Reduced high-energy phosphate levels in rat hearts. I. Effects of alloxan diabetes

1976 ◽  
Vol 230 (6) ◽  
pp. 1744-1750 ◽  
Author(s):  
TB Allison ◽  
SP Bruttig ◽  
Crass MF ◽  
RS Eliot ◽  
JC Shipp
Keyword(s):  
Oxidative Metabolism ◽  
Oxygen Delivery ◽  
Rat Heart ◽  
High Energy ◽  
Diabetic Rat ◽  
High Energy Phosphate ◽  
Atp Production ◽  
Rat Hearts

Significant alterations in heart carbohydrate and lipid metabolism are present 48 h after intravenous injection of alloxan (60 mg/kg) in rats. It has been suggested that uncoupling of oxidative phosphorylation occurs in the alloxanized rat heart in vivo, whereas normal oxidative metabolism has been demonstrated in alloxan-diabetic rat hearts perfused in vitro under conditions of adequate oxygen delivery. We examined the hypothesis that high-energy phosphate metabolism might be adversely affected in the alloxan-diabetic rat heart in vivo. Phosphocreatine and ATP were reduced by 58 and 45%, respectively (P is less than 0.001). Also, oxygen-dissociation curves were shifted to the left by 4 mmHg, and the rate of oxygen release from blood was reduced by 21% (P is less than 0.01). Insulin administration normalized heart high-energy phosphate compounds. ATP production was accelerated in diabetic hearts perfused in vitro with a well-oxygenated buffer. These studies support the hypothesis that oxidative ATP production in the alloxan-diabetic rat heart is reduced and suggest that decreased oxygen delivery may have a regulatory role in the oxidative metabolism of the diabetic rat heart.

Metabolic inhibition in the perfused rat heart: evidence for glycolytic requirement for normal sodium homeostasis

1998 ◽  
Vol 274 (4) ◽  
pp. H1082-H1089 ◽  
Author(s):  
José Dizon ◽  
Daniel Burkhoff ◽  
Joseph Tauskela ◽  
John Whang ◽  
Paul Cannon ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Rat Heart ◽  
High Energy ◽  
Shift Reagent ◽  
Resonance Spectroscopy ◽  
High Energy Phosphate ◽  
Perfused Rat Heart ◽  
Rat Hearts ◽  
Rapid Pacing ◽  
Subcellular Compartmentalization

Subcellular compartmentalization of energy stores to support different myocardial processes has been exemplified by the glycolytic control of the ATP-sensitive K+ channel. Recent data suggest that the control of intracellular sodium (Nai) may also rely on glycolytically derived ATP; however, the degree of this dependence is unclear. To examine this question, isolated, perfused rat hearts were exposed to hypoxia, to selectively inhibit oxidative metabolism, or iodoacetate (IAA, 100 μmol/l), to selectively inhibit glycolysis. Nai and myocardial high-energy phosphate levels were monitored using triple-quantum-filtered (TQF)23Na and31P magnetic resonance spectroscopy, respectively. The effects of ion exchange mechanisms (Na+/Ca2+, Na+/H+) on Nai were examined by pharmacological manipulation of these channels. Nai, as monitored by shift reagent-aided TQF 23Na spectral amplitudes, increased by ∼220% relative to baseline after 45 min of perfusion with IAA, with or without rapid pacing. During hypoxia, Nai increased by ∼200% during rapid pacing but did not increase in unpaced hearts or when the Na+/H+exchange blocker ethylisopropylamiloride (EIPA, 10 μmol/l) was used. Neither EIPA nor a low-Ca2+perfusate (50 μmol/l) could prevent the rise in Nai during perfusion with IAA. Myocardial function and high-energy phosphate stores were preserved during inhibition of glycolysis with IAA and continued oxidative metabolism. These results suggest that glycolysis is required for normal Na+ homeostasis in the perfused rat heart, possibly because of preferential fueling of Na-K-adenosinetriphosphatase by glycolytically derived ATP.

Effect of cyclocreatine feeding on levels of amino acids in rat hearts before and after an ischemic episode

1991 ◽  
Vol 261 (6) ◽  
pp. H1919-H1926
Author(s):  
M. Osbakken ◽  
D. N. Zhang ◽  
D. Nelson ◽  
M. Erecinska
Keyword(s):  
Amino Acids ◽  
High Energy ◽  
Global Ischemia ◽  
Sprague Dawley ◽  
High Energy Phosphate ◽  
Rat Hearts ◽  
Before And After ◽  
Reperfusion Period ◽  
Phosphate Compounds

Feeding Sprague-Dawley rats for 3 wk a diet containing 1% by weight of cyclocreatine increased the reservoir of the high-energy phosphate compounds but also caused alterations in the levels of the two key amino acids, aspartate and glutamate. Both were decreased by approximately 50% in the presence of an unaltered content of glutamine. In vitro exposure of these hearts to sequential perfusion, global ischemia, and reperfusion in the absence of added amino acids resulted in changes in aspartate, glutamate, and glutamine that were different from those in hearts from control rats. In the cyclocreatine-fed group, aspartate concentration ([aspartate]) and [glutamate] fell after global ischemia, whereas [glutamine] was unaltered. [Glutamine] decreased, however, in the reperfusion period. In control hearts, the predominant effect was a steady decline in glutamine, which was accompanied by either less than 10% (after global ischemia) or 30-50% fall (after reperfusion) in [aspartate] and [glutamate]. The concentration of tissue Pi was smaller in hearts from cyclocreatine-fed rats and appeared to increase more slowly during ischemia. In the presence of rotenone and aminooxyacetate, heart homogenates catalyzed production of glutamate from glutamine, which was markedly stimulated by Pi and inhibited by H+. It is postulated that 1) phosphate-activated glutaminase is an important enzyme that determines cardiac [glutamate], 2) lower [phosphate] in hearts from rats fed cyclocreatine is responsible for the apparently lesser activity of glutaminase, 3) breakdown of the high-energy phosphate compounds and consequent rise in Pi activates glutaminase, and 4) slow breakdown of glutamine during global ischemia is a result of inhibition of glutaminase by H+.

scholarly journals Ca2+-Dependent Interaction of S100A1 with F1-ATPase Leads to an Increased ATP Content in Cardiomyocytes

2007 ◽  
Vol 27 (12) ◽  
pp. 4365-4373 ◽  
Author(s):  
Melanie Boerries ◽  
Patrick Most ◽  
Jonathan R. Gledhill ◽  
John E. Walker ◽  
Hugo A. Katus ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Atpase Activity ◽  
Cardiac Contractility ◽  
Gel Filtration ◽  
Dependent Manner ◽  
Atp Content ◽  
Atp Production ◽  
Rat Hearts

ABSTRACT S100A1, a Ca2+-sensing protein of the EF-hand family that is expressed predominantly in cardiac muscle, plays a pivotal role in cardiac contractility in vitro and in vivo. It has recently been demonstrated that by restoring Ca2+ homeostasis, S100A1 was able to rescue contractile dysfunction in failing rat hearts. Myocardial contractility is regulated not only by Ca2+ homeostasis but also by energy metabolism, in particular the production of ATP. Here, we report a novel interaction of S100A1 with mitochondrial F1-ATPase, which affects F1-ATPase activity and cellular ATP production. In particular, cardiomyocytes that overexpress S100A1 exhibited a higher ATP content than control cells, whereas knockdown of S100A1 expression decreased ATP levels. In pull-down experiments, we identified the α- and β-chain of F1-ATPase to interact with S100A1 in a Ca2+-dependent manner. The interaction was confirmed by colocalization studies of S100A1 and F1-ATPase and the analysis of the S100A1-F1-ATPase complex by gel filtration chromatography. The functional impact of this association is highlighted by an S100A1-mediated increase of F1-ATPase activity. Consistently, ATP synthase activity is reduced in cardiomyocytes from S100A1 knockout mice. Our data indicate that S100A1 might play a key role in cardiac energy metabolism.

Studies on Glycogen Metabolism in Normal and Diabetic Rat Heart In Vivo

1973 ◽  
Vol 51 (5) ◽  
pp. 637-641 ◽  
Author(s):  
Indrajit Das
Keyword(s):  
Rat Heart ◽  
Glycogen Synthesis ◽  
Active Form ◽  
Glycogen Metabolism ◽  
Significant Loss ◽  
Diabetic Rat ◽  
Type I ◽  
Glycogen Synthetase

A study has been made on the key enzymes involved in synthesis and breakdown of glycogen and the major intermediates in glycogen synthesis in isolated normal and streptozotocin diabetic rat heart. A significant loss of hexokinase isoenzyme type I and type II was observed in the soluble fraction of hearts from starved and diabetic rats.No significant change was observed in total and active form of glycogen synthetase and phosphorylase in diabetic rat heart, but glycogen synthetase phosphatase activity in vitro was found to be considerably less. Treatment with insulin restored the synthetase phosphatase in vitro activity, and also significantly increased synthetase I in vivo.Tissue content of the major intermediates on the glycogen synthetic pathway, glucose 6-phosphate, glucose 1-phosphate, and UDP-glucose, was found to be significantly higher in diabetic rat heart than in normal. Insulin (4 I.U./kg for 30 min) was able to normalize the high values of tissue content of the glycogen precursors found in diabetic heart. The decreased glycogen synthesis in diabetic rat heart seems to be mainly due to the decreased activity of glycogen synthetase phosphatase.

Redox regulation of Ito remodeling in diabetic rat heart

2005 ◽  
Vol 288 (3) ◽  
pp. H1417-H1424 ◽  
Author(s):  
Xun Li ◽  
Zhi Xu ◽  
Shumin Li ◽  
George J. Rozanski
Keyword(s):  
Ion Channels ◽  
Rat Heart ◽  
Redox Regulation ◽  
Control Level ◽  
Diabetic Rat ◽  
Cell Functions ◽  
Control Heart ◽  
Rat Hearts ◽  
Glucose 6 Phosphate Dehydrogenase

Oxidative stress and the resulting change in cell redox state are proposed to contribute to pathogenic alterations in ion channels that underlie electrical remodeling of the diseased heart. The present study examined whether K+ channel remodeling is controlled by endogenous oxidoreductase systems that regulate redox-sensitive cell functions. Diabetes was induced in rats by streptozotocin, and experiments were conducted after 3–5 wk of hyperglycemia. Spectrophotometric assays of ventricular tissue extracts from diabetic rat hearts revealed divergent changes in two major oxidoreductase systems. The thioredoxin (TRX) system in diabetic rat heart was characterized by a 52% decrease in TRX reductase (TRXR) activity from control heart ( P < 0.05), whereas TRX activity was 1.7-fold greater than control heart ( P < 0.05). Diabetes elicited similar changes in the glutaredoxin (GRX) system: glutathione reductase was decreased 35% from control level ( P < 0.05), and GRX activity was 2.5-fold greater than in control heart ( P < 0.05). The basal activity of glucose-6-phosphate dehydrogenase, which generates NADPH required by the TRX and GRX systems, was not altered by diabetes. Voltage-clamp studies showed that the characteristically decreased density of the transient outward K+ current ( Ito) in isolated diabetic rat myocytes was normalized by in vitro treatment with insulin (0.1 μM) or the metabolic activator dichloroacetate (1.5 mM). The effect of these agonists on Ito was blocked by inhibitors of glucose-6-phosphate dehydrogenase. Moreover, inhibitors of TRXR, which controls the reducing activity of TRX, also blocked upregulation of Ito by insulin and dichloroacetate. These data suggest that K+ channels underlying Ito are regulated in a redox-sensitive manner by the TRX system and the remodeling of Ito that occurs in diabetes may be due to decreased TRXR activity. We propose that oxidoreductase systems are an important repair mechanism that protects ion channels and associated regulatory proteins from irreversible oxidative damage.

scholarly journals Reduced metabolism in the hypothalamus of the anorectic anx/anx mouse

2017 ◽  
Vol 233 (1) ◽  
pp. 15-24 ◽  
Author(s):  
Ulrika Bergström ◽  
Charlotte Lindfors ◽  
Marie Svedberg ◽  
Jeanette E Johansen ◽  
Jenny Häggkvist ◽  
...  
Keyword(s):  
Food Intake ◽  
Metabolic Stress ◽  
High Energy ◽  
Neuronal Firing ◽  
Energy Status ◽  
High Energy Phosphate ◽  
Aberrant Expression ◽  
High Energy Phosphate Metabolism

The anorectic anx/anx mouse exhibits a mitochondrial complex I dysfunction that is related to aberrant expression of hypothalamic neuropeptides and transmitters regulating food intake. Hypothalamic activity, i.e. neuronal firing and transmitter release, is dependent on glucose utilization and energy metabolism. To better understand the role of hypothalamic activity in anorexia, we assessed carbohydrate and high-energy phosphate metabolism, in vivo and in vitro, in the anx/anx hypothalamus. In the fasted state, hypothalamic glucose uptake in the anx/anx mouse was reduced by ~50% of that seen in wild-type (wt) mice (P < 0.05). Under basal conditions, anx/anx hypothalamus ATP and glucose 6-P contents were similar to those in wt hypothalamus, whereas phosphocreatine was elevated (~2-fold; P < 0.001) and lactate was reduced (~35%; P < 0.001). The anx/anx hypothalamus had elevated total AMPK (~25%; P < 0.05) and GLUT4 (~60%; P < 0.01) protein contents, whereas GLUT1 and GLUT3 were similar to that of wt hypothalamus. Interestingly, the activation state of AMPK (ratio of phosphorylated AMPK/total AMPK) was significantly decreased in hypothalamus of the anx/anx mouse (~60% of that in wt; P < 0.05). Finally, during metabolic stress (ischemia), accumulation of lactate (measure of glycolysis) and IMP and AMP (breakdown products of ATP) were ~50% lower in anx/anx vs wt hypothalamus. These data demonstrate that carbohydrate and high-energy phosphate utilization in the anx/anx hypothalamus are diminished under basal and stress conditions. The decrease in hypothalamic metabolism may contribute to the anorectic behavior of the anx/anx mouse, i.e. its inability to regulate food intake in accordance with energy status.

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.

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