Energy Metabolism In Liver Research Articles

Hepatic O2 exchange and liver energy metabolism in hyperdynamic porcine endotoxemia: effects of iloprost.

To compare the effects of a 12 h continuous infusion of iloprost, a stable prostacyclin analogue, on hepatic blood flow (Qliv), O2 exchange, and energy metabolism during a 24 h hyperdynamic, porcine endotoxemia with volume resuscitation alone. Prospective, randomized, experimental study with repeated measures. Investigational animal laboratory. Twenty-eight domestic pigs: 16 animals during endotoxemia with volume resuscitation alone (ETX), 12 with endotoxemia, volume resuscitation, and treatment with iloprost (ILO). Endotoxemia was initiated by continuous infusion of E. coli lipopolysaccharide. Animals were resuscitated with hetastarch, aimed at maintaining a MAP of > 60 mmHg. After 12 h of endotoxemia, iloprost was administered for 12 h in the treatment group, titrated to avoid pharmacologically induced hypotension (MAP < 60 mmHg). Iloprost significantly increased Qliv, with no effect on hepatic O2 delivery. Mean capillary hemoglobin O2 saturation (HbScO2) on the liver surface, as well as HbScO2 frequency distributions--a measure of microcirculatory O2 availability--remained unchanged. Treatment with iloprost, however, significantly attenuated the endotoxin-induced derangements of cellular energy metabolism as reflected by the diminished progressive decrease in hepatic lactate uptake rate and a blunted increase in hepatic venous lactate/pyruvate ratios. While endotoxin significantly increased endogenous glucose production (EGP) rate, iloprost restored EGP to normal at the end of the experiment. Thus, in a clinically relevant model of human sepsis, iloprost did not produce potential adverse effects but rather ameliorated hepatic metabolic disturbances and, thereby, hepatic energy balance.

Effect of catecholamine depletion on oxidative energy metabolism in rat liver, brain and heart mitochondria; use of reserpine.

Regulation of mitochondrial functions in vivo by catecholamines was examined indirectly by depleting the catecholamines stores by reserpine treatments of the experimental animals. Reserpine treatment resulted in decreased respiratory activity in liver and brain mitochondria with the two NAD+-linked substrates: glutamate and pyruvate + malate with succinate ATP synthesis rate decreased in liver mitochondria only. With ascorbate + TMPD system, the ADP/O ratio and ADP phosphorylation rate decreased in brain mitochondria. For the heart mitochondria, state 3 respiration rates decreased for all substrates. In the liver mitochondria basal ATPase activity decreased by 51%, but in the presence of Mg2+ and/or DNP increased significantly. In the brain and heart mitochondria ATPase activities were unchanged. The energy of activation in high temperature range increased liver mitochondrial ATPase while in brain mitochondria reserpine treatment resulted in abolishment in phase transition. Total phospholipid (TPL) content of the brain mitochondria increased by 22%. For the heart mitochondria TPL content decreased by 19% and CHL content decreased by 34%. Tissue specific differential effects were observed for the mitochondrial phospholipid composition. Liver mitochondrial membranes were more fluidized in the reserpine-treated group. The epinephrine and norepinephrine contents in the adrenals decreased by 68 and 77% after reserpine treatment.

Cold preservation injury in rat liver: effect of liposomally-entrapped adenosine triphosphate

Background/Aims: Energy charge and capacity for adenosine triphosphate (ATP) synthesis have been demonstrated to play a major role in the maintenance of organ function after liver preservation for transplantation. The aim of this study was to evaluate whether a supply of liposomally-entrapped ATP during preservation could improve the energy state and metabolism of cold-stored rat liver. Methods: In the first set of experiments, the uptake of ATP-containing liposomes and their effects on hepatic viability were determined in isolated perfused unstored rat liver. In the second set of experiments, rat livers were preserved for 18 h at 4°C in UW solution in the presence of these liposomes, and effects on energy state, cell volume and metabolism were evaluated. In each part, data were compared with adequate control, unloaded liposome-treated, and free ATP-treated groups ( n=6 in each group). Results: In non-stored livers, ATP-containing liposomes were taken up by the liver; they did not alter hepatic viability and induced a decrease in energy substrate consumption (glucose and amino acids), and an improvement in intrahepatic ATP content (+23% vs. Control). Addition of liposomally-entrapped ATP during cold storage produced a significant attenuation of the decrease in hepatic ATP content (Lip ATP 2: 524±45 vs. Control 2: 364±106 nmol/g; p<0.05), and induced, during reperfusion, a decrease in proteolysis associated with an increase in cell volume compared with the other groups (Lip ATP 2: 633±63 vs. Control 2: 532±38, Unloaded Lip 2: 483±55 and Free ATP 2: 500±29 μl/g; p<0.01). Conclusions: These data indicate that liposomally-entrapped ATP represents an effective means to improve liver graft energy state and function. The decrease in protein degradation may be related to the modification of cell volume.

A novel hydroxyl radical scavenger, nicaraven, protects the liver from warm ischemia and reperfusion injury

Background: Reactive oxygen species have been considered to be involved in liver injury at the procurement, preservation, and transplantation from donors without beating hearts. A novel hydroxyl radical scavenger, nicaraven with hydrophilic and lipophilic properties, infiltrates both intracellular and extracellular spaces where it effectively scavenges reactive oxygen species. Protection by nicaraven against ischemia and reperfusion damage of the brain, heart, and kidneys has been shown. The effect of this agent on the liver remains unclear. Methods: Two-hour total hepatic vascular exclusion was used. Eighteen beagle dogs were randomly assigned to 2 groups: 12 animals were not treated (group I) and 6 were treated with nicaraven (group II). Nicaraven was administered intravenously (2mg/kg/min) for 60 minutes before ischemia and for 3 hours, starting 30 minutes before reperfusion. Results: Two-week survival rates were 25% in group I and 100% in group II (P <.01). Nicaraven inhibited lipid peroxidation in the liver, improved hepatic and systemic hemodynamics and energy metabolism, and suppressed liver enzyme release, endothelin-1 elevation in hepatic venous blood, histologic damage, and neutrophil infiltration into the liver. Conclusions: Nicaraven exerted hepatic protection against warm ischemia and reperfusion injury. This may indicate nicaraven as a potential candidate to attenuate liver injury from warm ischemia and preservation in transplantation from donors without beating hearts. (Surgery 2000;127:661-9.)

Influence of hepatic ammonia removal on ureagenesis, amino acid utilization and energy metabolism in the ovine liver.

The mass transfers of O2, glucose, NH3, urea and amino acids across the portal-drained viscera (PDV) and the liver were quantified, by arterio-venous techniques, during the last 4 h of a 100 h infusion of 0 (basal), 150 or 400 mumol NH4HCO3/min into the mesenteric vein of three sheep given 800 g grass pellets/d and arranged in a 3 x 3 Latin-square design. Urea irreversible loss rate (ILR) was also determined by continuous infusion of [14C]urea over the last 52 h of each experimental period. PDV and liver movements of glucose, O2 and amino acids were unaltered by NH4HCO3 administration, although there was an increase in PDV absorption of non-essential amino acids (P = 0.037) and a trend for higher liver O2 consumption and portal appearance of total amino acid-N, glucogenic and non-essential amino acids at the highest level of infusion. PDV extraction of urea-N (P = 0.015) and liver removal of NH3 (P < 0.001), release of urea-N (P = 0.002) and urea ILR (P = 0.001) were all increased by NH4HCO3 infusion. Hepatic urea-N release (y) and NH3 extraction (x) were linearly related (R2 0.89), with the slope of the regression not different from unity, both for estimations based on liver mass transfers (1.16; SE 0.144; P(b) not equal to 1 = 0.31) and [14C]urea (0.97; SE 0.123; P(b) not equal to 1 = 0.84). The study indicates that a sustained 1.5 or 2.4-fold increase in the basal NH3 supply to the liver did not impair glucose or amino acid supply to non-splanchnic tissues; nor were additional N inputs to the ornithine cycle necessary to convert excess NH3 to urea. Half of the extra NH3 removed by the liver was, apparently, utilized by periportal glutamate dehydrogenase and aspartate aminotransferase for sequential glutamate and aspartate synthesis and converted to urea as the 2-amino moiety of aspartate.

Effect of aluminium-induced Alzheimer like condition on oxidative energy metabolism in rat liver, brain and heart mitochondria

Prolonged exposure of rats to aluminium (Al) can result in an Alzheimer-like condition. To get better insights into the biochemical defects underlying AD, senility and ageing we exposed rats for long durations (90–100 days) to soluble salt of aluminium (AlCl 3) and checked its influence on mitochondrial respiratory activity in the liver, brain and heart. In the liver and brain mitochondria the ADP/O ratio was impaired with NAD + linked substrates. State three respiration decreased with glutamate in the liver. For succinate, the ADP/O ratio decreased in the liver mitochondria while state three and four respiration decreased in the brain mitochondria. In both the tissues respiration rates decreased with ascorbate+TMPD as the substrate. In the heart mitochondria ADP/O ratios with NAD + linked substrates decreased, while respiration rates increased with all the substrates except for ascorbate+TMPD. Temperature kinetics data showed different effects on ATPase in the mitochondria from the three tissues. Data on lipid/phospholipid profiles suggested that the observed changes in energy metabolism were not mediated via lipid changes. Long-term exposure to Al resulted in≈100% increase in Al content of liver and brain mitochondria but in the heart there was phenomenal 11-fold increase, indicating thereby that the effects of Al exposure were indirect rather than direct due to Al accumulation.

An enhancement of nitric oxide production regulates energy metabolism in rat hepatocytes after a partial hepatectomy

Background/Aims: Infection after a liver resection often results in hepatic failure. Nitric oxide is one of the candidates which has been suspected to cause cellular dysfunction during infection in the liver. We have previously reported that the inflammatory cytokine interleukin-1β (IL-1β) induced the expression of the inducible nitric oxide synthase gene in primary cultured rat hepatocytes. We hypothesized that an enhancement of nitric oxide production after the resection was implicated in a change in liver energy metabolism, thus resulting in liver dysfunction. Methods: In this study, we performed a 70% hepatectomy or a sham operation in rats, and then isolated hepatocytes from the remnant liver by collagenase perfusion. The cultured hepatocytes were treated with cytokines including IL-1β. The effects on nitric oxide induction, the ATP content and ketone body ratio (acetoacetate/β-hydroxybutyrate) were then compared between the partial hepatectomized (PH) and shamoperated (control) rats. Results: IL-1β augmented the induction of nitric oxide production two-fold in hepatocytes from the PH rats as compared to the control rats. IL-1β markedly decreased the ATP content in the PH rats, although IL-1β also decreased the ATP content in the control rats, but to a lesser extent. IL-1β also decreased the ketone body ratio in both groups. The addition of l-arginine further stimulated the inhibition of the ATP levels and the ketone body ratio concomitantly with increased nitric oxide production in the PH rats. N G-monomethyl- l-arginine, an inhibitor of nitric oxide synthase, abolished the effects of IL-1β on the ATP levels and ketone body ratio, as well as on the nitric oxide production. Conclusions: These results demonstrate that the decreased ATP content observed in PH rats resulted from an increase in nitric oxide production. The decrease in ketone body ratio indicates that nitric oxide-induced mitochondrial dysfunction contributes significantly to ATP attenuation in hepatocytes. Therefore, the regulation of nitric oxide induction may be crucial for preventing liver failure after a hepatic resection.

Protective role of nitric oxide in ischemia and reperfusion injury of the liver

Background: The suppressed production of nitric oxide (NO), associated with endothelial dysfunction, is thought to be a cause of ischemia and reperfusion injury of the liver. But findings of the salutary effects of NO enhancement on such injury have been conflicting. In this study, we tested our hypothesis that NO enhancement would attenuate ischemic liver injury. For this purpose, an NO precursor, L-arginine, and a novel NO donor, FK409, were applied to a 2-hour total hepatic vascular exclusion model in dogs. Study Design: L-arginine was administered IV at a dose of 100 mg/kg twice (n = 5), while 300 mg/kg twice of FK409 was infused continuously into the portal vein (n = 5). The drugs were given to the animals for 30 and 60 minutes before and after ischemia, respectively. Nontreated animals were used as the control (n = 10). Two-week survival, systemic and hepatic hemodynamics indices, liver function tests, energy metabolism, and histopathology were analyzed. Results: Both treatments comparably augmented hepatic tissue blood flow, decreased liver enzyme release, and increased high-energy phosphate restoration during the reperfusion period, all of which contributed to rescuing all of the treated animals from the 2-hour total hepatic ischemia. In contrast, ischemia caused 70% mortality in the control group. Histologically, structural abnormality and neutrophil infiltration were markedly attenuated by the treatments. Systemic hypotension was observed in the animals treated with FK409, however. Conclusions: Our data demonstrate that NO enhancement alleviates the liver injury caused by ischemia and reperfusion. The supplementation of L-arginine, rather than FK409, is considered more applicable to clinical use because of the absence of systemic adverse effects.

Energy Metabolism in Liver of Anoxia-Tolerant Turtle Species (Pseudemys scripta): A Model for Studying Hepatic Tolerance to Cold Hypoxia

We have studied biochemical markers of energy metabolism and glycolysis by enzyme analyses and1H NMR spectroscopy in livers of the freshwater turtle,Pseudemys scripta,after vascular flush and cold storage. Values for hepatic ATP content and energy charge remained unchanged for 24 h and showed only small declines between 24 and 48 h of cold hypoxia. Lactate and glucose levels increased over the 48-h period, demonstrating, respectively, progressive glycolysis and glycogenolysis. These observations are in contrast to those made in mammalian liver, where ATP levels fall precipitously during the first few hours of cold hypoxia and glycolysis is inhibited. Additional changes suggested by1H NMR spectroscopy may indicate a role for other metabolic pathways. Isolated organs of species such asPseudemysmay be useful models for studying the biochemical basis of resistance to cold hypoxic damage.

Liver energy metabolism during hibernation in the golden-mantled ground squirrel,Spermophilus lateralis

Large changes in ATP production capacities and rates have been reported in mammalian hibernators throughout the different stages of the hibernation cycle. In this study we showed that total extractable liver [ATP], [ADP], and [ATP]/[ADP] do not differ among summer normothermic, hibernating, and aroused golden-mantled ground squirrels, Spermophilus lateralis, indicating that metabolism remains well balanced throughout the hibernation cycle. This implies that rates of ATP consumption must be down-regulated during deep hibernation in order to maintain this balance. Despite this, basal oxygen-consumption rates [Formula: see text] of hepatocytes isolated from hibernating, aroused, and summer cold-acclimated ground squirrels were 22.4–35.1% higher than those from ground squirrels in the summer normothermic condition when measured at 37 °C. The relatively high hepatocyte [Formula: see text] may help to minimize interbout arousal times, reducing energy demands during the hibernation season. At 7 °C, hepatocyte [Formula: see text] values do not differ among the four groups; however, the Q10for hepatocyte [Formula: see text] is significantly lower for the summer group, suggesting lower temperature sensitivity. Despite the seasonal changes in thyroid hormone status known to occur in scuirid hibernators, the proportion of hepatocyte [Formula: see text] attributed to Na+,K+-ATPase, estimated by inhibition with 1 mM ouabain, is only around 15% and does not differ among hibernation/seasonal conditions.

Effect of a nucleotide and nucleosides mixture on energy metabolism in rat liver during ischemia and reperfusion : Mitsutoshi Ogino, Makoto Usami, Kouji Furichi, Ichirou Yasuda, Taichi Kanamaru, Hiroshi Kasahara, Kai Sun, Youichi Saitoh, Hideaki Nomura, Shin-ichi Nishimatsu, Harumasa Ohyanagi, Hideki Kamidaira and Hiroomi Yokoyama From the First Department of Surgery, Kobe University School of Medicine: 7-5-2 Chuo-ku, Kobe, 650,

Effect of a nucleotide and nucleosides mixture on energy metabolism in rat liver during ischemia and reperfusion : Mitsutoshi Ogino, Makoto Usami, Kouji Furichi, Ichirou Yasuda, Taichi Kanamaru, Hiroshi Kasahara, Kai Sun, Youichi Saitoh, Hideaki Nomura, Shin-ichi Nishimatsu, Harumasa Ohyanagi, Hideki Kamidaira and Hiroomi Yokoyama From the First Department of Surgery, Kobe University School of Medicine: 7-5-2 Chuo-ku, Kobe, 650,

The effect of tilsuprost on the liver mitochondria in taurocholate pancreatitis in rats with antecedent acute ethanol abuse.

The damage to the liver appears to be an important aspect of multisystem organ failure in acute pancreatitis with poor prognosis. The objective of this study was to evaluate the protective effect of stable prostacyclin analogue--tilsuprost on the liver energy metabolism in taurocholate pancreatitis in rats preceded by acute ethanol intake. The respiratory control ratio (RCR) and ADP/O ratio of liver mitochondria with glutamate+malate as substrates and mitochondrial DNP (uncoupler)-dependent ATPase activity were significantly depressed after 12 h of taurocholate pancreatitis-the effects that were not significantly aggravated by antecedent acute ethanol intake. Tilsuprost (0.3 mg/kg i.g.) given just before induction of pancreatitis partly prevented the impairment of mitochondrial oxidative and phosphorylative functions, however these positive effects were limited in acute pancreatitis preceded by acute ethanol intake. These results suggest that prostacyclin analogues could be effective in the treatment of hepatic complications in acute pancreatitis, however their effectiveness could be limited in the case of acute ethanol antecedent abuse.

Glucose and Energy Metabolism in Rat Liver after Ischemic Damage Assessed by13C and31P NMR Spectroscopy

Glucose and energy metabolism in rat liver after ischemic damage was investigated byin vivo31P NMR spectroscopy,1H-detected13C NMR spectroscopy, andin vitro13C NMR spectroscopy using [1-13C]glucose as a tracer. Arterial ketone body ratio (AKBR; acetoacetate/β-hydroxybutylate) and oxygen consumption of isolated mitochondria were also examined to evaluate hepatic function. The rats were divided into three groups: (A) without ischemia, (B) 10-min ischemia, and (C) 30-min ischemia. ATP was almost depleted at 10 min of ischemia and recovered after reperfusion, but the recovery was not complete. The recovery after 30-min ischemia was smaller than that after 10-min ischemia. [13C]Glucose was infused immediately after the reperfusion, andin vivo1H-detected13C NMR demonstrated sequential glucose incorporation into the liver. However, the incorporation depended on the blood sugar levels and did not reflect hepatic function.In vitro13C NMR disclosed the glycogen C-1 signal in the nonischemic group and alanine C-3 and lactate C-3 signals in the ischemic groups. The intensity of glycogen was correlated positively (r= 0.648,P= 0.002) and those of alanine and lactate were correlated negatively (r= −0.831,P< 0.005 andr= −0.710,P= 0.005, respectively) to the ATP levels as measured byin vivo31P NMR. These results suggested that ATP level participates in glycogenesis and gluconeogenesis in the liver. The AKBR and oxygen consumption of isolated mitochondria were the highest in the 10-min ischemia group, which might reflect mitochondrial compensatory response to the decreased ATP level.

Effects of ischemia-hypoxia induced by interruption of uterine blood flow on fetal rat liver and brain enzyme activities and offspring behavior

The effects of acute perinatal ischemia-hypoxia on fetal liver and brain energy metabolism, fetal brain total free fatty acid concentration and subsequent offspring behavior were investigated in rats. Ischemia-hypoxia was induced at term either by ligation of the uterine blood vessels or submersion of the entire uterine horn in warmed saline. Fetuses of the adjacent horn served as within-dam controls for all assessments and fetuses of dams which had not undergone the surgical stress served as independent controls for enzyme assays. Ischemia-hypoxia was associated with reduced activity of fatty acid synthase in the liver and brain. Total free fatty acid concentration significantly increased in the fetal hypoxic brain. Pups not used for enzyme analyses were cross-fostered for behavioral assessments. Relative to the enzymatic alterations, there were few behavioral alterations associated with ischemia-hypoxia. At postnatal day 30, rats made hypoxic by ligation of the uterine blood vessels had decreased caudate nucleus and brain stem weights relative to within-dam controls. At postnatal day 85, rats made hypoxic by submersion of the uterine horn had decreased olfactory bulb weight. The results of this study indicate an initial acute response to a brief period of ischemia-hypoxia at term pregnancy in the fetal rat brain and liver.

Energy metabolism and regeneration in transgenic mouse liver expressing creatine kinase after major hepatectomy

BACKGROUND & AIMS: The catalysis of a creatinine/phosphocreatine system by creatine kinase is not expressed in the liver. The aim of this study was to examine the energy energy metabolism and regeneration after hepatectomy using transgenic mouse liver expressing creatine kinase to clarify the effects of phosphocreatine on liver regeneration. METHODS: Transgenic mice were divided into two groups: group 1 was fed normal chow, and group 2 was fed 10% creatine chow for 5 days. Hepatic energy metabolism was evaluated before and after hepatectomies. Changes in remnant liver weight gain and bromodeoxyuridine labeling index were measured after 70% and 80% hepatectomies. RESULTS: Hepatic adenosine triphosphate level 24 hours after 70% hepatectomy was significantly higher in group 2 than group 1 (P<0.05). In group 2, mitochondrial adenosine triphosphate synthesis was enhanced because of elevated intramitochondrial adenine nucleotide content before hepatectomy, leading to sufficient adenosine triphosphate synthesis after a 70% hepatectomy. Bromodeoxyuridine DNA labeling index 24 hours after a 70% hepatectomy was significantly higher in group 2 than group 1. Rapid liver weight gain was observed in group 2 after a 70% hepatectomy. CONCLUSIONS: Abundant phosphocreatine promotes liver regeneration by reinforced hepatic energy metabolism. Gene transfer of creatine kinase to the liver may be a potential method in liver surgery. (Gastroenterology 1996 Apr;110(4):1166-74)

Doxorubicin-Induced Disturbance of the Energy Metabolism after Hepatectomy

This study was designed to clarify effects of γ-glutamylcysteine ethyl ester, a prodrug of glutathione, on doxorubicin-induced changes in liver energy metabolism after hepatectomy. Rats were divided into two major groups dependent on whether hepatectomy had been performed. Rats undergoing hepatectomy were subdivided into three groups: the control group, 70% of the liver was resected; the doxorubicin group, after hepatectomy 2 mg/kg body weight doxorubicin was administered intraperitoneally; and the doxorubicin + γ-glutamylcysteine group, 30 min before hepatectomy 50 mg/kg body weight of γ-glutamylcysteine ethyl ester was injected intravenously and other procedures were performed as in the doxorubicin group. In the group not undergoing hepatectomy, 2 mg/kg body weight doxorubicin was administered intraperitoneally after a sham operation. Rats in each group were sacrificed 24, 72, and 120 hr after hepatectomy or sham operation, and the remnant liver was isolated. Liver mitochondrial function, adenine nucleotide concentrations, and glutathione and glutathione peroxidase activities were determined. Doxorubicin did not show any significant effects on parameters measured in rats not undergoing hepatectomy. Liver mitochondrial function was increased significantly 24 hr after hepatectomy, and significant decreases in adenine nucleotide concentrations were observed 24 and 72 hr after hepatectomy. Doxorubicin inhibited the increase in mitochondrial function associated with hepatectomy and delayed recovery of liver adenine nucleotide concentrations. Significant increases in tissue glutathione concentrations were observed 24 and 72 hr after hepatectomy. These significant increases in glutathione concentrations were not observed in rats treated with doxorubicin 72 hr after hepatectomy. Furthermore, doxorubicin decreased glutathione peroxidase activity after hepatectomy. Administration of γ-glutamylcysteine ethyl ester lessened these doxorubicin-induced changes. These results indicate that changes in the glutathione redox system might be involved in the doxorubicin-induced deterioration of the remnant liver energy metabolism. Clinical application of γ-glutamylcysteine ethyl ester might be expected.

Regulation of energy metabolism in liver

Energy metabolism in liver has to cope with the special tasks of this organ in intermediary metabolism. Main ATP-generating processes in the liver cell are the respiratory chain and glycolysis, whereas main ATP-consuming processes are gluconeogenesis, urea synthesis, protein synthesis, ATPases and mitochondrial proton leak. Mitochondrial respiratory chain in the intact liver cell is subject to control mainly by substrate (hydrogen donors, ADP, oxygen) transport and supply and proton leak/slip. Whereas hormonal control is mainly on substrate supply to mitochondria, proton leak/slip is supposed to play an important role in the modulation of the efficiency of oxidative phosphorylation.

The Importance of Calcium-Related Effects on Energetics at Hypothermia: Effects of Membrane-Channel Antagonists on Energy Metabolism of Rat Liver

During normothermic metabolism, the active pumping of Ca2+ across the cell membrane, mitochondria, and specialized sequestration organelles accounts for a large proportion of total energy expenditure in the cell. This study was designed to determine the effects of Ca2+ channel antagonists (chlorpromazine, verapamil, nifedipine, prenylamine, and nisoldipine) on energy metabolism and levels of glycolytic substrate (glucose) and anaerobic endproduct (lactate) during cold ischemia in rat livers. We hypothesized that if the passive channels were blocked during cold ischemia, then the ATP requirement of active ion pumping would be reduced and ATP levels and energy charge ratios would remain higher throughout the ischemic period; thus, viability of the liver would also be increased after prolonged ischemia. The most positive effect on energy metabolism was observed in the chlorpromazine-treated livers, followed by verapamil treatment. In the chlorpromazine treatment, total adenylate (TA) contents were 0.5-1.0 μmol/g (P < 0.05) higher than the sham group for most of the 24-h time course. Energy charge (EC) ratios were 0.05-0.07 higher than sham values up to 4-10 h ischemia. Verapamil treatment was less effective, but still exhibited positive effects on TA levels at several time points (20 min, 10 h, and 24 h) throughout the entire 24-h period. In both of these groups, TA values by 24 h ischemia were similar to levels at 10 h in the sham group (3.1 μmol/g), thus showing a considerable effect in maintaining adenylate levels. Despite similar pharmacological antagonist activities, ATP levels in the nifedipine, prenylamine, and nisoldipine treatment groups were 1.0-1.5 μmol/g (P < 0.05) less than the corresponding sham group (without Ca2+ antagonists) over the first 1 h ischemia. The decreases in high energy adenylate levels were reflected in lower EC ratios in these three groups; values were 0.06-0.17 (P < 0.05) lower than corresponding sham values. Finally, it was an unexpected finding that the sham injection (0.5 μmg/kg ethanol + PEG400) resulted in the sustained elevation of ATP, total adenylates, and EC values over the first h; EC ratios remained at initial (t = 0) values (EC = 0.71 ± 0.01) up to 1 h.

Protective effect of heat shock pretreatment with heat shock protein induction before hepatic warm ischemic injury caused by Pringle's maneuver

Induction of heat shock proteins is thought to have a > cytoprotective effect against environmental stress and to result in a better ischemic tolerance. The protective ability of heat exposure and heat shock protein 72 (HSP 72) induction before warm ischemia caused by Pringle's maneuver was evaluated in rats. Heat exposed rats (HS) were compared with control animals (C). The gene expression (messenger RNA) of HSP 72 and HSP 72 were detected by Northern and Western blot analyses. During 40 minutes of in situ reperfusion, liver energy metabolism and levels of standard liver enzymes were evaluated. The survival rate was determined after postoperative day 7. After heat exposure and recovery, messenger RNA of HSP 72 and HSP 72 can be detected strongly in HS group but not in C group. During reperfusion HS group exhibited a significantly (p < 0.01) improved energy metabolism, and the release of liver enzymes was significantly (p < 0.001) reduced compared with C group. Seven-day survival rate was 100% in HS group but at 50% was significantly impaired (p < 0.05) in C group. Heat exposure associated with HSP induction has a significant protective effect against warm ischemic liver injury, which results in a relevant improvement of survival rate.

Effects of fasting, intermittent feeding, or continuous parenteral nutrition on rat liver and brain energy metabolism as assessed by 31P-NMR

We wanted to determine what happens to brain PCr and ATP relative to that in liver during a series of dietary manipulation consisting of a severe fast, during eating (when nutrients are intermittently supplied), and during and after PN-100, when an excess amount of nutrients are continuously supplied, using 31P-NMR spectroscopy, in rats randomized to a Fast or Fed group in which energy was provided either as chow or as PN-100. Liver ATP concentration, and brain and liver 31P-nuclear magnetic resonance (NMR) spectras were measured serially. Brain energy metabolism was not different between groups and among days. In contrast, Fasted group showed increased liver ATP/Pi ratio and decreased ATP concentration and ATP/phosphomonoester ratio, there being no difference between Fed and PN-100 groups. Data suggest that brain energy metabolism is maintained regardless of whether energy is supplied intermittently or continuously, and during a negative caloric intake period, brain energy metabolism is quantitatively preserved, suggesting that ATP production by liver is subservient to brain ATP state.