phosphocreatine and Shock--Septic

To explore the role of uncoupling protein 2 (UCP2) during myocardial dysfunction in a canine model of endotoxin shock, 26 mongrel canines were randomly divided into the following four groups: A (control group; n = 6), B2 (shock after 2 h; n = 7), B4 (shock after 4 h; n = 7), and B6 (shock after 6 h; n = 6). Escherichia coli endotoxin was injected into the canines via the central vein, and hemodynamics were monitored. Energy metabolism, UCP2 mRNA and protein expression, and UCP2 localization were analyzed, and the correlation between energy metabolism changes, and UCP2 expression was determined. After the canine endotoxin shock model was successfully established, the expression of UCP2 mRNA and protein was found to increase, with later time points showing significant increases (P < 0.05). Immunofluorescence assays of UCP2 in heart tissue showed that UCP2 was localized in the cytoplasm, and its expression pattern was the same as that found in the mRNA and protein analyses. The energy metabolism results revealed that the ADP levels increased, but the ATP and phosphocreatine (PCr) levels and ATP/ADP and PCr/ATP ratios decreased in the model. In particular, the PCr/ATP ratio was significantly different from that of the control group 6 h after shock (P < 0.05). Furthermore, correlation analysis showed that the UCP2 protein and mRNA levels were negatively correlated with myocardial energy levels. In summary, decreased energy synthesis can occur in the myocardium during endotoxin shock, and UCP2 may play an important role in this process. The negative correlation between UCP2 expression and energy metabolism requires further study, as the results might contribute to the treatment of sepsis with heart failure.

Topics: Adenosine Triphosphate; Animals; Disease Models, Animal; Dogs; Energy Metabolism; Female; Immunohistochemistry; Ion Channels; Male; Mitochondrial Proteins; Myocardium; Phosphocreatine; RNA, Messenger; Shock, Septic; Uncoupling Protein 2

The mechanisms responsible for acute renal failure in sepsis are not understood. Measurement of tissue ATP might help to understand this process but, in the large animal, it is hampered by major technical difficulties.. To develop a technique to monitor ATP in the kidney of a large mammal during the induction of septic shock and then circulatory arrest.. Implantation of a custom-made phosphorus coil around the left kidney. Induction of septic shock by intravenous E. coli administration. Acquisition of 31 P magnetic resonance (MR) spectroscopic data at 3-tesla before and during septic shock over several hours. Induction of euthanasia and measurement of the same 31 P signal immediately and thirty minutes after circulatory arrest.. Clear reproducible 31 P MR spectra were obtained before and after the induction of septic shock and euthanasia. They indicated limited changes in ATP during septic shock. An expected rapid and dramatic decrease in ATP occurred with euthanasia.. It is possible to sequentially monitor renal bioenergetics in a large mammal during septic shock using an implanted custom-made phosphorus coil and 3-tesla MR technology. This technique offers a novel approach to the investigation of septic renal failure.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Bacteremia; Disease Models, Animal; Escherichia coli Infections; Female; Kidney; Magnetic Resonance Spectroscopy; Phosphocreatine; Phosphorus Isotopes; Sheep; Shock; Shock, Septic; Thionucleotides

Norepinephrine (NE), a standard of care, AVP, an alternative candidate, and L-canavanine (LC), a selective inhibitor of inducible nitric oxide synthase, were compared for efficacy and innocuousness on global and regional hemodynamics, plasmatic and tissue lactate-to-pyruvate ratio (L/P), tissue high-energy phosphates, renal function, and tissue capillary permeability in a rat model of endotoxic normokinetic shock. Mean arterial pressure (MAP) decreased ( approximately 35%) but aortic blood flow increased during endotoxin infusion (P < 0.05 vs. control). Additionally, there was a decrease in mesenteric (MBF) and renal (RBF) blood flows along with regional-to-systemic ratio (P < 0.05 vs. control). All tested drugs restored MAP to basal levels but slightly decreased abdominal aortic flow; however, RBF and MBF remained unchanged. Endotoxin significantly decreased diuresis and inulin clearance ( approximately 3- to 4-fold), whereas AVP or LC attenuated this drop (P < 0.05 vs. control). In contrast, NE did not improve endotoxin-induced renal dysfunction. Endotoxin induced gut and lung hyperpermeability (P < 0.05 vs. control). Endotoxin-induced gut hyperpermeability was inhibited by AVP, LC, and NE. Endotoxin-induced lung hyperpermeability was further worsened by NE ( approximately 2-fold increase) but not AVP infusion (P < 0.05 vs. endotoxin). LC significantly improved endotoxin-induced pulmonary hyperpermeability. Endotoxin increased renal lactate and decreased renal ATP. NE did not change renal lactate or renal ATP. AVP and LC decreased renal lactate and normalized renal ATP. Finally, endotoxin was associated with increased lactate levels and L/P ( approximately 2- and 1.5-fold increases vs. control, respectively), whereas AVP and LC, but not NE, normalized both parameters after endotoxin challenge. These results suggest that, in a short-term endotoxic shock model, AVP improves systemic hemodynamics without side effects and has particular beneficial effects on renal function.

Topics: Acid-Base Equilibrium; Adenosine Triphosphate; Animals; Canavanine; Energy Metabolism; Enzyme Inhibitors; Hemodynamics; Intestinal Mucosa; Kidney; Lactic Acid; Lung; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Norepinephrine; Permeability; Phosphocreatine; Pyruvic Acid; Rats; Rats, Wistar; Renal Agents; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Lipid disorders have been treated with fibrates for many years. Rhabdomyolysis is one of the side effects of these drugs. We report a case of a septic-toxic shock due to rhabdomyolysis in a 75-year old patient, who had been treated with fenofibrate for 2 years. This case shows necessity of the standard monitoring of aminotransferase, phosphocreatine kinase and creatinine levels during treatment with fibrates.

Topics: Aged; Creatine Kinase; Creatinine; Female; Fenofibrate; Humans; Hypercholesterolemia; Hypolipidemic Agents; Phosphocreatine; Rhabdomyolysis; Shock, Septic; Transaminases

Overproduction of NO by an inducible NO synthase (iNOS) plays a role in the pathophysiology of septic shock. In such situations, NOS inhibition might be of therapeutic value, although detrimental side effects possibly related to inhibition of constitutive NOS have been reported. The use of L-canavanine, a selective inhibitor of iNOS, might be more suitable. The aim of the study was to compare in a rodent endotoxic shock the effects of saline (2 mL/h), N(G)-methyl-L-arginine(L-NMMA) (10 mg/kg/h) and L-canavanine (100 mg/kg/h) on muscle intracellular pH (pHi) and intracellular bioenergetic patterns (ATP, phosphocreatine/inorganic phosphate ratio) using in vivo 31P magnetic resonance spectroscopy (31P MRS). Three groups of anesthetized, mechanically ventilated and paralyzed rats received an intravenous infusion of 15 mg/kg of endotoxin. A fourth time-matched control group (n = 8) received 2 mL/h of saline. Mean arterial pressure, femoral blood flow, arterial blood gases, lactate, nitrate level, and 31P nuclear magnetic resonance (31P MRS) measurements were acquired at onset (T = 0), 90 min (T = 90), and 180 min (T180) after the endotoxin challenge. Femoral oxygen delivery was calculated as the product of femoral blood flow (mL/min) and arterial oxygen content. Endotoxin induced a marked decrease in arterial pressure and femoral oxygen delivery and an increase in lactate level. Intracellular pH and phosphocreatine/inorganic phosphate ratio decreased. ATP level did not change. Both L-NMMA and L-canavanine reversed the endotoxin-induced decrease in arterial pressure. L-NMMA attenuated the decrease in femoral oxygen delivery and the increase in lactate level while these were corrected by L-canavanine. Considering 31P MRS derived bioenergetic indices, the endotoxin-induced decrease in pHi and Pcr/Pi was attenuated by L-NMMA and corrected by L-canavanine. In conclusion, in a rodent model of endotoxinic shock, the continuous infusion of L-canavanine, a selective iNOS inhibitor, improved the systemic hemodynamic parameters and the intracellular bio-energetic patterns estimated by in vivo 31P MRS. To the contrary, the continuous infusion of both constitutive and inducible NOS inhibitor L-NMMA was not followed by the same achievement.

Topics: Adenosine Triphosphate; Animals; Canavanine; Energy Metabolism; Enzyme Inhibitors; Hydrogen-Ion Concentration; Lactic Acid; Lipopolysaccharides; Muscle, Skeletal; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; omega-N-Methylarginine; Phosphates; Phosphocreatine; Phosphorus Isotopes; Rats; Rats, Sprague-Dawley; Shock, Septic; Sodium Chloride; Spectrum Analysis

To study the influence of shock on muscle and plasma adenine nucleotide and creatine pools and their metabolites, and to identify early markers of cellular injury in shock.. Surgical research laboratory, Kuwait and UAE.. Experimental study.. 19 New Zealand rabbits.. 15 rabbits were injected with Escherichia coli endotoxin, and an additional 4 rabbits acted as controls.. Blood and muscle energy metabolites, platelet count, arterial blood gas tensions, and arterial pressure were followed until the animals died.. Five minutes after injection of endotoxin muscle ATP, creatine phosphate, and total adenine purine concentration decreased. This decrease was later reversed, but again decline to a critical level in the terminal phase. Loss of the muscle creatine pool indicated cellular damage after 3 hours. Plasma hypoxanthine, creatine, and lactate concentrations increased continuously throughout the study.. Hypoxanthine formation is a possible source of oxygen free radicals in shock. The rise of hypoxanthine, creatine, and lactate concentrations in plasma during septic shock may reflect early high energy nucleotide failure, membrane injury, and anaerobic metabolism, respectively.

Topics: Adenine; Adenine Nucleotides; Adenosine Triphosphate; Animals; Biomarkers; Blood Pressure; Carbon Dioxide; Creatine; Endotoxins; Energy Metabolism; Escherichia coli Infections; Free Radicals; Hypoxanthine; Hypoxanthines; Lactates; Lipopolysaccharides; Muscles; Oxygen; Phosphocreatine; Platelet Count; Rabbits; Reactive Oxygen Species; Shock, Septic

To identify possible alterations in the skeletal muscle high-energy phosphate metabolism at the early phase of endotoxic shock in rats.. A prospective, randomized study of skeletal muscle energetics in endotoxemic and in control rats, by in vivo 31P nuclear magnetic resonance (NMR) spectroscopy at rest, under regional ischemia, and during reperfusion.. Biochemical NMR laboratory equipped for surgery and hemodynamic monitoring.. Wistar rats were randomized to different groups. Eight rats were injected with Escherichia coli endotoxin (15 mg/kg, survival time 19 +/- 4 hrs) intraperitoneally. Seven other rats served as controls. The additional nine rats were studied for the saturation recovery pulse sequence.. In the treatment group, endotoxin was injected 8 hrs before NMR spectroscopy. The right hind limbs were studied under anaesthesia using a surface coil NMR probe. Their high-energy phosphate contents and intracellular pH were determined by 31P NMR spectroscopy. After baseline measurements, an ischemia-reperfusion challenge was imposed on the muscle by transient clamping of the abdominal aorta. Contralateral femoral artery pressure was constantly monitored.. During the baseline period, the endotoxin-treated muscles did not show any difference in the distribution of the high-energy phosphate compounds or in intracellular pH, as compared with the controls. Ischemia resulted in a significantly faster decline of the inorganic phosphate/creatine phosphate ratio in the endotoxin-treated rats (1.35 +/- 0.17 vs. 0.51 +/- 0.06 at the end of the 38-min ischemic period). Skeletal muscle acidosis developed earlier and was deeper in the endotoxemic animals (pH: 6.94 +/- 0.02 vs. 7.02 +/- 0.03 at the end of ischemia). During reperfusion, the calculated time constants of recovery of inorganic phosphate to phosphocreatine ratios were identical between groups.. Resting nonischemic muscles of endotoxin-treated rats show no evidence of alterations in high-energy phosphate metabolism. However, under ischemic conditions, high-energy phosphate metabolism deteriorates faster in the skeletal muscles of treated animals. These data support the hypothesis of a greater mismatch during perfusion at very low pressure between residual oxygen availability and oxygen needs in the endotoxin-treated muscle cell.

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Endotoxins; Energy Metabolism; Escherichia coli; Hemodynamics; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Muscles; Phosphates; Phosphocreatine; Phosphorus; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Shock, Septic

Renal failure often complicates endotoxin shock. This might be due to renal hypoperfusion, but endotoxemia could also have additional effects. We studied in anesthetized rats renal plasma flow (RPF), glomerular filtration rate (GFR), and metabolism (ATP, CrP = creatine phosphate, energy charge = [ATP + 0.5 ADP]/[ATP + ADP + AMP], lactate, glucose) during endotoxin shock (Escherichia coli endotoxin, 10 mg/kg for 60 min; n = 10) and "balloon shock" (balloon inflated in vena cava below renal vein to cause comparable decreases in cardiac output and RPF as in endotoxin-treated rats; n = 10). A third group of rats served as controls (n = 10). At t = 0 infusion of endotoxin was started. At t = 90 min, when cardiac output was low and serum lactate was high (indicating shock), GFR and RPF were obtained from plasma disappearance rates (from t = 90 to t = 135 min) of 125I-thalamate and 131I-hippurate, respectively. Experiments ended at t = 135 min. In both shock groups RPF decreased (by ca. - 75% compared with control rats), but filtration fraction only increased (by 72%) in the "balloon shock" rats. In renal biopsies lactate concentration increased more (by 407 vs. 167%) and ATP decreased more (by -63 vs. - 35%) during endotoxin shock than during "balloon shock"; the endotoxin-treated rats also showed a significant decrease in CrP (by - 58%), energy charge (by - 31%), and glucose concentration (by - 34%), and an increase in the number of leukocytes in the glomeruli (by 730%). Renal function and metabolism thus was more affected in this hypodynamic form of endotoxin shock than in "balloon shock." This may be caused by the effects of endotoxin on sticking of leukocytes and renal metabolism.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Animals; Blood Glucose; Hemodynamics; Hippurates; Iothalamic Acid; Ischemia; Kidney; Lactates; Male; Phosphocreatine; Rats; Rats, Inbred Strains; Shock, Septic

High energy phosphate concentrations were determined in the isolated perfused (in vitro) and intact (in situ) heart preparations in the rat during a control period and at various time intervals (1,2,4,8 or 16 h) following the intraperitoneal injection of 4 mg.kg-1 E coli endotoxin. Arterial glucose and lactate concentrations were determined just prior to excising the hearts. Following the induction of endotoxin shock, myocardial ATP and creatine phosphate decreased in both the in situ and in vitro preparations, while AMP increased only in the in situ group. There was no significant alteration in ADP in either group throughout the 16 h experimental period. Myocardial energy charge decreased at 1 h following endotoxin shock and remained depressed throughout the 16 h study period. Total heart weights as well as the wet/dry ratio were unaltered throughout the experiment. The reductions in ATP and creatine phosphate during endotoxin shock were a direct result of the shock state and not due to the loss of myocardial mass or the presence of oedema. One hour following the induction of endotoxin shock plasma glucose increased then returned to the control value by 2 h and remained at the pre-endotoxin level throughout the experimental protocol. Arterial lactate concentration increased following endotoxin administration and remained elevated until 16 h, where it was not different from the control value. Data from the present study clearly indicate a myocardial energy deficit during acute hypodynamic endotoxin shock in the rat and may provide a mechanism for the cardiac dysfunction normally associated with this shock paradigm.

Topics: Adenosine Monophosphate; Adenosine Triphosphate; Animals; Endotoxins; Escherichia coli; Heart; Myocardium; Perfusion; Phosphates; Phosphocreatine; Rats; Rats, Inbred Strains; Shock, Septic

For comparison of the extent of metabolite content alteration caused by etiologically different types of shock, septic peritonitis and hemorrhagic shock (mean arterial blood pressure at 40 mm Hg for 1 h or 2 h) were produced in rats. Contents of metabolites were determined in the liver and the muscle. Characteristic differences were found in the alteration modes of hepatic lactate level, muscle adenine nucleotide concentrations, and muscle protein content between these shock models. Rapid and significant alterations were observed in the levels of adenine nucleotides, glucose-6-phosphate and lactate in the liver in both types of shock. Hepatic energy charge and contents of glycogen and protein also significantly decreased. On the other hand, noticeable changes in the muscles were elevation of lactate level and the decrease of phosphocreatine and protein concentrations. Another distinct change was the decrease of total adenine nucleotide content in the muscle of septic rats, whereas it remained unchanged in the muscle of hemorrhagic shock rats. Thus, the changes of metabolite levels did not occur simultaneously in different tissues, and their rate and magnitude varied between different types of shock. The difference in adaptive response of metabolism may result in pathophysiologic diversity in shock.

Topics: Adenine Nucleotides; Animals; DNA; Energy Metabolism; Glucose-6-Phosphate; Glucosephosphates; Lactates; Lactic Acid; Liver; Liver Glycogen; Malates; Male; Muscles; Phosphocreatine; Phosphoenolpyruvate; Proteins; Rats; Rats, Inbred Strains; RNA; Shock, Hemorrhagic; Shock, Septic

The effects of 2-[(5-chloro-2-methoxyphenyl)azo]-1H-imidazole (M6434) were investigated in experimental models of lethal shock produced by hemorrhage, injection of endotoxin, or coronary ligation. M6434 improved the survival rate of rabbits in hemorrhagic shock. M6434, at the dose of 3 or 10 micrograms/kg/min, completely reversed the decreases in the blood pressure and the urine output of shocked rabbits, but did not affect the decreased regional blood flow through the kidneys in the animals. Survival rates of cardiogenic-shock rats improved, and the content of ATP and creatine phosphate in myocardium of these animals were restored by the treatment with 1 or 3 micrograms/kg/min of M6434. Intravenous infusion of M6434, at a dose of 3 or 10 micrograms/kg/min for 3 hr, increased the survival rate of the endotoxin-shocked rabbits. These results indicate that M6434 may be evaluated as a possible therapeutic agent for shock.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Diuresis; Dobutamine; Dopamine; Heart Rate; Imidazoles; Male; Myocardium; Phosphocreatine; Rabbits; Rats; Rats, Inbred Strains; Renal Circulation; Shock, Cardiogenic; Shock, Hemorrhagic; Shock, Septic; Sympathomimetics

The relative performance of whole blood and saline, a balanced salt-albumin solution, and Fluosol-43 were compared in an experimental animal model of combined hypoxia and hypotension. The test fluids were evaluated in terms of their respective ability to restore mean arterial pressure and provide adequate oxygen to restore and maintain a normal brain cytochrome a,a3 redox state, restore and sustain normal cerebral cortical ATP and creatinine phosphate concentrations (CP), and return cerebral cortical lactate concentrations to normal after the hypoxic-hypotensive period. With regard to ATP, CP, lactate, and cytochrome a,a3, all three test fluids performed equally well inasmuch as there were no significant differences between groups. None of the test regimens resulted in normal ATP concentration post-hypoxic hypotension. Although CP concentrations were lower than baseline after resuscitation, the difference was not statistically significant. Fluosol-43 resuscitation resulted in a significantly higher (p less than 0.05) mean arterial pressure by 120 minutes post-resuscitation. It was concluded that Fluosol-43 is an acceptable resuscitative fluid, most beneficial at extremely low hematocrits, but that selection of Fluosol-43 over balanced salt-albumin could not be supported when post-resuscitation hematocrits were in the 20 to 25% range.

Topics: Adenosine Triphosphate; Animals; Brain; Brain Chemistry; Fluorocarbons; Hypotension; Hypoxia; Lactates; Male; Oxygen Consumption; Phosphocreatine; Rats; Rats, Inbred Strains; Resuscitation; Shock, Septic

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Brain; Cats; Cerebral Cortex; Cisterna Magna; Endotoxins; Female; Injections; Male; Phosphocreatine; Shock, Septic

Topics: Adenosine Triphosphate; Animals; Assisted Circulation; Body Temperature; Carbon Dioxide; Dogs; Female; Glycogen; Hemodynamics; Intestine, Small; Intra-Aortic Balloon Pumping; Kidney; Klebsiella Infections; Liver; Male; Myocardial Contraction; Myocardium; Oxygen; Phosphocreatine; Respiration; Shock, Septic

Exogenous adenosine triphosphate (ATP) (in combination with MgCl2) and also creatine phosphate (CrP), have been administered intravenously to endotoxin-shocked cats. Untreated shocked cats exhibited systemic hypotension during the first hour and again from four hours. Cardiac output fell progressively, and markedly elevated arterial lactate levels were evident within one hour of endotoxin administration. Treatment with ATP (10 mg/kg every 30 minutes) during shock led to rapid hemodynamic deterioration in all cats; most of the cats were dead before completion of dosing (at three hours). Long-lasting systemic hypotension and bradycardia were associated with this ATP administration and marked hypoglycemia developed in the survivors. Neither ATP (62 mg/kg) administered before endotoxin, nor CrP (500 mg/kg; administered either prior to endotoxin, or one hour afterwards) significantly modified the hemodynamic or metabolic changes associated with endotoxin shock in this species. Neither ATP nor CrP increased survival (assessed at five hours). Other workers have demonstrated improved survival from shock with ATP treatment. There may be species differences in the responsiveness to exogenous ATP or, alternatively, a difference in the role of high-energy phosphates in different types of shock.

Topics: Adenosine Triphosphate; Animals; Blood Glucose; Blood Pressure; Cardiac Output; Cats; Heart Rate; Hemodynamics; Lactates; Phosphocreatine; Shock, Septic

The effects of a bolus injection of gram-negative endotoxin (Pseudomonas aeruginosa) on the high energy phosphate and glycogenolytic metabolite levels of skeletal muscle and liver were studied in dogs. After endotoxin injection there was a sharp increase in the G-6-P and lactate levels within 5--15 min, especially in muscle, followed by an additional but much slower increase of these metabolites during the next 2 h. The CrP and ATP levels were also increased in skeletal muscle early after the endotoxin injection and the levels of these high energy phosphate compounds were still, 2 h after endotoxin, higher than those in control animals. In the liver an early gluconeogenetic response was observed. The results indicate that tissue hypoxia and a consequent exhaustion of tissue high energy phosphate compounds do not occur during the initial period of endotoxin shock. The increased high energy phosphate levels are probably partly caused by sympathicoadrenal stimulation but direct endotoxin effects at the cell membrane level may also play an important role.

Topics: Adenosine Triphosphate; Animals; Blood Platelets; Blood Pressure; Depression, Chemical; Dogs; Endotoxins; Energy Metabolism; Female; Glucose; Glucosephosphates; Lactates; Leukocyte Count; Liver; Male; Muscles; Phosphates; Phosphocreatine; Pseudomonas aeruginosa; Shock, Septic; Stimulation, Chemical; Vascular Resistance

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Blood Glucose; Endotoxins; Escherichia coli; Fructosephosphates; Glucose; Glucosephosphates; Glycolysis; Hematocrit; Hydrogen-Ion Concentration; Injections, Intravenous; Lactates; Liver; Muscles; Myocardium; Oxygen; Phosphates; Phosphocreatine; Pyruvates; Rabbits; Shock, Septic; Time Factors