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PubMed1991

Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine.

We studied the effects of rapid atrial pacing during the final 10 minutes of a 70-minute, 31% reduction in coronary blood flow in anesthetized swine to understand the significance of apparent metabolic improvements during the initial 60 minutes of segmental ischemia. Within 5-10 minutes of ischemia, subendocardial phosphocreatine (PCr) and ATP were depleted to 47% and 63% of control, respectively; lactate accumulated within the subendocardium to 300% of control; and net arteriovenous lactate production occurred. Despite continued ischemia and no significant changes in the external determinants of myocardial oxygen consumption, by 60 minutes subendocardial PCr and lactate contents returned to near control levels and there was net arteriovenous lactate consumption. Ischemic left ventricular wall thickening and ATP levels remained depressed throughout the experiment. Atrial pacing during the final 10 minutes of ischemia again resulted in depletion of PCr and lactate production. Since the myocardium was capable of hydrolyzing PCr in response to atrial pacing at 60 minutes of ischemia, we conclude it was capable of hydrolyzing PCr during the period of constant ischemia when instead it was accumulating PCr. We propose the ischemic myocardium downregulates regional energy requirements below blood flow-limited rates of energy production during ischemia. This appears to be an active adaptation to ischemia and not a result of passive damage or cellular injury.

Adaptation, Physiological↗
PubMed1995

In vitro platelet ageing at 22 degrees C is reduced compared to in vivo ageing at 37 degrees C.

In these studies, platelet ageing during in vitro at 22 degrees C was compared with in vivo ageing using isotope labelling. Paired fresh and 5-d-stored platelets had a mean residual life-span (MRL) of 4.8 +/- 0.7 d and 3.2 +/- 0.9 d, respectively. After 2.1 +/- 0.4 d in vivo circulation, the MRL of the fresh platelets was equivalent to that of the 5-d-stored in vitro platelets. This suggests that platelet ageing for 5 d in vitro at 22 degrees C corresponds to 2.1 d in vivo ageing at 37 degrees C. Thus, the relative ageing at 22 degrees C in vitro was (2.1 d/5 d) = 0.42 of that at 37 degrees C in vivo. A similar ageing ratio (0.44) was obtained by measurement of the decrease in MRL during storage at 22 degrees C of platelets stored for 1, 5, 7, 10 and 14 d relative to the decrease in MRL of fresh platelets in vivo. ATP turnover rate at 22 degrees C was compared to the rate of 37 degrees C by measurement of the rates of platelet oxygen consumption and lactate production in vitro. In vitro ATP turnover at 22 degrees C versus 37 degrees C, was found to be 10.5 +/- 1.0 versus 21.6 +/- 1.4 mumol/10(12) plts/min, respectively. Thus, the ATP turnover ratio (0.48) at these two temperatures suggests that the relative decrease in ageing at 22 degrees C compared to 37 degrees C is similar to the relative decrease in metabolic rate at this temperature.

Adenosine Triphosphate↗
PubMed1990

Glycolytic component of rat spermatid energy and acid-base metabolism.

The impact of glycolysis on rat spermatid energy metabolism is made apparent by the simultaneous occurrence of the following three events upon glucose addition to the extracellular medium of a rat spermatid cell suspension: decrease in ATP content, exit of acid equivalents, and increased lactate production and efflux. In this work, we have studied the interrelations between these three phenomena. By measuring ATP content, net acid transport, lactate exit, oxygen consumption, intracellular pH, CO2 production, and glycolytic intermediates in the presence of glucose and glucose analogues, we conclude that 1) lactate production, decrease in ATP content, and acid equivalent exit are dependent on the metabolism of glucose up to different stages in glycolysis. 2) The decrease in ATP content is not directly related to the exit of acid equivalents from rat spermatids. 3) Glucose metabolism is a net ATP-consuming process at high intracellular ATP content but is a net ATP-producing process at low intracellular ATP concentration in rat spermatids. 4) Acid equivalent production arises from the metabolism of glucose beyond glyceraldehyde 3-phosphate dehydrogenase. 5) Lactic acid diffusion and/or lactate transport and CO2 production and exit could account for the glucose-dependent acid equivalent efflux in rat spermatids.

Acid-Base Equilibrium↗
PubMed1984

[Changes in energy metabolism and spinal cord blood flow following severe spinal cord injury].

Using a rat severe spinal cord injury model, serial determinations of local spinal cord blood flow and energy metabolism including ATP, ADP, AMP, energy charges, local tissue oxygen consumption and changes in pH values in the injured spinal cord tissue were compared topographically. Initially, following injury, energy metabolism was increased with increased ATP utilization and within 30 minutes energy metabolites were severely depleted. By 2 hours after spinal cord injury, a state of severe anaerobic metabolism was associated with the depletion of energy metabolites. This severe state of metabolic disruption and energy metabolite depletion, especially ATP, was followed by a progressive disturbance of spinal cord blood flow. By 3 hours following injury, the disturbances of spinal cord blood flow and energy metabolism were equal in severity. This study suggested that in the severely injured rat spinal cord, an initial depletion of energy metabolites creates a disruption of metabolic function which results in a progression of pathophysiological factors including.

Adenosine Triphosphate↗
PubMed1989

Protamine-induced reductions of endothelial cell ATP.

Protamine, a polycationic protein used to reverse heparin anticoagulation, is frequently associated with decreased oxygen consumption, systemic hypotension, pulmonary artery hypertension, and bradycardia. This investigation examines the hypothesis that these events reflect toxic effects of protamine on endothelial cells. Cultured bovine pulmonary artery endothelium was exposed to protamine (12.5 to 500 micrograms/ml, corresponding to clinical doses 0.75 to 30 mg/kg), either alone (n = 6) or 3 minutes after exposure to heparin, 0.1 IU/microgram protamine (n = 6). ATP was measured 1 to 180 minutes after protamine by a luciferase-luciferin assay and cell viability determined by trypan blue exclusion. Ultrastructure was assessed by transmission electron microscopy. Polylysine, 25 micrograms/ml, a cytotoxic polycationic agent, was also studied. Dose-dependent reductions in ATP (range, -11% to -51%) and ATP per viable cell (up to -41%) occurred. Decreases in ATP did not occur until after 30 minutes with protamine alone, compared with differences as early as 1 minute after protamine with prior heparin. Progressive mitochondrial injury was noted evident by swollen cristae, vacuolization, and eventual disruption. Polylysine caused similar changes. Protamine decreases endothelial cell ATP and prior heparin exposure accelerates this effect. The toxicity may reside in the positive charges on these molecules and mitochondrial damage may account for reductions in cellular ATP and systemic oxygen consumption.

Adenosine Triphosphate↗
PubMed1990

Metabolic and functional consequences of barium-induced contracture in rabbit myocardium.

Barium contracture tonically activates myocardium while preserving cellular integrity. We studied the metabolic and mechanical consequences of sustained Ba2+ contracture. We measured the time course of phosphocreatine (PCr), ATP, Pi, total phosphate, and intracellular pH via 31P nuclear magnetic resonance (NMR) in isolated, isovolumic rabbit hearts. For mechanical studies, we measured force transients and dynamic stiffness in excised rabbit right ventricular papillary muscles at different elapsed times in Ba2+ contracture. In the perfused hearts, PCr fell steadily to 20% of control after 60 min. ATP remained constant for approximately 25 min then fell to 25% by 60 min. Pi rose to 200% within 15 min and then remained unchanged, whereas total phosphate dropped steadily to 50% of control by 60 min. Myocardial O2 consumption remained near control for 30 min and then declined to 50% by 60 min. Consistent with ATP and O2 consumption measurements, mechanical responses were unchanged for approximately the first half hour. Because of the elevated Pi, however, myofilament kinetics may have been accelerated compared with the control metabolic state. After the initial period of stable contracture, the gradual alteration of mechanical behavior exhibited a progressive trend toward more rigor-like characteristics. In summary, myocardium in Ba2+ contracture is metabolically and mechanically stable for approximately 30 min but begins to degrade thereafter. When compared with other tonic states of activation, Ba2+ contracture appears to be less demanding energetically.

Animals↗
PubMed1999

Role of K+ATP channels in local metabolic coronary vasodilation.

ATP-sensitive potassium (K+ATP) channels have been shown to play a role in the maintenance of basal coronary vascular tone in vivo. K+ATP channels are also involved in the coronary vasodilator response to adenosine. The aim of this study was to determine the role of K+ATP channels in local metabolically mediated increases in coronary blood flow during cardiac electrical paired pacing without catecholamine effects. In 10 anesthetized closed-chest dogs, coronary blood flow was measured in the left circumflex coronary artery, and myocardial O2 consumption was calculated using the arteriovenous O2 difference. Cardiac interstitial adenosine concentration was estimated from coronary venous and arterial plasma adenosine measurements using a previously described, multicompartmental, axially distributed, mathematical model. Paired stimulation increased heart rate from 57 to 120 beats/min, myocardial O2 consumption 88%, and coronary blood flow 76%. During K+ATP channel blockade with glibenclamide, baseline coronary blood flow decreased in relation to myocardial O2 consumption and thus coronary sinus O2 tension fell. Paired-pulse pacing with glibenclamide resulted in increases in myocardial O2 consumption and coronary blood flow similar to those during control pacing. Coronary venous and estimated interstitial adenosine concentration did not increase sufficiently to overcome the glibenclamide blockade. In conclusion, K+ATP channels are not required for locally mediated metabolic increases in coronary blood flow that accompany myocardial O2 consumption during pacing tachycardia without catecholamines, and adenosine levels do not increase sufficiently to overcome the glibenclamide blockade.

Adenosine↗
PubMed1990

Metabolic changes in alveolar type II cells after exposure to hydrogen peroxide.

Since oxygen metabolites may play an important role in pulmonary oxidant injury, the effects of hydrogen peroxide (H2O2) on energy metabolism in alveolar type II cells isolated from rats were studied. The major effect of H2O2 is a rapid and dramatic reduction in the steady-state level of cellular ATP; e.g., ATP levels are reduced by 77 +/- 3% after only 5 min of exposure to H2O2 (0.5 mM). Cellular oxygen consumption is affected in a similar manner, suggesting that ATP synthesis is impaired. Experiments with isolated lung mitochondria demonstrate that exposure to 0.5 mM H2O2 for 5 min inhibits the rate of mitochondrial ATP synthesis by 51 +/- 3%. The site of mitochondrial ATP synthesis inhibition by H2O2 appears to be the adenosinetriphosphatase-synthase enzyme complex which phosphorylates ADP to ATP. Mitochondrial electron transport is unaffected. The association of 3-O-methylglucose with type II cells and glycolytic metabolism, measured as lactate production, are reduced by 25-35% by H2O2. The data also show that the cells are capable of recovery following exposure to H2O2, at least at lower exposure levels. These results indicate that exposure of type II cells to H2O2 alters the energy state of the cells by decreasing ATP synthesis. In turn, other important cellular functions may be impaired.

3-O-Methylglucose↗
PubMed2003

Formation of steady-state oxygen gradients in vitro: application to liver zonation.

We have developed a perfusion bioreactor system that allows the formation of steady state oxygen gradients in cell culture. In this study, gradients were formed in cultures of rat hepatocytes to study the role of oxygen in modulating cellular functions. A model of oxygen transport in our flat-plate reactor was developed to estimate oxygen distribution at the cell surface. Experimental measurements of outlet oxygen concentration from various flow conditions were used to validate model predictions. We showed that cell viability was maintained over a 24-h period when operating with a physiologic oxygen gradient at the cell surface from 76 to 5 mmHg O(2) at the outlet. Oxygen gradients have been implicated in the maintenance of regional compartmentalized metabolic and detoxification functions in the liver, termed zonation. In this system, physiologic oxygen gradients in reactor cultures contributed to a heterogeneous distribution of phosphoenolpyruvate carboxykinase (predominantly localized upstream) and cytochrome p450 2B (predominantly localized downstream) that correlates with the distribution of these enzymes in vivo. The oxygen gradient chamber provides a means of probing the oxygen effects in vitro over a continuous range of O(2) tensions. In addition, this system serves as an in vitro model of zonation that could be further extended to study the role of gradients in ischemia-reperfusion injury, toxicity, and bioartificial liver design.

Animals↗
PubMed1995

Adenine nucleotide depletion in cryopreserved human cardiac valves: the "stunned" leaflet interstitial cell population.

Preparation protocols for human cardiac valves are intended to minimize cytotoxicity because it has been thought that viable leaflet interstitial cells may enhance homograft durability. Preimplantation factors influencing the status of these cells at the time of transplantation include ischemia, disinfection, and cryopreservation freezing programs. In these experiments, adenine nucleotide quantitation was undertaken to assess metabolic consequences of preparation; preharvest ischemia served as an independent variable to examine the relationship between time of procurement (postmortem) and high-energy phosphate status of the cryopreserved leaflets at thaw. Nucleotides were measured using high-performance liquid chromatography performed on extracts of semilunar cusps from 25 cryopreserved human valves with documented ischemic times. Results indicate total adenine nucleotides (TAN; [ATP] + [ADP] + [AMP], in nmol TAN/mg leaflet protein) are higher (P < 0.05) after < 2 h of harvest ischemia (1.16 +/- 0.36) than with ischemic times of 3-6 h (undetected), 7-12 h (0.18 +/- 0.07), and 13-20 h (0.06 +/- 0.06). Depletion of ATP was similar, with many leaflets devoid of detectable levels. Net utilization of leaflet energy stores demonstrates time dependency when assayed after completed processing. However, relatively elevated catabolites, even with brief ischemia, and infrequently identified ATP, ADP, and AMP, suggest a consumption so accelerated that the following cryopreservation it is virtually independent of procurement-associated ischemia. We conclude resumption of a functional cell population obligates significant de novo phosphoanhydride boned reformation or a repopulation of dead/dying interstitial cells from a subset surviving the apparently severe rigors of valve preparation.

Adenine Nucleotides↗
PubMed1987

Phosphate-induced efflux of adenine nucleotides from rat-heart mitochondria: evaluation of the roles of the phosphate/hydroxyl exchanger and the dicarboxylate carrier.

Upon the addition of inorganic phosphate, isolated rat-heart mitochondria released endogenous adenine nucleotides. To elucidate the mechanism of this phosphate-induced efflux, we evaluated the relative roles of three inner mitochondrial membrane carriers: the adenine nucleotide translocase, the phosphate/hydroxyl exchanger, and the dicarboxylate carrier. Atractyloside (a specific inhibitor of the adenine nucleotide translocase) prevented this efflux, but did not inhibit mitochondrial swelling. Inhibitors of the phosphate/hydroxyl exchanger (200 microM n-ethylmaleimide and 10 microM mersalyl) did not inhibit phosphate-induced efflux. 200 microM mersalyl (which inhibited both the phosphate/hydroxyl exchanger and the dicarboxylate carrier) inhibited the rate of efflux approx. 65% Phenylsuccinate and 2-n-butylmalonate (inhibitors of the dicarboxylate carrier) partially inhibited phosphate-induced efflux and adenine nucleotide translocase activity. Mersalyl (200 microM) had no effect on adenine nucleotide translocase activity. Partial inhibition of the adenine nucleotide translocase by phenylsuccinate and butylmalonate could not explain the extent of inhibition of phosphate-efflux by these agents. Moreover, the rates of adenine nucleotide efflux in the presence of phenylsuccinate, butylmalonate, or mersalyl correlated well with the ability of these agents to inhibit succinate-supported respiration. We conclude that phosphate-induced efflux of adenine nucleotides from rat heart mitochondria occurs over the adenine nucleotide translocase, and that the site of action of the phosphate is not the phosphate/hydroxyl exchanger, but is likely the dicarboxylate carrier.

Adenine Nucleotides↗
PubMed1983

Rat heart mitochondria release adenosine.

Isolated rat heart mitochondria release adenosine under specific conditions. Lowest adenosine release occurs at 4 degrees C while highest release occurs in the presence of pyruvate + malate or rotenone at 30 degrees C. The release is attenuated during state 3 respiration, in the presence of atractyloside or in the presence of 1799. Oligomycin only partially decreases adenosine release. Release is unaffected by 200 microM Ca++ and is independent of oxygen concentration as low as 2 microM. The data are consistent with the hypothesis that adenosine is released from mitochondria via the adenine nucleotide transporter and the release is regulated by the intramitochondrial ATP to ADP ratio.

Adenosine↗
PubMed1984

Rhodamine 123 inhibits bioenergetic function in isolated rat liver mitochondria.

Rhodamine 123 accumulates in the mitochondria of living cells and exhibits selective anticarcinoma activity. The biochemical basis of toxicity was investigated by testing the effect of the dye on isolated rat liver mitochondria. Much lower concentrations of rhodamine 123 were required to inhibit ADP-stimulated respiration and ATP synthesis in well-coupled energized mitochondria than were required to inhibit uncoupled respiration and uncoupler-stimulated ATP hydrolysis. The amount of rhodamine 123 associated with the mitochondria was several-fold greater under energized as compared to non-energized conditions, which may explain why coupled functions appeared to be more sensitive than uncoupled functions to inhibition at low concentrations of rhodamine 123. It was concluded that the site of rhodamine 123 inhibition is most likely the F0F1 ATPase complex and possibly electron transfer reactions as well.

2,4-Dinitrophenol↗
PubMed1986

Mechanism of interaction of ticlopidine and its analogues with the energy-conserving mechanism in mitochondria.

It was shown recently that the antiaggregating agent ticlopidine and some of its analogues inhibit the energy-conserving mechanism in mitochondria [Abou-Khalil et al., Biochem. Pharmac. 33, 3893 (1984)]. In the present investigation, the mechanism of inhibition by these drugs was investigated by studying their effects on key reactions of oxidative phosphorylation. Liver mitochondria were isolated from Sprague-Dawley male rats, and the interactions of ticlopidine and six of its analogues with those key reactions were tested. We found: The transport of phosphate, glutamate and succinate into mitochondria was not affected significantly by ticlopidine or any of its analogues; however, it was inhibited by both mersalyl and N-ethylmaleimide as expected. There was no inhibitory effect of the tested drugs on the mitochondrial [3H]ADP translocation activity; rather, ticlopidine produced a concentration-dependent increase of that activity, reaching 54% with 20 micrograms/ml. Ticlopidine and its analogue, PCR 5325, increased the latent ATPase activity by about 400% and the DNP-dependent ATPase by about 50%. Also, PCR 4099 caused a 115% increase in the latent activity, whereas the effects of the remaining analogues varied from slight activation to slight inhibition. Under nonphosphorylation conditions, the mitochondrial H+ extrusion resulting from succinate oxidation was inhibited by ticlopidine in a concentration-dependent manner reaching a quasi total inhibition with 40 micrograms/ml. While PCR 5325 gave results similar to ticlopidine, PCR 4099 was less inhibitory and the other analogues were ineffective. These data indicate that the inhibitory action caused by ticlopidine and some of its analogues on oxidative phosphorylation does not reside at one particular site in the mitochondrial membrane; rather, the inhibition seems to be the outcome of profound alterations in mitochondrial ADP translocase, latent ATPase, and proton translocation in the respiratory chain.

Adenosine Diphosphate↗
PubMed1984

Malonyl CoA inhibition of carnitine palmityltransferase in rat heart mitochondria.

The effects of malonyl CoA on carnitine palmityltransferase I (CPT-I), fatty acid-supported state 3 respiration, and carnitine reversal of palmityl CoA inhibition of state 3 respiration and of the adenine nucleotide translocator, were studied in isolated rat heart mitochondria. Malonyl CoA was a potent competitive inhibitor of CPT-I with an I50 of 0.8 microM. Fasting did not affect CPT-I activity or the I50 value of malonyl CoA. Malonyl CoA inhibited fatty acid-supported respiration and prevented carnitine from reversing the inhibition of the adenine nucleotide translocator by palmityl CoA. These findings suggest that malonyl CoA may affect fatty acid oxidation in the heart.

Acyl Coenzyme A↗