Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oxygen-dependence of cellular energetics was investigated in hepatocytes from goldfish Carassius auratus (anoxia-tolerant) and rainbow trout Oncorhynchus mykiss (anoxia-intolerant). In goldfish hepatocytes, an approximately 50 % reduction in the rate of oxygen consumption was observed in response to both acute and prolonged hypoxia, the latter treatment shifting the threshold for this reduction to a higher oxygen level. A concomitant increase in the rate of lactate production did not compensate for the decreased aerobic ATP supply, resulting in an overall metabolic depression of 26 % during acute hypoxia and of 42 % during prolonged hypoxia. Trout hepatocytes showed a similar suppression of cellular respiration after prolonged hypoxia but were unresponsive to acute hypoxia. Similarly, the rate of lactate production was unaltered during acute hypoxia but was increased during prolonged hypoxia, metabolic depression amounting to 7 % during acute hypoxia and 30 % during prolonged hypoxia. In both species, the affinity of hepatocytes for oxygen decreased during hypoxia, but this alteration was not sufficient in absolute terms to account for the observed decrease in aerobic ATP supply. Protein synthesis was suppressed in both cell types under hypoxia, whereas Na(+)/K(+)-ATPase activity decreased in trout but not in goldfish hepatocytes, emphasising the importance of membrane function in these cells during conditions of limited energy supply.
 ...
PMID:Oxygen-dependent energetics of anoxia-tolerant and anoxia-intolerant hepatocytes. 1066 79

A number of mechanisms have been proposed to play a role in the regulation of activity-dependent variations in extracellular potassium concentration ([K(+)](o)). We tested possible regulatory mechanisms for [K(+)](o) during spontaneous recurrent epileptiform activity induced in the dentate gyrus of hippocampal slices from adult rats by perfusion with 8 mM potassium and 0-added calcium medium in an interface chamber. Local application of tetrodotoxin blocked local [K(+)](o) changes, suggesting that potassium is released and taken up locally. Perfusion with barium or cesium, blockers of the inward rectifying potassium channel, did not alter the baseline [K(+)](o), the ceiling level of [K(+)](o) reached during the burst, or the rate of [K(+)](o) recovery after termination of the bursts. Decreasing gap junctional conductance did not change the baseline [K(+)](o) or the half-time of recovery of the [K(+)](o) after the bursts but did cause a decrease in the ceiling level of [K(+)](o). Perfusion with furosemide, which will block cation/chloride cotransporters, or perfusion with low chloride did not change the baseline [K(+)](o) or the half-time of recovery of the [K(+)](o) after the bursts but did increase the ceiling level of [K(+)](o). Bath or local application of ouabain, a Na(+)/K(+)-ATPase inhibitor, increased the baseline [K(+)](o), slowed the rate of [K(+)](o) recovery, and induced spreading depression. These findings suggest that potassium redistribution by glia only plays a minor role in the regulation of [K(+)](o) in this model. The major regulator of [K(+)](o) in this model appears to be uptake via a Na(+)/K(+)-ATPase, most likely neuronal.
 ...
PMID:Sodium pump activity, not glial spatial buffering, clears potassium after epileptiform activity induced in the dentate gyrus. 1071 71

Extracellular acidosis has been demonstrated to play a key role in the process of metabolic depression under long-term environmental stress, exemplified in the marine invertebrate Sipunculus nudus. These findings led to the hypothesis that acid-base regulation is associated with a visible cost depending on the rate and mode of H(+)-equivalent ion exchange. To test this hypothesis, the effects of different ion-transport inhibitors on the rate of pH recovery during hypercapnia, on energy turnover and on steady-state acid-base variables were studied in isolated body wall musculature of the marine worm Sipunculus nudus under control conditions (pHe 7.90) and during steady-state extracellular acidosis (pHe 7.50 or 7.20) by in vivo (31)P-NMR and oxygen consumption analyses. During acute hypercapnia (2 % CO(2)), recovery of pHi was delayed at pHe 7.5 compared with pHe 7.9. Inhibition of the Na(+)/H(+)-exchanger by 5-(N,N-dimethyl)-amiloride (DMA) at pHe 7.5 delayed recovery even further. This effect was much smaller at pHe 7.9. Inhibition of anion exchange by the addition of the transport inhibitor 4, 4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) prevented pH recovery at pHe 7.5 and delayed recovery at pHe 7.9, in accordance with an effect on Na(+)-dependent Cl(-)/HCO(3)(-) exchange. The effects of ouabain, DIDS and DMA on metabolic rate were reduced at low pHe, thereby supporting the conclusion that acidosis caused the ATP demand of Na(+)/K(+)-ATPase to fall. This reduction occurred via an inhibiting effect on both Na(+)/H(+)- and Na(+)-dependent Cl(-)/HCO(3)(-) (i.e. Na(+)/H(+)/Cl(-)/HCO(3)(-)) exchange in accordance with a reduction in the ATP demand for acid-base regulation during metabolic depression. Considering the ATP stoichiometries of the two exchangers, metabolic depression may be supported by the predominant use of Na(+)/H(+)/Cl(-)/HCO(3)(-) exchange under conditions of extracellular acidosis.
 ...
PMID:Modulation of the cost of pHi regulation during metabolic depression: a (31)P-NMR study in invertebrate (Sipunculus nudus) isolated muscle. 1090 56

The cold submerged frog (Rana temporaria) serves as a useful model for many hibernating ectotherms that take refuge in hypoxic ponds and lakes until more favourable conditions of climate and food availability return. In all such animals, entry into a hypometabolic state effectively extends their survival time by lessening the impact of ATP demands on endogenous substrates. At the cellular level, metabolic depression may be brought about by decreasing energy-consuming processes and/or by increasing the efficiency of energy-producing pathways. Since the mitochondrion is the major contributor to the total energy production during aerobic metabolism and frog survival during winter depends on entry into a hypometabolic state, this review focuses on the respiratory properties of mitochondria that serve to increase the efficiency of energy production in hibernation. Energy conservation during overwintering also occurs through decreases in the ATP demand of the energy-consuming processes. For example, hibernating frogs decrease their ATP demands for Na(+)/K(+)-ATPase activity as part of a coordinated process of energy conservation wherein O(2)-limitation initiates a generalised suppression of ion channel densities and/or channel leak activities. The net result is that cell membrane permeabilities are reduced, thereby lowering the energetic costs of maintaining transmembrane ion gradients.
 ...
PMID:Mechanisms of metabolic defense against hypoxia in hibernating frogs. 1171 64

During hibernation, animals undergo metabolic changes that result in reduced utilization of glucose and oxygen. Fat is known to be the preferential source of energy for hibernating animals. Malonyldialdehyde (MDA) is an end product of fatty acid oxidation, and is generally used as an index of lipid peroxidation. We report here that peroxidation of lipids is increased in the plasma and in the membranes of red blood cells in black bears during hibernation. The plasma MDA content was about four fold higher during hibernation as compared to that during the active, non-hibernating state (P < 0.0001). Similarly, MDA content of erythrocyte membranes was significantly increased during hibernation (P < 0.025). The activity of Ca(2+)/Mg(2+)-ATPase in the erythrocyte membrane was significantly decreased in the hibernating state as compared to the active state. Na(+)/K(+)-ATPase activity was also decreased, though not significant, during hibernation. These results suggest that during hibernation, the bears are under increased oxidative stress, and have reduced activities of membrane-bound enzymes such as Ca(2+)/Mg(2+)-ATPase and Na(+)/K(+)-ATPase. These changes can be considered part of the adaptive for survival process of metabolic depression.
 ...
PMID:Increased oxidative stress and decreased activities of Ca(2+)/Mg(2+)-ATPase and Na(+)/K(+)-ATPase in the red blood cells of the hibernating black bear. 1203 85

Myocardial depression after cardiac surgery is modulated by cardiopulmonary bypass (CPB) and the underlying heart disease. The sodium pump is a key component for myocardial function. We hypothesized that the change in sodium pump expression during CPB correlates with intraoperative and postoperative laboratory and clinical parameters in neonates and children with various congenital heart defects. Sodium pump isoforms alpha1 (ATP1A1) and alpha3 (ATP1A3) mRNA expression in right atrial myocardium, excised before and after CPB, was quantified. Groups were assigned according to presence (VO group, n = 8) or absence (NO group, n = 8) of right atrial volume overload. CPB and aortic clamp time correlated with postoperative troponin-I values and ICU stay. ATP1A1 (P = 0.008) and ATP1A3 (P = 0.038) mRNA expression were significantly reduced during CPB. Longer aortic clamp times were associated with lower postoperative ATP1A1 (P = 0.045) and ATP1A3 (P = 0.002) mRNA expression. Low postoperative ATP1A1 (P = 0.043) and ATP1A3 (P = 0.002) expressions were associated with high troponin-I values. These results were restricted to the VO group. No correlation of sodium pump mRNA expression was found with the duration of ICU stay or ventilation. The postoperative troponin-I and clinical parameters correlated with the length of CPB, regardless of volume overload. In contrast, only dilated right atrium seemed to be susceptible to CPB in terms of sodium pump expression, showing a reduction during the operation and a correlation of sodium pump with postoperative troponin-I values.
 ...
PMID:Sodium pump reduction correlates with aortic clamp time in pediatric heart surgery. 1694 98

Ca(2+) in cardiac myocytes regulates contractility and relaxation, and Ca(2+) and Na (+)regulation are linked via Na(+)/Ca(2+) exchange (NCX). Heart failure (HF) is accompanied by contractile dysfunction and arrhythmias, both of which may be due to altered cellular Ca(2+) handling. Smaller Ca(2+) transient and sarcoplasmic reticulum (SR) Ca(2+) content cause systolic dysfunction in HF. The reduced SR Ca(2+) content is due to: (a) reduced SR Ca(2+)-ATPase function (which also contributes to diastolic dysfunction), (b) increased expression and function of NCX (which competes with SR Ca(2+)-ATPase during relaxation, but preserves diastolic function), and (c) enhanced diastolic SR Ca(2+) leak. Relative contributions of these may vary with HF etiology and stage. Triggered arrhythmias (e.g., delayed afterdepolarizations [DADs]) are prominent in HF. DADs are due to spontaneous SR Ca(2+) release and consequent activation of transient inward NCX current, which in HF allows DADs to more readily trigger arrhythmogenic action potentials. Thus NCX and Na(+) are critical in systolic and diastolic function and arrhythmias. [Na(+)](i) is elevated in HF, which may limit SR unloading and provide some Ca(2+) influx during the HF action potential, thus limiting the depression of systolic function. High [Na(+)](i) in HF is due to enhanced Na(+) influx. Cellular Na(+)/K(+)-ATPase (NKA) function appears unaltered, despite reduced NKA expression. This dichotomy led us to test NKA regulation by phospholemman (PLM). We find that PLM regulates NKA in a manner analogous to phospholamban regulation of SR Ca(2+)-ATPase (i.e., inhibition that is relieved by PLM phosphorylation). We measured intermolecular FRET between PLM and NKA, which is reduced upon PLM phosphorylation. The lower expression level of more phosphorylated PLM in HF may explain the above dichotomy. Thus, altered Ca(2+) and Na(+) handling contributes to altered contractile function and arrhythmogenesis in HF.
 ...
PMID:Regulation of Ca2+ and Na+ in normal and failing cardiac myocytes. 1713 83

The common goldfish (Carassius auratus) is extremely anoxia tolerant and here we provide evidence that "channel arrest" in the brain of these fish contributes to ATP conservation during periods of anoxia. Whole-cell patch-clamp recordings of slices taken from the telencephalon indicated that the N-methyl-d-aspartate (NMDA) receptor, an ionotropic glutamate receptor and Ca(2+)-channel, underwent a 40-50% reduction in activity during 40 min of acute anoxia. This is the first direct evidence of channel arrest in an anoxia-tolerant fish. Because goldfish produce ethanol as a byproduct of anaerobic metabolism we then conducted experiments to determine if the observed reduction in NMDA receptor current amplitude was due to inhibition by ethanol. NMDA receptor currents were not inhibited by ethanol (10 mmol L(-1)), suggesting that channel arrest of the receptor involved other mechanisms. Longer-term (48 h) in vivo exposure of goldfish to anoxic conditions (less than 1% dissolved O(2)) provided indirect evidence that a reduction in Na(+)/K(+)-ATPase activity also contributed to ATP conservation in the brain but not the gills. Anoxia under these conditions was characterized by a decrease in brain Na(+)/K(+)-ATPase activity of 30-40% by 24 h. Despite 90% reductions in the rates of ventilation, no change was observed in gill Na(+)/K(+)-ATPase activity during the 48-h anoxia exposure, suggesting that branchial ion permeability was unaffected. We conclude that rapid "channel arrest" of NMDA receptors likely prevents excitotoxicity in the brain of the goldfish, and that a more slowly developing decrease in Na(+)/K(+)-ATPase activity also contributes to the profound metabolic depression seen in these animals during oxygen starvation.
 ...
PMID:Evidence of anoxia-induced channel arrest in the brain of the goldfish (Carassius auratus). 1862 76

There have been suggestions that heat caused by cerebral metabolic activity may constrain mammalian brain evolution, architecture, and function. This article investigates physical limits on brain wiring and corresponding changes in brain temperature that are imposed by thermodynamics of heat balance determined mainly by Na(+)/K(+)-ATPase, cerebral blood flow, and heat conduction. It is found that even moderate firing rates cause significant intracellular Na(+) build-up, and the ATP consumption rate associated with pumping out these ions grows nonlinearly with frequency. Surprisingly, the power dissipated by the Na(+)/K(+) pump depends biphasically on frequency, which can lead to the biphasic dependence of brain temperature on frequency as well. Both the total power of sodium pumps and brain temperature diverge for very small fiber diameters, indicating that too thin fibers are not beneficial for thermal balance. For very small brains blood flow is not a sufficient cooling mechanism deep in the brain. The theoretical lower bound on fiber diameter above which brain temperature is in the operational regime is strongly frequency dependent but finite due to synaptic depression. For normal neurophysiological conditions this bound is at least an order of magnitude smaller than average values of empirical fiber diameters, suggesting that neuroanatomy of the mammalian brains operates in the thermodynamically safe regime. Analytical formulas presented can be used to estimate average firing rates in mammals, and relate their changes to changes in brain temperature, which can have important practical applications. In general, activity in larger brains is found to be slower than in smaller brains.
 ...
PMID:Thermodynamic constraints on neural dimensions, firing rates, brain temperature and size. 1941 77

The epaulette shark (Hemiscyllium ocellatum) represents an ancestral vertebrate model of episodic hypoxia and anoxia tolerance at tropical temperatures. We used two-dimensional gel electrophoresis and mass spectrometry-based proteomics approaches, combined with a suite of physiological measures, to characterize this species' responses to 1) one episode of anoxia plus normoxic recovery, 2) one episode of severe hypoxia plus recovery, or 3) two episodes of severe hypoxia plus recovery. We examined these responses in the cerebellum and rectal gland, two tissues with high ATP requirements. Sharks maintained plasma ionic homeostasis following all treatments, and activities of Na(+)/K(+)-ATPase and caspase 3/7 in both tissues were unchanged. Oxygen lack and reoxygenation elicited subtle adjustments in the proteome. Hypoxia led to more extensive proteome responses than anoxia in both tissues. The cerebellum and rectal gland exhibited treatment-specific responses to oxygen limitation consistent with one or more of several strategies: 1) neurotransmitter and receptor downregulation in cerebellum to prevent excitotoxicity, 2) cytoskeletal/membrane reorganization, 3) metabolic reorganization and more efficient intracellular energy shuttling that are more consistent with sustained ATP turnover than with long-term metabolic depression, 4) detoxification of metabolic byproducts and oxidative stress in light of continued metabolic activity, particularly following hypoxia in rectal gland, and 5) activation of prosurvival signaling. We hypothesize that neuronal morphological changes facilitate prolonged protection from excitotoxicity via dendritic spine remodeling in cerebellum (i.e., synaptic structural plasticity). These results recapitulate several highly conserved themes in the anoxia and hypoxia tolerance, preconditioning, and oxidative stress literature in a single system. In addition, several of the identified pathways and proteins suggest potentially novel mechanisms for enhancing anoxia or hypoxia tolerance in vertebrates. Overall, our data show that episodic hypoxic or anoxic exposure and recovery in the epaulette shark amplifies a constitutive suite of compensatory mechanisms that further prepares them for subsequent insults.
 ...
PMID:Compensatory proteome adjustments imply tissue-specific structural and metabolic reorganization following episodic hypoxia or anoxia in the epaulette shark (Hemiscyllium ocellatum). 2037 47


1 2 3 Next >>