phosphocreatine and Hypothermia

Topics: Adenosine Triphosphate; Animals; Cell Nucleus; Citrates; Coronary Disease; Disease Models, Animal; Dogs; Endoplasmic Reticulum; Glycogen; Heart Arrest; Hypothermia; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Phosphates; Phosphocreatine; Potassium; Potassium Chloride; Procaine; Rats

The remarkable time-resolution enhancement by deep lethargic hypothermia (15 degrees C rectal temperature, "cold narcosis," "anesthesia by internal cold") of metabolic events in the rat brain after oxygen deprivation has been exploited to monitor metabolic changes by in vivo (31)P-NMR. A correlation was established between the bioenergetic status of the brain and physiological descriptors of tolerance (survival and revival times) determined in parallel experiments with large series of animals. Spectral peak integrals were transformed into absolute concentrations by comparison to biochemically determined time series of data obtained in freeze-trapping experiments conducted under identical conditions. Serial spectra were used to reconstruct the time-course kinetics of intracellular brain pH and of concentration changes of inorganic phosphate, phosphocreatine, ATP, and ADP. Both the biochemical and NMR time series of data were simultaneously fitted by a set of exponential kinetic equations accounting for relationships imposed by the Lohmann and adenylate kinase reactions. Depletion profiles were then computed for a number of descriptors of brain energy status (energy charge, phosphorylation potential, total adenylate, and primary energy stores expressed as the sum of high-energy phosphate-bond equivalents). The results contribute to the understanding of the role of brain energetics in tolerance to oxygen deprivation.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adenylate Kinase; Animals; Brain; Energy Metabolism; Glucose; Hydrogen-Ion Concentration; Hypothermia; Hypoxia; Kinetics; Magnetic Resonance Spectroscopy; Phosphates; Phosphocreatine; Phosphorus Isotopes; Rats

The genesis of the J wave during hypothermia has been attributed to injury current, delayed ventricular depolarization and early repolarization, tissue anoxia, and acidosis. To our knowledge, no studies have addressed the appearance of the J wave in relation to the myocardial K+ transfer and metabolism during hypothermia. Dogs (n = 9) were progressively cooled, blood samples were taken from the aorta and coronary sinus, and myocardial tissue samples were obtained for adenosine triphosphate (ATP), creatine phosphate (CP), and glycolytic intermediate determination. In every instance, the appearance of the J wave was preceded by a net loss of K+ from the myocardium. In one dog, there was no myocardial K+ loss and the J wave was absent. The J wave appeared when the esophageal temperature was between 27 degrees and 24 degrees C (26.6 +/- 0.73 degrees C). At that temperature, the animals were hypotensive and bradycardic, but arterial oxygen partial pressure, carbon dioxide partial pressure, and pH were within the physiologic range at that temperature. The myocardial ATP and CP from the hypothermic dogs was lower compared with the value obtained from dogs at 37 degrees C (p < .025 and p < .005, respectively). The levels of the glycolytic intermediates, fructose-1,6-diphosphate, dihydroxyacetone phosphate, and pyruvate, were lower and the level of lactate was higher compared with those from the normothermic dogs (not significant; p < .007, p < .02, p < .001, respectively). These findings suggest that the appearance of the J wave on electrocardiography during cooling is a result of depression of the metabolic process concerned with maintenance of the partition of ions across the cell membrane, as evidenced by decreased myocardial energy content and K+ loss during the hypothermic state.

Topics: Adenosine Triphosphate; Animals; Dogs; Electrocardiography; Female; Glycolysis; Hypothermia; Ion Transport; Male; Myocardium; Phosphocreatine; Potassium

In the present study we examined the impact of glycolysis and glucose oxidation on myocardial calcium control and mechanical function of fatty acid-perfused rat hearts subjected to hypothermia rewarming. One group (control) was given glucose (11.1 mM) and palmitate (1.2 mM) as energy substrates. In a second group glycolysis was inhibited by iodoacetate (IAA, 100 microM) and replacement of glucose with pyruvate (5 mM), whereas in the third group glucose oxidation was stimulated by administration of dichloroacetate (DCA, 1 mM) and insulin (500 microU/ml). All groups showed a rise in myocardial calcium ([Ca]total in response to hypothermia (10 degrees C). However, [Ca]total was significantly lower both in IAA- and DCA-treated hearts, as compared to controls (2.20 +/- 0.22 and 2.94 +/- 0.20 v 3.83 +/- 0.29 nmol/mg dry wt., P < 0.025). The reduced calcium load in the treated hearts was correlated with higher levels of high energy phosphates. Following rewarming control and DCA-treated hearts still showed elevated [Ca]total, whereas IAA-treated hearts [Ca]total was not different from the pre-hypothermic value. All groups showed a reduction in cardiac output following rewarming. Furthermore, the control group, in contrast to both IAA- and DCA-treated hearts, showed a significant reduction in systolic pressure. These results show that hypothermia-induced calcium uptake in glucose and fatty acid-perfused rat hearts was reduced by two different metabolic approaches: (1) inhibition of glycolysis by IAA while simultaneously by-passing the glycolytic pathway by exogenous pyruvate: and (2) stimulation of glucose oxidation by DCA. Thus, glycolytic ATP is not an essential regulator of sarcolemmal calcium transport under the present experimental conditions. Instead, we suggest that a change in oxidative substrate utilization in favour of carbohydrates may improve myocardial calcium homeostasis during hypothermia and rewarming.

Topics: Adenosine Triphosphate; Animals; Calcium; Carbohydrate Metabolism; Cardiac Output; Fatty Acids; Glucose; Glycogen; Hypothermia; Lactic Acid; Male; Myocardial Reperfusion; Myocardium; Oxidation-Reduction; Perfusion; Phosphocreatine; Rats; Rats, Sprague-Dawley

Intraischemic hypothermia (34 degrees C and 31 degrees C) has a profound neuroprotective effect on the brain of the immature rat. Hypothermia immediately after hypoxia-ischemia is not beneficial. To determine the mechanisms by which mild to moderate hypothermia affects cerebral energy metabolism of the brain of the newborn rat pup, we examined alterations in cerebral glycolytic intermediates and high-energy phosphate compounds during intraischemic and postischemic hypothermia and correlated these findings with known neuropathologic injury.. Seven-day-old rat pups underwent unilateral common carotid artery ligation and exposure to hypoxia in 8% oxygen at either 37 degrees C, 34 degrees C, or 31 degrees C for 3.0 hours. Separate groups were exposed to hypoxia-ischemia at 37 degrees C for 3 hours but recovered at either 37 degrees C, 34 degrees C, or 31 degrees C. At 60, 120, and 180 minutes of intraischemic hypothermia and at 10, 30, 60, and 240 minutes of postischemic hypothermia, individual rat pups were quick-frozen in liquid nitrogen for later determination of cerebral concentrations of glucose, lactate, ATP, and phosphocreatine.. Cerebral glucose was significantly higher and lactate significantly lower in the 31 degrees C animals during hypoxia-ischemia than either the 34 degrees C or 37 degrees C groups. Brain ATP concentrations were completely preserved during hypoxia-ischemia at 31 degrees C, whereas 34 degrees C of hypothermia had no effect on preserving high-energy phosphate compounds compared with those animals in the 37 degrees C group. Postischemic hypothermia of either 34 degrees C or 31 degrees C had no effect on the rate or extent of recovery of glycolytic intermediates or high-energy phosphate compounds compared with the normothermic 37 degrees C rat pups.. Moderate hypothermia of 31 degrees C completely inhibits the depletion of ATP during hypoxia-ischemia, a mechanism that likely accounts for its neuroprotective effect. No preservation of ATP was seen, however, during intraischemic mild hypothermia of 34 degrees C despite the relatively profound neuroprotective effect of this degree of temperature reduction. Thus, the mechanisms by which mild hypothermia is neuroprotective are temperature dependent and may act at more than one point along the cascade of events eventually leading to hypoxic-ischemic brain damage in the immature rat.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Brain; Energy Metabolism; Glucose; Glycolysis; Hypothermia; Hypothermia, Induced; Hypoxia, Brain; Ischemic Attack, Transient; Phosphocreatine; Rats; Temperature; Time Factors

The effects of arterial alphastat regulation on brain intracellular pH (pHi) and several phosphate metabolites were assessed in anesthetized rats during hypothermia (28.6 +/- 0.2 degrees C) and normothermia (36.2 +/- 0.2 degrees C) by using 31P high-field (8.5 T) nuclear magnetic resonance (NMR). There were significant differences in pHi and metabolite ratios at the two temperatures under conditions of equal minute ventilation. During hypothermia, the brain pHi was 0.09 U higher, the phosphocreatine-to-inorganic phosphate (PCR/Pi) ratio 49% larger, and Pi-to-ATP 20% lower than at normothermia. These changes were fully reversible on warming the animal. The change in brain pHi/temperature was -0.011U/degrees C (95% confidence interval -0.007 to -0.016). The brain's ability to regulate its pHi and phosphate metabolism during hypercapnic acid-base stress was studied by using 10% CO2 ventilation. Hypothermic rats showed a larger fall in brain pHi (0.145 +/- 0.01 U, 7.15-7.01) with 10% CO2 than normothermic rats (0.10 +/- 0.02 U, 7.06-6.96). Similarly ventilated rats had a larger fall in arterial pH with 10% CO2 at hypothermia (0.36 +/- 0.04 U) than normothermia (0.24 +/- 0.01 U), so the delta brain pH/delta arterial pH was the same at both temperatures. The brain PCr-to-Pi ratio decreased approximately 20% during 10% CO2 breathing in both hypothermic and normothermic animals. Brain pHi and metabolite ratios returned to base line 30-50 min after CO2 washout in both groups. In summary, lowering body temperature while maintaining constant ventilation leads to changes in brain pHi and metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Hydrogen-Ion Concentration; Hypothermia; Magnetic Resonance Spectroscopy; Phosphates; Phosphocreatine; Phosphorus; Rats; Rats, Inbred Strains

Cerebral high energy phosphates were studied in the intact rabbit brain using nuclear magnetic resonance spectroscopy. The effect of hypothermia on degradation kinetics in total ischemia due to circulatory arrest was examined, measuring phosphocreatine, adenosine triphosphate, and inorganic phosphate as a function of time at three different temperatures (35, 24, 21 degrees C). Phosphocreatine- and ATP-decays followed single exponential functions at all three temperatures. The half-life times increased by approximately a factor of three upon lowering the temperature from 35 to 21 degrees C with activation energies of 15-20 kcal/mol, which corresponds to values of Q10 between 2.4 and 3.2. In the temperature range studied, no critical temperature was found below which metabolism would stop completely. We conclude that nuclear magnetic resonance spectroscopy allows, in the intact animal, quantitative assessment of the influence of hypothermia on energy metabolism in the brain. This influence is a major concern in the field of cardiac surgery in infants and children who are often operated in total circulatory arrest under deep hypothermia.

Topics: Adenosine Triphosphate; Animals; Brain; Energy Metabolism; Heart Arrest; Hypothermia; Kinetics; Magnetic Resonance Spectroscopy; Male; Models, Neurological; Phosphocreatine; Phosphorus; Rabbits; Thermodynamics

Currently there are no techniques available for the intraoperative on-line assessment of the adequacy of myocardial preservation during cardiac operation. The efficacy of a new intramyocardial pH electrode in quantitating myocardial ischemic damage and monitoring myocardial preservation was investigated by correlating changes in intramyocardial pH with the time course of metabolic, histologic, and ultrastructural alterations during global ischemia. Seventeen open-chest dogs were placed on cardiopulmonary bypass and the aorta was cross-clamped for 2 hours. In Group I (n = 8), aortic cross-clamping was performed under normothermia. Group II (n = 9) received 4 degrees C potassium cardioplegia immediately after cross-clamping and consecutively every 30 minutes thereafter. Intramyocardial carbon dioxide tension (Pco2) and intramyocardial pH were measured continuously. Serial transmural biopsies were obtained before and at 5, 15, 30, 60, 90, and 120 minutes after cross-clamping for biochemical and structural analysis. During the period of cross-clamping, mean myocardial temperature was 33 degrees C in Group I and 19 degrees C in Group II. Intramyocardial pH at the end of 2 hours of anoxic arrest reached 5.39 +/- 0.08 in Group I and 6.49 +/- 0.13 in Group II (both values p less than 0.01 compared to prebypass values). Intramyocardial Pco2 rose from 41 +/- 4 to 234 +/- 13 mm Hg in Group I (p less than 0.001) and did not change in Group II. Tissue content of adenosine triphosphate (ATP) decreased by 51% in Group I and by 14% in Group II (p less than 0.01 compared to prebypass value). Tissue creatine phosphate was depleted in Group I and decreased by 48% in Group II. The degree of ischemic damage assessed by a mean ischemic score was 2.15 +/- 0.06 in Group I and 0.75 +/- 0.19 in Group II (p less than 0.001). Irreversible structural damage assessed by electron microscopy occurred in Group I 60 to 90 minutes after cross-clamping and was associated with an intramyocardial pH below 6.2. No such damage was observed in Group II. Therefore, intramyocardial pH is shown to be a reliable indicator of the severity of ischemic damage during anoxic arrest under normothermic conditions and of the adequacy of preservation under hypothermic conditions. Measurement of intramyocardial pH may provide a potentially useful tool for the intraoperative on-line monitoring of the adequacy of myocardial preservation in patients undergoing cardiac operation.

Topics: Adenosine Triphosphate; Animals; Carbon Dioxide; Dogs; Female; Heart Arrest, Induced; Hydrogen-Ion Concentration; Hypothermia; Ischemia; Male; Monitoring, Physiologic; Myocardium; Phosphocreatine; Time Factors

Topics: Adenine Nucleotides; Animals; Heart Arrest; Heart Arrest, Induced; Hydrogen-Ion Concentration; Hypothermia; Lactates; Lactic Acid; Myocardium; Perfusion; Phosphocreatine; Swine

The effects of different levels of arterial blood oxygen content (CaO2) on brain tissue adenosine triphosphate (ATP), phosphocreatine (PCr), lactate, and reduced nicotinamide adenine dinucleotide (NADH) were studied during cerebral hypoxia in normothermic and hypothermic male Wistar rats with unilateral carotid ligation. Animals were exposed to hypoxia (PaO2 19--26 torr) for 25 min, and brain tissue metabolite values measured microfluorometrically were compared with those of normothermic normoxic controls. CaO2 was 4.0 +/- 0.2 ml/dl (mean +/- SEM) at PaO2 26 torr in normothermic animals. CaO2 was increased to 8.2 +/- 0.3 ml/dl at PaO2 26 torr by means of bicarbonate infusion producing a leftward shift of the oxyhemoglobin-dissociation curve in one normothermic hypoxic group. In all normothermic hypoxic groups ATP and PCr decreased and lactate and NADH increased significantly compared with control values. There was no significant difference in brain tissue metabolite values among these groups despite an increase in CaO2 by twofold in one group. Hypothermia (32 C) resulted in CaO2 8.4 +/- 0.2 ml/dl at PaO2 26 torr. This was decreased to 4.0 +/- 0.2 ml/dl by decreasing PaO2 to 19 torr in another group at the same temperature. ATP and PCr were well preserved in both groups despite the difference in CaO2s. Although the lactate and NADH levels were increased in the hypothermic group with CaO2 4.0 +/- 0.2 ml/dl, they were significantly lower than those values in normothermic hypoxic groups. These results indicate that the increase in CaO2 produced by hypothermia is not a major determinant in hypothermic protection during cerebral hypoxia.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Brain; Carbon Dioxide; Energy Metabolism; Hydrogen-Ion Concentration; Hypothermia; Hypoxia; Lactates; Male; NAD; Oxygen; Phosphocreatine; Rats

Topics: Adenosine Triphosphate; Animals; Brain; Cyclic AMP; Electroshock; Glucose; Glycogen Synthase; Hypothermia; Lactates; Male; Mice; Phosphocreatine; Phosphorylases; Postmortem Changes

The influence of elevated and reduced body temperatures upon the metabolic state of the brain was evaluated from the tissue concentrations of phosphocreatine (PCr) ATP, ADP and AMP and from the concentrations of glucose, lactate and pyruvate in immobilized and artificially ventilated rats anesthetized with 70% N2O. The results were compared to the results obtained in normothermic animals. It was found that rats with body temperatures of 32 degrees and 22 degrees C had the same brain tissue concentrations of high energy phosphates and the same adenylate energy charge as the controls, but hypothermia led to a progressive decrease of both cerebral and arterial lactate and pyruvate concentrations. A metabolic acidosis but no excess lactate appeared in the blood. At a body temperature of 42 degrees C, the metabolic pattern in the brain agreed with a state of hypoxia at a time when there was no sign of substrate depletion. Arterial blood showed excess lactate which may indicate an inadequacy of the oxygen supply also to other tissues.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Body Temperature; Brain; Carbon Dioxide; Energy Metabolism; Fever; Glucose; Hydrogen-Ion Concentration; Hypothermia; Lactates; Male; Oxygen; Oxygen Consumption; Partial Pressure; Phosphocreatine; Pyruvates; Rats

Topics: Adenosine Triphosphate; Animals; Cardiac Surgical Procedures; Extracorporeal Circulation; Heart; Heart Arrest, Induced; Hyperkalemia; Hypothermia; Ischemia; Male; Myocardium; Perfusion; Phosphocreatine; Potassium; Rats; Ventricular Fibrillation

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Brain; Catheterization; Cerebral Cortex; Cold Temperature; Electric Conductivity; Glucose; Glycogen; Hypothermia; Lactates; Perfusion; Phosphates; Phosphocreatine; Rabbits; Time Factors

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Dogs; Heart; Heart Ventricles; Hypothermia; Myocardium; Oxygen Consumption; Perfusion; Phosphocreatine; Potassium; Sodium; Time Factors; Venous Pressure; Water

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Dogs; Glycerophosphates; Glycolysis; Heart Arrest; Hypothermia; Lactates; Myocardium; Phosphates; Phosphocreatine

Topics: Acid-Base Equilibrium; Adenosine Triphosphate; Animals; Brain; Brain Edema; Carbon Dioxide; Electrolytes; Extracorporeal Circulation; Glucose; Glycogen; Hydrogen-Ion Concentration; Hypothermia; Hypothermia, Induced; Hypoxia; Lactates; Male; Nucleosides; Partial Pressure; Phosphates; Phosphocreatine; Potassium; Pyruvates; Rats; Sodium; Water

Topics: Adenosine Triphosphate; Animals; Coenzymes; Electrocardiography; Electron Transport Complex II; Glycogen; Histocytochemistry; Hypothermia; Hypothermia, Induced; Lactates; Metabolism; Myocardium; NAD; NADP; Oxidoreductases; Phosphocreatine; Pyruvates; Rats; Research; Rodentia; Sciuridae; Succinate Dehydrogenase

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Cardiac Surgical Procedures; Coenzymes; Dogs; Heart; Heart Arrest; Heart Arrest, Induced; Heart Function Tests; Hypothermia; Hypothermia, Induced; Injections, Intra-Arterial; Myocardium; Phosphates; Phosphocreatine; Potassium; Research; Thoracic Surgery