Temporal changes of the apparent diffusion coefficients of water and metabolites in rats with hemispheric infarction: experimental study of transhemispheric diaschisis in the contralateral hemisphere at 7 tesla.
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The purpose of the present study was to clarify the temporal changes of the apparent diffusion coefficients (ADCs) of cerebral metabolites during early focal ischemia using stimulated echo acquisition mode with short echo time at a 7 T magnet to assess the pathophysiology of the reduction in diffusion properties observed both in the ischemic cerebral hemisphere and in the contralateral hemisphere. The ADCs of metabolites in the infarcted hemisphere 1 hour and 3 hours after the onset of ischemia decreased with 25% and 29% for choline containing compounds (Cho), 16% and 26% for creatine and phosphocreatine (Cre), and 19% and 19% for N-acetylaspartate (NAA), respectively, compared with the ADC values 2 hours later in the contralateral hemisphere. There were decreases in the ADC of Cho, Cre, and NAA with 21%, 7%, and 18% 8 hours later, respectively, in the noninfarcted hemisphere, which suggested transhemispheric diaschisis in rats with focal cerebral ischemia. The present study proposed that the diffusion characteristics of the brain metabolites might offer new insights into circulatory and metabolic alteration in the cerebral intracellular circumstance. (+info)
Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival.
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Coupled cellular respiration requires that ATP and ADP be efficiently exchanged between the cytosol and the mitochondrial matrix. When growth factors are withdrawn from dependent cells, metabolism is disrupted by a defect in ATP/ADP exchange across the mitochondrial membranes. Unexpectedly, we find that this defect results from loss of outer mitochondrial membrane permeability to metabolic anions. This decrease in anion permeability correlates with the changes in conductance properties that accompany closure of the voltage-dependent anion channel (also known as mitochondrial porin). Loss of outer membrane permeability (i) results in the accumulation of stored metabolic energy within the intermembrane space in the form of creatine phosphate, (ii) is prevented by the outer mitochondrial membrane proteins Bcl-x(L) and Bcl-2, and (iii) can be reversed by growth factor readdition. If outer membrane impermeability persists, the disruption of mitochondrial homeostasis culminates in loss of outer mitochondrial membrane integrity, cytochrome c redistribution, and apoptosis. The recognition that outer membrane permeability is regulated under physiological conditions has important implications for the understanding of bioenergetics and cell survival. (+info)
Energy liberation and chemical change in frog skeletal muscle during single isometric tetanic contractions.
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Recent data obtained from Rana temporaria sartorius muscles during an isometric tetanus indicate that the time-course of phosphocreatine (PC) splitting cannot account for the total energy (heat + work) liberation (Gilbert et al. 1971. J. Physiol. (Lond.) 218:)63). As this conclusion is important to an understanding of the chemical energetics of contraction, similar experments were performed on unpoisoned, oxygenated Rana pipiens sartorius muscles. The muscles were tetanized (isometrically) at 0 degrees C for 0.6, 1, or 5 s; metabolism was rapidly arrested by freezing the muscles with a specially designed hammer apparatus, and the frozen muscles were chemically analyzed. Comparable myothermal measurments were made on frogs from the same batch. Results of these experiments indicate: (a) The energy liberation parallels the PC and ATP breakdown with a proportionality constant of 10.7 kcal/mol; (b) comparably designed experiments with sartorius muscles of R. temporaria revealed that the ratio of energy liberation to PC splitting was significantly greater than that observed in R. pipiens sartorius muscles; (c) there is no systematic difference between experiments in which metabolism was arrested by the hammer apparatus and others using a conventional immersion technique. (+info)
ATP synthesis during low-flow ischemia: influence of increased glycolytic substrate.
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BACKGROUND: Our goals were to (1) simulate the degree of low-flow ischemia and mixed anaerobic and aerobic metabolism of an acutely infarcting region; (2) define changes in anaerobic glycolysis, oxidative phosphorylation, and the creatine kinase (CK) reaction velocity; and (3) determine whether and how increased glycolytic substrate alters the energetic profile, function, and recovery of the ischemic myocardium in the isolated blood-perfused rat heart. METHODS AND RESULTS: Hearts had 60 minutes of low-flow ischemia (10% of baseline coronary flow) and 30 minutes of reperfusion with either control or high glucose and insulin (G+I) as substrate. In controls, during ischemia, rate-pressure product and oxygen consumption decreased by 84%. CK velocity decreased by 64%; ATP and phosphocreatine (PCr) concentrations decreased by 51% and 63%, respectively; inorganic phosphate (P(i)) concentration increased by 300%; and free [ADP] did not increase. During ischemia, relative to controls, the G+I group had similar CK velocity, oxygen consumption, and tissue acidosis but increased glycolysis, higher [ATP] and [PCr], and lower [P(i)] and therefore had a greater free energy yield from ATP hydrolysis. Ischemic systolic and diastolic function and postischemic recovery were better. CONCLUSIONS: During low-flow ischemia simulating an acute myocardial infarction region, oxidative phosphorylation accounted for 90% of ATP synthesis. The CK velocity fell by 66%, and CK did not completely use available PCr to slow ATP depletion. G+I, by increasing glycolysis, slowed ATP depletion, maintained lower [P(i)], and maintained a higher free energy from ATP hydrolysis. This improved energetic profile resulted in better systolic and diastolic function during ischemia and reperfusion. These results support the clinical use of G+I in acute MI. (+info)
Anoxic ATP depletion in neonatal mice brainstem is prevented by creatine supplementation.
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BACKGROUND: Sufficient ATP concentrations maintain physiological processes and protect tissue from hypoxic damage. With decreasing oxygen concentration, ATP synthesis relies increasingly on the presence of phosphocreatine. AIM: The effect of exogenously applied creatine on phosphocreatine and ATP concentrations was studied under control and anoxic conditions. METHODS: Pregnant mice were fed orally with creatine monohydrate (2 g/kg body weight/day). Brainstem slices from these mice pups were compared with those from pups of non-creatine supplemented pregnant mice. Measurements were performed under normoxic and anoxic conditions. In addition, brainstem slices from non-creatine treated mice pups were incubated for 3 hours in control artificial cerebrospinal fluid (CSF) (n = 10) or in artificial CSF containing 200 microM creatine (n = 10). ATP and phosphocreatine contents were determined enzymatically in single brainstem slices. RESULTS: ATP concentrations were in the same range in all preparations. However, there was a significant increase of phosphocreatine in the brainstems from pups of creatine fed mice when compared with the brainstems of pups from non-creatine treated mice or in non-incubated brainstems of control animals. After 30 minutes anoxia, ATP as well as phosphocreatine concentrations remained significantly higher in creatine pretreated slices compared with controls. CONCLUSION: The data indicate that exogenous application of creatine is effective in neuroprotection. (+info)
Phosphorus 31 nuclear magnetic resonance spectroscopy suggests a mitochondrial defect in claudicating skeletal muscle.
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OBJECTIVE: Decreased oxygen supply is generally accepted as the primary cause of muscle dysfunction in patients with peripheral arterial occlusive disease (PAOD) and intermittent claudication, although reported morphologic changes in the mitochondria of claudicating muscle suggest that impaired energy utilization may also play a role. With the measurement of the phosphate-rich compounds of muscle energy metabolism (adenosinetriphosphate [ATP], adenosinediphosphate [ADP], and phosphocreatine [PCr]) and pH, phosphorus P 31 magnetic resonance spectroscopy ((31)P MRS) provides a unique, noninvasive method to investigate this hypothesis further. METHODS: Calf muscle bioenergetics were studied in 12 men with moderate claudication (ankle-brachial index >/=0.5 and .5, Pearson moment correlation). CONCLUSIONS: Phosphorus 31 MRS provides the first direct evidence of defective energy metabolism in the mitochondria of claudicating calf muscle. This defect appears to be independent of both arterial flow and the severity of occlusive disease in patients with mild to moderate claudication. Coupled with documented ultrastructural and DNA abnormalities in the mitochondria of claudicating skeletal muscle, these data provide evidence for a secondary cause of muscle dysfunction in intermittent claudication. (+info)
Aerobic recovery metabolism following a single isometric tetanus in frog sartorius muscle at 0 degrees C.
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1. Basal and recovery O2 consumption, delatO2, in frog sartorius muscles at 0 degrees C were measured with a polarographic electrode. Reproducible observations were made with the same muscle over many hours. 2. The experimental records had an exponential form except for the early phases of recovery following a single isometric tetanus. Diffusion of O2 within the muscle was adequate to account for this deviation from an exponential time course of recovery. The time constant of the recovery O2 consumption increased with the duration of tetanic stimulation from 5 to 20 sec. 3. Lactate synthesis was measureable in unstimulated aerobic muscles and increased in proportion to total O2 consumption as long as the muscle did not lack O2. The contribution of glycolysis to the total chemical energy production during recovery was 6-9%; for hypoxic muscles it was greater. 4. The resynthesis of phosphorylcreatine and the decrease in inorganic phosphate and free creatine following a tetanus showed an exponential time course similar to recovery O2. Initial concentrations were re-attained within 60 min following a 20 sec tetanus. 5. We conclude that recovery O2 consumpation is a useful and accurate measure of the net chemical energy utilization for a single contraction. (+info)
A temporal dissociation of energy liberation and high energy phosphate splitting during shortening in frog skeletal muscles.
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Measurements of the time course of high energy phosphate splitting and energy liberation were performed on rapidly shortening Rana pipiens skeletal muscles. In muscles contracting 30 times against small loads (less the 0.02P), the ratio of explained heat + work (H + W) (calculated from the measured high energy phosphate splitting) to observed H + W (from myothermal and mechanical measurements) was 0.68 +/- 0.08 and is in agreement with results obtained in isometric tetani of R. pipiens skeletal muscle. In lightly afterloaded muscles which were tetanized for 0.6a and whose metabolism was arrested at 3.0 s after the beginning of stimulation, a similar ratio of explained H + W to observed H + W was obtained. However, in identical contractions in which metabolism was arrested at 0.5-0.75 s after the beginning of stimulation, the ratio of explained H + W to observed H + W declined significantly to values ranging from 0.15 to 0.40. These results suggest that rapid shortening at the beginning of contraction induces a delay between energy production and measurable high energy phosphate splitting. This interpretation was tested and confirmed in experiments in which one muscle of a pair contracted isometrically while the other contracted against a small afterload. The afterload and stimulus pattern were arranged so that at the time metabolism was arrested, 0.5 s after the beginning of stimulation, the total energy production by both muscles was the same. Chemical analysis revealed that the isotonically contracting muscle spilt only 25% as much high energy phosphate as did the isometrically contracting muscle. (+info)