of the study demonstrated that hibernation in W. pigra was characterized by a profound decrease in energy metabolic during deep hibernation that was interrupted by rewarming arousal. And energy metabolic increased significantly during the rewarming arousal. Regulated suppression of energy metabolism probably contributes to energy savings. Oxidative stress decreased during deep hibernation along with a reduction in oxidative metabolism, but increased during entrance into hibernation and arousal from hibernation. This up-regulation of antioxidant defense (AD) during arousal was interpreted as protection of the intestine against oxidative damage to come with the enormous increase in metabolic activity during arousal from hibernation, and the up-regulation of AD during entrance into hibernation was interpreted that leech are exposed to significant stresses (cold acclimation) that must be dealt with appropriately to avoid irreversible tissue damage. It can be concluded that W. pigra has a strong AD system that protects it from the injurious effects of free radicals either during periods of entrance into hibernation and arousal. These results indicate the adaptive mechanism of hibernation that may be applied to increase production efficiency of leech by interrupting or shortening hibernation.

Hypoxaemia‐induced catecholamine secretion from adrenal chromaffin cells inhibits glucose‐stimulated hyperinsulinaemia in fetal sheep

Abstract Hypoxaemia elicits adrenergic suppression of fetal glucose-stimulated hyperinsulinaemia. We postulate that this effect is mediated by catecholamines, exclusively, from fetal adrenal chromaffin cells. To investigate this hypothesis, square-wave hyperglycaemic clamp studies were performed under normoxaemic (26 ± 0.9 mmHg) and hypoxaemic (14 ± 0.3 mmHg) steady-state conditions in near-term fetal sheep that had undergone either surgical sham or bilateral adrenal demedullation (AD), values mentioned are ± SEM. Under normoxaemic conditions plasma noradrenaline concentrations were lower in AD fetuses than in sham-operated fetuses (457 ± 122 versus 1073 ± 103 pg ml(-1), P < 0.05). Plasma insulin concentrations were not different at euglycaemia between shams (0.46 ± 0.07 ng ml(-1)) and AD fetuses (0.44 ± 0.04 ng ml(-1)) and increased (P < 0.05) with hyperglycaemia in both groups although to a lesser extent in AD fetuses (0.94 ± 0.19 ng ml(-1)) compared to shams (1.31 ± 0.15 ng ml(-1); P < 0.05). Hypoxaemia increased plasma adrenaline (26-fold) and noradrenaline (5-fold) in shams but elicited no change in AD fetuses. Under hypoxaemic conditions, euglycaemic plasma insulin concentrations were reduced (P < 0.05) in both sham and AD fetuses to 0.30 ± 0.05 ng ml(-1) and 0.27 ± 0.01 ng ml(-1) respectively, and the insulin response to hyperglycaemia was abolished in shams but not affected in AD fetuses (0.33 ± 0.06 versus 0.73 ± 0.02 ng ml(-1), P < 0.05). Hypoxaemia also induced hyperlactacaemia and hypocarbia to a greater extent in shams than in AD fetuses, indicating that catecholamines potentiate reductions in oxidative metabolism independently of insulin. These findings demonstrate that the fetal adrenal chromaffin cells are the source for acute hypoxaemia-induced elevations in fetal plasma catecholamines and suppression of glucose-stimulated hyperinsulinaemia, but other factors reduce plasma insulin at euglycaemia.

Molecular Signatures of Amyotrophic Lateral Sclerosis Disease Progression in Hind and Forelimb Muscles of an SOD1G93AMouse Model

This study utilized proteomics, biochemical and enzymatic assays, and bioinformatics tools that characterize protein alterations in hindlimb (gastrocnemius) and forelimb (triceps) muscles in an amyotrophic lateral sclerosis (ALS) (SOD1(G93A)) mouse model. The aim of this study was to identify the key molecular signatures involved in disease progression. Both muscle types have in common an early down-regulation of complex I. In the hindlimb, early increases in oxidative metabolism are associated with uncoupling of the respiratory chain, an imbalance of NADH/NAD(+), and an increase in reactive oxygen species (ROS) production. The NADH overflow due to complex I inactivation induces TCA flux perturbations, leading to citrate production, triggering fatty acid synthase (FAS), and lipid peroxidation. These early metabolic changes in the hindlimb followed by sustained and comparatively higher metabolic and cytoskeletal derangements over time precede and may catalyze the progressive muscle wasting in this muscle at the late stage. By contrast, in the forelimb, there is an early down-regulation of complexes I and II that is associated with the reduction of oxidative metabolism, which promotes metabolic homeostasis that is accompanied by a greater cytoskeletal stabilization response. However, these early compensatory systems diminish by a later time point. The identification of potential early- and late-stage disease molecular signatures in an ALS model: muscle albumin, complex I, complex II, citrate synthase, FAS, and phosphoinositide 3-kinase functions as diagnostic markers and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers. The differing pattern of cellular metabolism and cytoskeletal derangements in the hind and forelimb identifies the potential dysmetabolism/hypermetabolism molecular signatures associated with disease progression, which may serve as diagnostic/disease progression markers in ALS patients.

Early Nonischemic Oxidative Metabolic Dysfunction Leads to Chronic Brain Atrophy in Traumatic Brain Injury

Chronic brain atrophy after traumatic brain injury (TBI) is a well-known phenomenon, the causes of which are unknown. Early nonischemic reduction in oxidative metabolism is regionally associated with chronic brain atrophy after TBI. A total of 32 patients with moderate-to-severe TBI prospectively underwent positron emission tomography (PET) and volumetric magnetic resonance imaging (MRI) within the first week and at 6 months after injury. Regional lobar assessments comprised oxidative metabolism and glucose metabolism. Acute MRI showed a preponderance of hemorrhagic lesions with few irreversible ischemic lesions. Global and regional chronic brain atrophy occurred in all patients by 6 months, with the temporal and frontal lobes exhibiting the most atrophy compared with the occipital lobe. Global and regional reduction in cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose were observed. The extent of metabolic dysfunction was correlated with the total hemorrhage burden on initial MRI (r=0.62, P=0.01). The extent of regional brain atrophy correlated best with CMRO(2) and CBF. Lobar values of OEF were not in the ischemic range and did not correlate with chronic brain atrophy. Chronic brain atrophy is regionally specific and associated with regional reductions in oxidative brain metabolism in the absence of irreversible ischemia.

Changes in the effectiveness of drugs in elderly people

Many physiological variables change their performance with age. This results in an altered effectiveness of drugs due to changes in both pharmacokinetic and pharmacodynamic characteristics. A reduction in oxidative metabolism yields higher absorption of drugs known to undergo extensive first-pass metabolism, the increase in fatty tissue a higher volume of distribution particularly relevant for drugs with low lipophilicity, the decrease in excretion calls for lower steady state dosages. On the other hand sensitivity for drug effects increases with age: CNS is more sensitive to sedative drug effects, circulation reacts more sensitive to drug effects lowering blood pressure, loss of feedback mechanisms in metabolism may cause hypoglycemia. Consequently elderly people are endangered by falls. Early symptoms of adverse drug effects include weakness, dementia, somnolence, depression, loss of appetite, and dehydration. Moreover, drugs may aggravate pre-existing comorbidity, such as renal insufficiency by NSAIDs. Therefore the reasons for initiation drug therapy have to be evaluated especially carefully in elderly patients, the less drugs the better, prescription schemes have to be simple and understandable.

Reduction of myocardial oxidative metabolism in dilated cardiomyopathy but not in remote areas in myocardial infarction

We performed PET with carbon-11 acetate in patients with LV dysfunction in order to assess alterations in myocardial metabolism in apparently well-perfused myocardium in patients with dilated cardiomyopathy (DCM) and myocardial infarction (MI). We studied 15 patients with DCM 4and 16 patients with MI. The clearance rate constant for carbon-11 acetate derived from monoexponential fitting (Kmono) was measured as a marker of myocardial oxidative metabolism. We also performed PET in 10 normal subjects as control. Kmono was significantly lower in patients with DCM than in the control subjects (0.049±0.008 vs. 0.060±0.010 /min; P<0.01). In contrast, Kmono in the remote areas in patients with MI was preserved (0.061±0.013), while Kmono in the infarcted areas (0.036±0.010) was significantly lower than that in the controls ( P<0.001). These data suggest that myocardial oxidative metabolism is preserved in remote area in patients with MI, despite LV remodeling, while it is decreased in patients with DCM. The reduction in oxidative metabolism may be one of the causes of LV dysfunction in patients with DCM but not in patients with MI.

Caenorhabditis elegans mutants resistant to phosphine toxicity show increased longevity and cross-resistance to the synergistic action of oxygen.

Phosphine (hydrogen phosphide, PH3) is the fumigant most widely used to protect stored products from pest infestation. Despite the importance of this chemical, little is known about its mode of action. We have created three phosphine-resistant lines (pre-1, pre-7, pre-33) in the model organism C. elegans, with LC50 values 2, 5, and 9 times greater than the fully susceptible parental strain. Molecular oxygen was shown to be an extremely effective synergist with phosphine as, under hyperoxic conditions, 100% mortality was observed in wild-type nematodes exposed to 0.1 mg/l phosphine, a nonlethal concentration in air. All three mutants were resistant to the synergistic effects of oxygen in proportion to their resistance to phosphine with one mutant, pre-33, showing complete resistance to this synergism. We take the proportionality of cross-resistance between phosphine and the synergistic effect of oxygen to imply that all three mutants circumvent a mechanism of phosphine toxicity that is directly coupled to oxygen metabolism. Compared with the wild-type strain, all three mutants have an extended average life expectancy of from 12.5 to 25.3%. This is consistent with the proposed involvement of oxidative stress in both phosphine toxicity and ageing. Because the wild-type and mutant nematodes develop at the same rate, the longevity is unlikely to be caused by a clk-type reduction in oxidative metabolism, a potential alternative mechanism of phosphine resistance.

Neuronal oxidative hypometabolism in the brainstem of the epaulette shark ( Hemiscyllium ocellatum) in response to hypoxic pre-conditioning

Reduced oxidative demand or neuronal hypometabolism is a neuroprotective strategy used by several anoxia and hypoxia-tolerant species. The epaulette shark, Hemiscyllium ocellatum inhabits shallow reef platforms that can become hypoxic. Hypoxic pre-conditioning (eight cycles of 0.34 mg O 2/l for 120 min, 12 h apart) was used to determine whether a reduction in oxidative metabolism could be elicited in the epaulette shark brain. Hypoxic pre-conditioning resulted in a significant overall reduction in oxidative activity in coronal sections of the brainstem, but key nuclei displayed heterogeneous levels of oxidative metabolism. Motor nuclei had significantly lower levels of oxidative activity while sensory nuclei did not. The epaulette shark's ability to enter this state of hypometabolism in response to hypoxic pre-conditioning revealed a neuroprotective mechanism, which would not only reduce neuronal damage during hypoxic exposure but also minimise re-oxygenation injury.

Chronic effect of fatty acids on insulin release is not through the alteration of glucose metabolism in a pancreatic beta-cell line (beta HC9).

Hyperinsulinaemia in the fasting state and a blunted insulin secretory response to acute glucose stimulation are commonly observed in obesity associated non-insulin-dependent diabetes mellitus. Hyperlipidaemia is a hallmark of obesity and may play a role in the pathogenesis of this beta-cell dysfunction because glucose metabolism in pancreatic beta cells may be altered by the increased lipid load. We tested this hypothesis by assessing the chronic effect of oleic acid on glucose metabolism and its relationship with glucose-induced insulin release in beta HC9 cells in tissue culture. Our results show: (1) A 4-day treatment with oleic acid caused an enhancement of insulin release at 0-5 mmol/l glucose concentrations while a significant decrease in insulin release occurred when the glucose level was greater than 15 nmol/l; (2) Hexokinase activity was increased and a corresponding left shift of the dose-dependency curve of glucose usage was observed associated with inhibition of glucose oxidation in oleic acid treated beta HC9 cells, yet the presumed glucose-related ATP generation did not parallel the change in insulin release due to glucose; (3) The rate of cellular respiration was markedly increased in oleic acid treated beta HC9 cells both in the absence of glucose and at all glucose concentrations tested. This enhanced oxidative metabolism may explain the increased insulin release at a low glucose level but is clearly dissociated from the blunted insulin secretion at high glucose concentrations. We conclude that a reduction of oxidative metabolism in pancreatic beta cells is unlikely to be the cause of the dramatic effect that high levels of non-esterified fatty acids have on glucose-induced insulin release.

Reduced oxidative muscle metabolism in chronic fatigue syndrome

The purpose of this study was to determine if chronic fatigue syndrome (CSF) is characterized by abnormalities in oxidative muscle metabolism. Patients with CFS according to Centers for Disease Control (CDC) criteria (n = 22) were compared to normal sedentary subjects (n = 15). CFS patients were also tested before and 2 days after a maximal treadmill test. Muscle oxidative capacity was measured as the maximal rate of postexercise phosphocreatine (PCr) resynthesis using the ADP model (Vmax) in the calf muscles using 31P magnetic resonance spectroscopy. Vmax was significantly reduced in CFS patients (39.6 +/- 2.8 mmol/L/min, mean +/- SE) compared to controls (53.8 +/- 2.8 mmol/L/min). Two days postexercise there was no change in resting inorganic phosphate (Pi)/PCr or Vmax in the CFS patients (n = 14). In conclusion, oxidative metabolism is reduced in CFS patients compared to sedentary controls. In addition, a single bout of strenuous exercise did not cause a further reduction in oxidative metabolism, or alter resting Pi/PCr ratios.

Effects of partial outlet obstruction on bladder-strip sensitivity to glucose deprivation: an in vitro study in the rat.

Partial outlet obstruction has been shown to result in contractile and metabolic dysfunctions. Specifically, there is a greater reduction in the response to field stimulation (FS) in comparison with the responses to bethanechol and KCl, a greater reduction in the tonic response to stimulation in comparison with the phasic response, and a reduction in oxidative metabolism of glucose accompanied by an increase in the glycolytic metabolism of glucose. The specific aim of the current study was to correlate the effects of partial outlet obstruction on the contractile responses of isolated strips of bladder smooth muscle to repetitive stimulation in the presence and absence of glucose. Adult male Sprague-Dawley rats were subjected to partial outlet obstruction by the surgical placement of silk ligatures around the urethra. After 2 weeks, each rate was anesthetized, the bladder was excised, and isolated strip studies were performed. These studies demonstrated that the maximal phasic response to FS was significantly decreased in the obstructed strips as compared with controls, with no difference being noted for responses to bethanechol or KCl; the tonic responses to all forms of stimulation were significantly decreased after obstruction, with the tonic response to FS being decreased to a greater degree than were the tonic responses to bethanechol and KCl; and in the absence of glucose, the tonic responses of control strips to all forms of stimulation were reduced to a greater degree than were the phasic responses. These studies demonstrate that the tonic response to FS is extremely sensitive to fatigue induced by repetitive stimulation.

The Pharmacotherapy of Alzheimer's Disease Based on the Cholinergic Hypothesis: an Update

Alzheimer's disease (AD) is a neurodegenerative disorder with impairment of cognitive function and personality. The synaptic loss, neuronal atrophy and degeneration of cholinergic nuclei in the basal forebrain may be associated with a reduction in oxidative metabolism of glucose, a fall in acetyl CoA and ATP. Current pharmacological strategies, aimed at increasing cholinergic activity include acetylcholinesterase (AChE) inhibitors, cholinergic agonists, acetylcholine (ACh) releasers and stimulants of nerve growth factors (NGF). AChE inhibitors, physostigmine and Tacrine can slow the decline of cognitive function and memory in some patients with mild or moderate AD, if given for at least 3–6 months in sufficient doses to inhibit brain AChE. Their main disadvantages are low oral bioavailability, peripheral cholinergic hyperactivity and liver toxicity with Tacrine. Newer, less toxic AChE inhibitors, with selective central activity, formulations of physostigmine, selective M 1and nicotinic agonists are becoming available with improved bioavailability and pharmacokinetics. These may increase the likelihood of therapeutic benefit in AD. Nootropic drugs, e.g. piracetam, which release ACh and are relatively non-toxic could possibly slow the progression of the disease. A combination of an AChE inhibitor, piracetam and a stimulator of NGF may show additive effects on memory processes but with a lower incidence of untoward effects.

Effects of anoxia on the biphasic response of isolated strips of rabbit bladder to field stimulation, bethanechol, methoxamine and KCl.

The contractile response of the bladder can be divided into two phases: an initial rapid increase in tension and a prolonged period of sustained tension (plateau phase). The bladder empties primarily during the plateau phase of the contractile response. These two phases can be differentiated using both pharmacologic and metabolic agents, indicating that the two phases have independent energy requirements. The present study compares the phasic (peak) and tonic (plateau) components of the responses of isolated strips of bladder body and base to field stimulation, bethanechol, methoxamine and KCl administration. New Zealand White rabbits were anesthetized with pentobarbital, and the bladder was removed. The bladder was divided between body and base at the level of the ureteral orifices. Three strips of bladder body and three strips of bladder base were mounted in separate baths containing Tyrode's solution at 37 degrees C and equilibrated with 95% O2, 5% CO2. Anoxia was produced by changing the gas mixture to 95% nitrogen, 5% CO2. The effects of anoxia on the responses to field stimulation, bethanechol, methoxamine and KCl were determined at different times after the initiation of anoxia. The results of these studies can be summarized as follows: (1) Anoxia induced time-dependent plateau phases of the response to field stimulation (2 and 32 Hz). (2) The rate of inhibition of the plateau phase was significantly and substantially greater than that of the peak phase in both the bladder body and base. (3) Similarly, anoxia inhibited the plateau phase of the bladder body's response to bethanechol to a significantly and substantially greater degree than anoxia inhibited the peak contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effect of Cimetidine on Anesthetic Metabolism and Toxicity

Because the H2-receptor antagonist cimetidine has been shown to inhibit drug metabolism, the effects of cimetidine on anesthetic metabolism and toxicity were investigated in a rat model. Cimetidine decreased inorganic plasma fluoride production after methoxyflurane administration both in 21% oxygen (P less than 0.001) and in 100% oxygen (P less than 0.001). Phenobarbital produces an increased fluoride formation after methoxyflurane anesthesia, and this fluoride formation is also reduced by cimetidine (P less than 0.005). There was no significant difference between the plasma fluoride levels in rats anesthetized with halothane or enflurane. Although cimetidine inhibited the in vivo defluorination of methoxyflurane, fluoride levels were still within the nephrotoxic range, and cimetidine is not likely to play a role as part of a preanesthetic regimen that would permit the increased clinical use of methoxyflurane. Cimetidine also inhibited the oxidative metabolism of halothane; cimetidine decreased (P less than 0.05) trifluoroacetic acid concentrations after halothane anesthesia in 21% oxygen and in 100% oxygen and decreased (P less than 0.05) bromide concentrations after halothane anesthesia in 100% oxygen. Trifluoroacetic acid levels were less (P less than 0.02) after halothane anesthesia in 14% oxygen as compared with 100% oxygen, indicating a reduction in oxidative metabolism under hypoxic conditions. However, bromide concentrations were maximal after halothane anesthesia in 21% oxygen, and significantly (P less than 0.001) less after halothane anesthesia in 14% and 100% oxygen. Bromide production, therefore, seems to be inhibited by both hypoxia and hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions between phosphate and oxidative metabolism in proximal renal tubules.

These studies examine the phosphate dependence of fluid absorption and oxidative metabolism in proximal tubules from rabbit kidney. Removal of inorganic phosphate from intraluminal fluid in isolated perfused tubules reduced fluid absorption (Jv) from 1.0 nl X mm-1 X min-1 to zero and removal of phosphate from the medium bathing tubules in suspension reduced O2 consumption rates (coupled, uncoupled, ouabain sensitive, and ouabain insensitive) and ATP contents by 30-40%. Inhibitions induced by removal of phosphate could be altered by addition of selected organic substrates to ambient fluids. Addition of succinate, citrate, or malate preserved uncoupled respiration and partially preserved Jv (0.4-0.9 nl X mm-1 X min-1), with succinate being most effective. Addition of short-chain fatty acids (butyrate or valerate) to phosphate-free media had little or no effect on Jv. n-Butylmalonate, an inhibitor of dicarboxylate anion transport into mitochondria, reduced oxidative metabolism, ATP content, and Jv when added to phosphate-containing media but had no further effect on these tubular functions when added to phosphate-free media. Together these results suggest that phosphate limitation reduces dicarboxylate anion availability to mitochondria and that this inhibition may contribute to the overall reduction in oxidative metabolism and Jv observed under these conditions.

Selective stimulation of human platelet lipoxygenase product 12-hydroxy-5,8,10,14-eicosatetraenoic acid by chlorpromazine and 8-( N, N-diethylamino)-octyl-3,4,5-trimethoxybenzoate

Stimulation of human platelets by thrombin and by the Ca 2+ ionophore A23187 leads to a rapid Ca 2+-dependent activation of phospholipases that release membrane-bound arachidonic acid for oxidation by a cyclooxygenase and lipoxygenase enzymes into so-called eicosanoids. Chlorpromazine and the intracellular calcium antagonist 8-( N, N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) inhibited the release of eicosanoids, as estimated by a quantitative glass capillary-gas chromatography analysis. TMB-8 was more efficient for thrombin- than for ionophore-induced eicosanoids liberation. Chlorpromazine, the more potent inhibitor, was active at the same concentration against either inducer. The reduction of oxidative metabolism by the cyclooxygenase pathway was more pronounced than reduction in the lipoxygenase pathway. When exogenous arachidonic acid was added to the platelets, both drugs stimulated selectively the production and the formation rate of 12-hydroxy-5,8,10,14-eicosatetraenoic acid by a factor of 2–2.5 in the absence of variation of cyclooxygenase products. Therefore, the stimulation of the lipoxygenase metabolite by the two drugs was obtained with both endogenous and exogenous arachidonic acid. This selective stimulation by drugs of a lipoxygenase product in the absence of inhibition of cyclooxygenase is the first reported of this type and suggests a differential control for the two oxidation enzymes. These findings emphasize the importance of a simultaneous quantitative analysis of both oxidation pathways.