scholarly journals Early Postischemic Dantrolene-Induced Amelioration of Poly(ADP-Ribose) Polymerase-Related Bioenergetic Failure in Neonatal Rat Brain Slices

1998 ◽  
Vol 18 (12) ◽  
pp. 1346-1356 ◽  
Author(s):  
Robert C. Tasker ◽  
Sati K. Sahota ◽  
Finbar E. Cotter ◽  
Stephen R. Williams
Keyword(s):  
Ex Vivo ◽  
Brain Slices ◽  
High Energy ◽  
Neonatal Rat ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Energy Depletion ◽  
Neonatal Rat Brain ◽  
Energy Failure ◽  
Induced Amelioration

In the infant brain, ischemia-induced ionic and enzyme mechanisms may independently lead to cell death by energy depletion: resequestration of calcium mobilized from intracellular stores consumes ATP, and activated poly(ADP-ribose) polymerase (PARP) uses oxidized nicotinamide adenine dinucleotide to form polyADP-ribosyl nuclear proteins associated with DNA damage, Using 31P nuclear magnetic resonance spectroscopy, we have monitored intracellular pH and cellular energy metabolites in ex vivo neonatal rat cerebral cortex before, during, and after substrate and oxygen deprivation, In an insult that exhibited secondary energy failure and apoptosis we identified a relative 25% augmentation of high-energy phosphates at the end of recovery when the ryanodine-receptor antagonist, dantrolene, was introduced in the early (0- to 40-minute) but not late (40- to 120-minute) stage of recovery ( P < 0,05). In contrast to the absence of a late dantrolene-sensitive effect, inhibition of PARP with 3-methoxybenzamide was as effective ( P < 0.05) as early dantrolene, even when introduced after a 40-minute delay. The dantrolene and 3-methoxybenzamide effects on high-energy phosphates were not additive, rather the early dantrolene-sensitive effect nullified the potential 3-methoxybenzamide effect. Therefore, in this vascular-independent neonatal preparation, postischemic mobilization of calcium from intracellular stores is associated with PARP-related energy depletion. Inhibition of either of these processes confers improved postischemic bioenergetic recovery in the developing brain.

scholarly journals Hypercarbia and Mild Hypothermia, Only When Not Combined, Improve Postischemic Bioenergetic Recovery in Neonatal Rat Brain Slices

2000 ◽  
Vol 20 (3) ◽  
pp. 612-619 ◽  
Author(s):  
Robert C. Tasker ◽  
Sati K. Sahota ◽  
Stephen R. Williams
Keyword(s):  
Mild Hypothermia ◽  
Ex Vivo ◽  
Brain Slices ◽  
Neonatal Rat ◽  
Resonance Spectroscopy ◽  
Immature Brain ◽  
Bicarbonate Buffer ◽  
Cellular Energy ◽  
Neonatal Rat Brain

In the immature brain, postischemic metabolism may be influenced beneficially by the effect of inducing hypercarbia or hypothermia. With use of 31P nuclear magnetic resonance spectroscopy, intracellular pH (pHi) and cellular energy metabolites in ex vivo neonatal rat cerebral cortex were measured before, during, and after substrate and oxygen deprivation in in vitro ischemia. Early postischemic hypothermia (fall in temperature −3.2 ± 1.0°C) delayed the normalization of pHi after ischemia by inducing an acid shift in pHi ( P < 0.01). Postischemic hypercarbia (Krebs—Henseleit bicarbonate buffer equilibrated with 10% carbon dioxide in oxygen) and hypothermia induced separate, but potentially additive, reversible decreases in pHi, each of approximately −0.16 pH unit ( P < 0.05). When these postischemic perturbations were applied in isolation, there was significant improvement of ∼20% in the recovery of β-ATP ( P < 0.05). In combination, however, hypercarbia and hypothermia worsened recovery in ATP by ∼20% ( P < 0.05). In control tissue, which had not been exposed to ischemia, ATP content was also significantly reduced by co-administration of the two treatments ( P < 0.05), an effect that persisted even after discontinuing the perturbing conditions. Therefore, in this vascular-independent neonatal preparation, early postischemic modulation of metabolism by hypercarbia or hypothermia appears to confer improved bioenergetic recovery, but only if they are not administered together.

scholarly journals Comparison of the Effects of Cyclosporin a on the Metabolism of Perfused Rat Brain Slices during Normoxia and Hypoxia

2002 ◽  
Vol 22 (3) ◽  
pp. 342-352 ◽  
Author(s):  
Natalie Serkova ◽  
Paul Donohoe ◽  
Sven Gottschalk ◽  
Carsten Hainz ◽  
Claus U. Niemann ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cyclosporin A ◽  
Rat Brain ◽  
Ex Vivo ◽  
Brain Slices ◽  
High Energy ◽  
Metabolic Effects ◽  
Resonance Spectroscopy ◽  
Buffer Solution ◽  
Mitochondrial Energy Metabolism

The authors evaluated and compared the metabolic effects of cyclosporin A in the rat brain during normoxia and hypoxia/reperfusion. Ex vivo31P magnetic resonance spectroscopy experiments based on perfused rat brain slices showed that under normoxic conditions, 500 μg/L cyclosporin A significantly reduced mitochondrial energy metabolism (nucleotide triphosphate, 83 ± 9% of controls; phosphocreatine, 69 ± 9%) by inhibition of the Krebs cycle (glutamate, 77 ± 5%) and oxidative phosphorylation (NAD+, 65 ± 14%) associated with an increased generation of reactive oxygen species (285 ± 78% of control). However, the same cyclosporin A concentration (500 μg/L) was found to be the most efficient concentration to inhibit the hypoxia-induced mitochondrial release of Ca2+ in primary rat hippocampal cells with cytosolic Ca2+ concentrations not significantly different from normoxic controls. Addition of 500 μg/L cyclosporin A to the perfusion medium protected high-energy phosphate metabolism (nucleotide triphosphate, 11 ± 15% of control vs. 35 ± 9% with 500 μg/L cyclosporin A) and the intracellular pH (6.2 ± 0.1 control vs. 6.6 ± 0.1 with cyclosporin A) in rat brain slices during 30 minutes of hypoxia. Results indicate that cyclosporin A simultaneously decreases and protects cell glucose and energy metabolism. Whether the overall effect was a reduction or protection of cell energy metabolism depended on the concentrations of both oxygen and cyclosporin A in the buffer solution.

scholarly journals Intracellular energetics and critical Po2 in resting ischemic human skeletal muscle in vivo

2010 ◽  
Vol 299 (5) ◽  
pp. R1415-R1422 ◽  
Author(s):  
Ian R. Lanza ◽  
Michael A. Tevald ◽  
Douglas E. Befroy ◽  
Jane A. Kent-Braun
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Ex Vivo ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Atp Production ◽  
Resting Muscle

During ischemia and some types of muscular contractions, oxygen tension (Po2) declines to the point that mitochondrial ATP synthesis becomes limited by oxygen availability. Although this critical Po2 has been determined in animal tissue in vitro and in situ, there remains controversy concerning potential disparities between values measured in vivo and ex vivo. To address this issue, we used concurrent heteronuclear magnetic resonance spectroscopy (MRS) to determine the critical intracellular Po2 in resting human skeletal muscle in vivo. We interleaved measurements of deoxymyoglobin using 1H-MRS with measures of high-energy phosphates and pH using 31P-MRS, during 15 min of ischemia in the tibialis anterior muscles of 6 young men. ATP production and intramyocellular Po2 were quantified throughout ischemia. Critical Po2, determined as the Po2 corresponding to the point where PCr begins to decline (PCrip) in resting muscle during ischemia, was 0.35 ± 0.20 Torr, means ± SD. This in vivo value is consistent with reported values ex vivo and does not support the notion that critical Po2 in resting muscle is higher when measured in vivo. Furthermore, we observed a 4.5-fold range of critical Po2 values among the individuals studied. Regression analyses revealed that time to PCrip was associated with critical Po2 and the rate of myoglobin desaturation ( r = 0.83, P = 0.04) but not the rate of ATP consumption during ischemia. The apparent dissociation between ATP demand and myoglobin deoxygenation during ischemia suggests that some degree of uncoupling between intracellular energetics and oxygenation is a potentially important factor that influences critical Po2 in vivo.

Magnetic resonance spectroscopy of high-energy phosphates and lactate immediately after coronary artery bypass surgery

Perfusion ◽  
1998 ◽  
Vol 13 (5) ◽  
pp. 328-333 ◽  
Author(s):  
D NF Harris ◽  
J A Wilson ◽  
S D Taylor-Robinson ◽  
K M Taylor
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Cerebral Ischaemia ◽  
Artery Bypass ◽  
High Energy ◽  
Jugular Bulb ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Intracellular Acidosis ◽  
High Incidence

Hypothermic cardiopulmonary bypass (CPB) is associated with a high incidence of neuropsychological defects, marked cerebral swelling immediately after surgery and jugular bulb desaturation during rewarming. This suggests cerebral ischaemia may occur, but evidence is indirect. We studied four patients with 31P magnetic resonance spectroscopy (MRS) and four with 1H MRS before and immediately after coronary surgery. There was no visible lactate in 1H MR spectra. In 31P MR spectra, the ratio of phosphocreatine to adenosine triphosphate was maintained (before: 2.13 ± 0.86 vs after: 2.57 ± 1.31; mean ± 1 SD) and there was no intracellular acidosis (intracellular pH: 7.1 ± 0.04 vs 7.16 ± 0.08), while phosphocreatine/inorganic phosphate was increased immediately after the operation (2.92 ± 0.37 vs 6.39 ± 2.67, p = 0.03). This suggests rebound replacement of energy stores following recovery from temporary cerebral ischaemia during CPB: intra-operative studies would be needed to test this hypothesis further.

Muscle metabolic responses to exercise above and below the “critical power” assessed using 31P-MRS

2008 ◽  
Vol 294 (2) ◽  
pp. R585-R593 ◽  
Author(s):  
Andrew M. Jones ◽  
Daryl P. Wilkerson ◽  
Fred DiMenna ◽  
Jonathan Fulford ◽  
David C. Poole
Keyword(s):  
Critical Power ◽  
Quadriceps Muscle ◽  
High Energy ◽  
Knee Extension ◽  
Work Rate ◽  
Metabolic Responses ◽  
Time To Exhaustion ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Constant Work Rate

We tested the hypothesis that the asymptote of the hyperbolic relationship between work rate and time to exhaustion during muscular exercise, the “critical power” (CP), represents the highest constant work rate that can be sustained without a progressive loss of homeostasis [as assessed using 31P magnetic resonance spectroscopy (MRS) measurements of muscle metabolites]. Six healthy male subjects initially completed single-leg knee-extension exercise at three to four different constant work rates to the limit of tolerance (range 3–18 min) for estimation of the CP (mean ± SD, 20 ± 2 W). Subsequently, the subjects exercised at work rates 10% below CP (<CP) for 20 min and 10% above CP (>CP) for as long as possible, while the metabolic responses in the contracting quadriceps muscle, i.e., phosphorylcreatine concentration ([PCr]), Pi concentration ([Pi]), and pH, were estimated using 31P-MRS. All subjects completed 20 min of <CP exercise without duress, whereas the limit of tolerance during >CP exercise was 14.7 ± 7.1 min. During <CP exercise, stable values for [PCr], [Pi], and pH were attained within 3 min after the onset of exercise, and there were no further significant changes in these variables (end-exercise values = 68 ± 11% of baseline [PCr], 314 ± 216% of baseline [Pi], and pH 7.01 ± 0.03). During >CP exercise, however, [PCr] continued to fall to the point of exhaustion and [Pi] and pH changed precipitously to values that are typically observed at the termination of high-intensity exhaustive exercise (end-exercise values = 26 ± 16% of baseline [PCr], 564 ± 167% of baseline [Pi], and pH 6.87 ± 0.10, all P < 0.05 vs. <CP exercise). These data support the hypothesis that the CP represents the highest constant work rate that can be sustained without a progressive depletion of muscle high-energy phosphates and a rapid accumulation of metabolites (i.e., H+ concentration and [Pi]), which have been associated with the fatigue process.

Influence of intracellular acidosis on contractile function in the working rat heart

1987 ◽  
Vol 253 (6) ◽  
pp. H1499-H1505 ◽  
Author(s):  
F. M. Jeffrey ◽  
C. R. Malloy ◽  
G. K. Radda
Keyword(s):  
Stroke Volume ◽  
Intracellular Ph ◽  
Rat Heart ◽  
Contractile Function ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Intracellular Acidosis ◽  
Tension Development ◽  
O2 Delivery

The decrease in myocardial contractility during ischemia, hypoxia, and extracellular acidosis has been attributed to intracellular acidosis. Previous studies of the relationship between pH and contractile state have utilized respiratory or metabolic acidosis to alter intracellular pH. We developed a model in the working perfused rat heart to study the effects of intracellular acidosis with normal external pH and optimal O2 delivery. Intracellular pH and high-energy phosphates were monitored by 31P nuclear magnetic resonance spectroscopy. Hearts were perfused to a steady state with a medium containing 10 mM NH4Cl (extracellular pH, 7.4). The subsequent washout of NH3 from the cytosol generated a slight acidosis (from intracellular pH 7.0 to 6.8) which was associated with little change in the determinants of O2 consumption (rate-pressure product) and O2 delivery (coronary flow). Acidosis induced a substantial decrease in aortic flow and stroke volume which was associated with little change in peak systolic pressure. Results were qualitatively similar at different external [Ca2+] (1.75, 2.5, 3.15 mM) and preload (12 or 21 cmH2O) but were most prominent at the lowest external [Ca2+] and left atrial pressure. In contrast to this model of isolated intracellular acidosis, hearts subject to a respiratory (extracellular plus intracellular) acidosis showed a marked reduction in pressure development. It was concluded that 1) for the same intracellular acidosis the influence on tension development was more pronounced with a combined extra- and intracellular acidosis than with an isolated intracellular acidosis, and 2) stroke volume at constant preload was impaired by intracellular acidosis even though changes in developed pressure were minimal. These observations suggest that isolated intracellular acidosis has adverse effects on diastolic compliance and/or relaxation.

scholarly journals Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

1995 ◽  
Vol 15 (1) ◽  
pp. 88-96 ◽  
Author(s):  
Yuichi Maruki ◽  
Raymond C. Koehler ◽  
Jeffrey R. Kirsch ◽  
Kathleen K. Blizzard ◽  
Richard J. Traystman
Keyword(s):  
Lipid Peroxidation ◽  
Blood Flow ◽  
Intracranial Pressure ◽  
Intracellular Ph ◽  
High Energy ◽  
Vehicle Group ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Early Reperfusion ◽  
Tirilazad Mesylate

Acidosis may augment cerebral ischemic injury by promoting lipid peroxidation. We tested the hypothesis that when acidosis is augmented by hyperglycemia, pretreatment with the 21-aminosteroid tirilazad mesylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400–500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spectroscopy. During ischemia, microsphere-determined CBF decreased to 8 ± 4 ml min−1 100 g−1 and intracellular pH decreased to 5.6 ± 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 ± 21% of baseline, but then declined progressively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the tirilazad group (77 ± 35 vs. 36 ± 19%), although postischemic hyperemia was similar. By 45 min, the tirilazad group had a higher intracellular pH (6.5 ± 0.5 vs. 5.9 ± 0.6) and a lower intracranial pressure (18 ± 6 vs. 52 ± 24 mm Hg). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was >67% and pH was >6.7 in six of eight tirilazad-treated dogs. Thus, tirilazad acts during early reperfusion to prevent secondary metabolic decay associated with severe acidotic ischemia. If tirilazad acts by inhibiting lipid peroxidation, then these data are consistent with extreme acidosis limiting recovery by a mechanism involving lipid peroxidation.

Regional blood flow and skeletal muscle energy status in endotoxemic rats

1987 ◽  
Vol 252 (5) ◽  
pp. E581-E587 ◽  
Author(s):  
M. M. Jepson ◽  
M. Cox ◽  
P. C. Bates ◽  
N. J. Rothwell ◽  
M. J. Stock ◽  
...  
Keyword(s):  
Blood Flow ◽  
Protein Synthesis ◽  
Regional Blood Flow ◽  
High Energy ◽  
Whole Body ◽  
Sublethal Dose ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Energy Status ◽  
Brown Adipose

Endotoxins induce muscle wasting in part as a result of depressed protein synthesis. To investigate whether these changes reflect impaired energy transduction, blood flow, O2 extraction, and high-energy phosphates in muscle and whole-body O2 consumption (VO2) have been measured. VO2 was measured for 6h after an initial sublethal dose of endotoxin (Escherichia coli lipopolysaccharide 0.3 mg/100 g body wt sc) or saline and during 6h after a second dose 24 h later. In fed or fasted rats, VO2 was either increased or better maintained after endotoxin. In anesthetized fed rats 3-4 after the second dose of endotoxin VO2 was increased, and this was accompanied by increased blood flow to liver (hepatic arterial supply), kidney, and perirenal brown adipose tissue and a 57 and 64% decrease in flow to back and hindlimb muscle, respectively, with no change in any other organ. Hindlimb arteriovenous O2 was unchanged, indicating markedly decreased aerobic metabolism in muscle, and the contribution of the hindlimb to whole-body VO2 decreased by 46%. Adenosine 5'-triphosphate levels in muscle were unchanged in endotoxin-treated rats, and this was confirmed by topical nuclear magnetic resonance spectroscopy, which also showed muscle pH to be unchanged. These results show that although there is decreased blood flow and aerobic oxidation in muscle, adenosine 5'-triphosphate availability does not appear to be compromised so that the endotoxin-induced muscle catabolism and decreased protein synthesis must reflex some other mechanism.

scholarly journals Noninvasive Monitoring of Training Induced Muscle Adaptation with -MRS: Fibre Type Shifts Correlate with Metabolic Changes

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Eike Hoff ◽  
Lars Brechtel ◽  
Patrick Strube ◽  
Paul Konstanczak ◽  
Gisela Stoltenburg-Didinger ◽  
...  
Keyword(s):  
Fibre Type ◽  
Gastrocnemius Muscle ◽  
Noninvasive Monitoring ◽  
High Energy ◽  
Metabolic Changes ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Type Ii ◽  
Fibre Type Composition ◽  
Fast Twitch

Purpose. To evaluate training induced metabolic changes noninvasively with magnetic resonance spectroscopy (-MRS) for measuring muscle fibre type adaptation.Methods. Eleven volunteers underwent a 24-week training, consisting of speed-strength, endurance, and detraining (each 8 weeks). Prior to and following each training period, needle biopsies and -MRS of the resting gastrocnemius muscle were performed. Fibre type distribution was analyzed histologically and tested for correlation with the ratios of high energy phosphates ([PCr]/[], [PCr]/[βATP] and [PCr + ]/[βATP]). The correlation between the changes of the -MRS parameters during training and the resulting changes in fibre composition were also analysed.Results. We observed an increased type-II-fibre proportion after speed-strength and detraining. After endurance training the percentage of fast-twitch fibres was reduced. The progression of the [PCr]/[]-ratio was similar to that of the fast-twitch fibres during the training. We found a correlation between the type-II-fibre proportion and [PCr]/[] (, ) or [PCr]/[βATP] (, ); the correlations between its changes (delta) and the fibre-shift were significant as well (delta[PCr]/[] , delta[PCr]/[βATP] , ).Conclusion. Shifts in fibre type composition and high energy phosphate metabolite content covary in human gastrocnemius muscle. Therefore -MRS might be a feasible method for noninvasive monitoring of exercise-induced fibre type transformation.

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