Decrease In Energy Charge Potential Research Articles

Effect of nadolol, a beta-adrenoceptor blocking agent, on myocardial metabolism in the dog ischaemic heart.

The effect of nadolol at a dose of 1 mg kg-1, i.v. on the ischaemic myocardial metabolism has been examined in the dog. Ischaemia was induced by ligating the left anterior descending coronary artery for 3 min, and nadolol was injected 5 min before ligation. Ischaemia caused myocardial metabolic changes; it decreased energy charge potential and inhibited glycolytic flux through phosphofructokinase reaction. Pretreatment with nadolol lessened the decrease in energy charge potential and the inhibition of glycolytic flux being caused by ischaemia. Nadolol may have a beneficial effect on the ischaemic myocardium.

Enteral Glutamine Administration Prevents the Decrease in Cell Energy Charge Potential Produced in Ileum After a Skin Burn in the Rat

A skin burn produces a decrease in cell energy charge potential (ECP), a marker of cell function, in the liver and other organs. The process appears to be oxidant induced because reduced glutathione (GSH) appears to be protective. The gut mucosal barrier is also known to be altered after burns and appears to be improved by glutamine, which is a source of energy and GSH production. Neither the relationship between the gut barrier change and the ECP of the gut barrier nor the mechanism of glutamine protection has been defined. The effect of a 20% total body surface area, full-thickness burn in a rat on ECP and GSH content in the ileum and the liver and the effect of oral glutamine (1 g/kg/d) on any changes were studied. Three groups of rats (14 rats per group) were studied: a control group, a group with burns alone, and a group with burns that were given glutamine. Half of the rats were killed 1 day after the burn, and the other half were killed 6 days after the burn. ECP did not decrease 1 day after the burn, but 6 days after the burn, ECP decreased from a control of 0.53+/-0.06 to 0.41+/-0.01 in the liver and from 0.64+/-0.04 to 0.29+/-0.04 in the ileum. In the ileum, glutamine prevented the decrease of the ECP (which increased to 0.58+/-.03), but in the liver, glutamine did not alter the ECP (which remained at 0.42+/-0.05). The GSH content was unchanged after the burn injury in both organs compared with the value before the burn injury. It can be concluded that a delayed decrease in ECP in the ileum occurs after a burn injury. Orally administered glutamine prevents the decrease in ECP, probably by providing cell energy rather than by increasing gut GSH (antioxidant) activity.

Energy charge potential and glutathione levels as predictors of outcome following burn injury complicated by endotoxemia.

We studied the effect of water-soluble antioxidants geared at restoring glutathione levels on oxygen consumption, cell energetics as measured by energy charge potential (ECP), glutathione levels, and mortality, in response to a 20% total body surface area (TBSA) third degree burn injury combined with endotoxemia, five days after burn in a rat model. The 20% TBSA third degree burn injury was not fatal for the six day study period. Oxygen consumption as well as red blood cell ECP remained unchanged from control values. Liver ECP was significantly reduced; however, liver glutathione was significantly increased. The 20% TBSA burn injury combined with endotoxemia produced a 60% mortality rate. Twenty-four hour survivors (40%) demonstrated a significant decrease in oxygen consumption, red blood cell ECP, and liver ECP. Liver glutathione was significantly decreased compared with burn but was not significantly decreased compared with control. Nonsurvivors of the burn injury combined with endotoxin (60%) demonstrated a significant reduction in liver glutathione levels compared with survivors. Oxygen consumption and ECP could not be measured in the nonsurvivors due to the rapid loss of ATP in the moribund state that occurred by 4 h postinjury. Antioxidants produced 100% survival, attenuated in the fall in liver ECP, and restored red blood cell ECP and liver glutathione levels to normal values. We conclude that a modest burn injury combined with endotoxemia produces a liver glutathione debt, oxygen debt, an energy deficit, and 60% mortality. The mechanism of injury is oxidant related as antioxidants prevented mortality restored liver glutathione levels, and prevented or attenuated the decrease in ECP. A decrease in ECP and glutathione levels appear to be more sensitive indicators of outcome than the presence of an oxygen debt. The survivors, in both burn plus endotoxin groups treated with or without antioxidants was comparable, indicating a critical value for oxygen consumption exists before death occurs.

Excessive liver oxidant stress causes mortality in response to burn injury combined with endotoxin and is prevented with antioxidants.

We studied the effect of the oral administration of a water-soluble antioxidant solution containing ascorbic acid, glutathione, and a precursor for glutathione synthesis, N-Acetyl-L-cysteine, on liver antioxidant activity, liver cell energetics, and mortality in rats in response to a 20% third-degree burn injury challenged 5 days later with an intraperitoneal injection of 30 mg/kg endotoxin. Rats with burns were fluid-resuscitated with subcutaneous Ringer's lactate solution according to the Parkland formula (4 cc/kg/%burn). Rats challenged with endotoxin 5 days after burn were given an additional 100 ml/kg of subcutaneous Ringer's lactate solution immediately after the injection of endotoxin. A group of rats with burns challenged with endotoxin 5 days after burn were given an oral antioxidant solution beginning after burn injury. Liver cell energetics were measured as tissue energy charge potential (ECP), adenosine triphosphate (ATP) content, and total adenine nucleotides. The levels of endogenous liver glutathione, catalase, vitamin C, and vitamin E were measured to monitor antioxidant status. We found that burn injury alone did not produce any mortality over the 6-day period despite a 35% decrease in liver energy charge potential resulting from a decrease in ATP, a 34% decrease in liver catalase activity, and a 20% decrease in liver vitamin C. It was interesting that glutathione increased and vitamin E remained unchanged. We found that endotoxin injury combined with burn injury produced a 61% mortality rate with a 63% decrease in liver energy charge potential, again resulting from a decrease in ATP, a 74% decrease in liver catalase activity, a 16% decrease in vitamin C, and a 29% decrease in vitamin E. Glutathione was significantly decreased compared with burn alone. We compared the liver antioxidant status of survivors with that of nonsurvivors who were killed when appearing moribund and found that glutathione was decreased by 51% and vitamin C by 73% in nonsurvivors over that in survivors, whereas catalase and vitamin E levels were comparable between the two groups. The oral administration of the antioxidants prevented mortality and the decrease in antioxidant activity and attenuated the decrease in energy charge potential. We conclude that a 20% burn produces a modest decrease in liver energy charge potential and antioxidant defenses without producing mortality. The addition of endotoxin further decreases liver antioxidant defenses, liver energy charge potential, and markedly increases mortality. Antioxidants, given post-burn, restored antioxidant defenses, attenuated the altered cell energetics, and prevented mortality, indicating oxidants to be the cause of mortality. This data also suggests that a critical value of decreases in antioxidant defenses and ATP exists, resulting in mortality.

Effects of iloprost, a PGI2 derivative, on ischemic myocardial energy and carbohydrate metabolism in dogs.

Effects of iloprost, which is a stable prostacyclin analogue, on the ischemic myocardium were examined in the open-chest dog heart in terms of biochemical parameters. Ischemia was initiated by ligating the left anterior descending coronary artery. When the coronary artery was ligated for 3 min, the levels or glycogen, fructose-1,6-diphosphate (FDP), adenosine triphosphate and creatine phosphate decreased, and the levels of glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), lactate, adenosine diphosphate and adenosine monophosphate increased. During ischemia, therefore, energy charge potential was significantly decreased from 0.89 +/- 0.01 to 0.82 +/- 0.01, and ([G6P] + [F6P])/[FDP] and [lactate]/[pyruvate] ratios were significantly increased from 1.75 +/- 0.30 to 29.05 +/- 5.70 and 13 +/- 3 to 393 +/- 112, respectively. Iloprost (0.1, 0.3, or 1 microgram.kg-1) was injected intravenously 5 min before the onset of ischemia. Iloprost (0.1, 0.3, and 1 micrograms.kg-1) reduced the ischemia-induced decrease in energy charge potential to 94, 74, and 86%, respectively, the increase in ([G6P] + [F6P])/[FDP] to 38, 29, 32%, respectively, and the increase in [lactate]/[pyruvate] to 67, 45, 65%, respectively. These results suggest that iloprost lessens the myocardial metabolic derangements produced by ischemia, and the most potent effect was obtained at the dose of 0.3 microgram.kg-1.

中枢性鎮痛薬Ｅｐｔａｚｏｃｉｎｅのマウス，ラットにおける虚血性脳障害に対する保護効果

The cerebral protective effect of eptazocine, an opioid mu-antagonist-kappa-agonist, was investigated using mice and rats subjected to ischemia. 1) Decapitation or concussive head injury (20 g, 30 cm)-induced ischemia in mice: Eptazocine (3,10 mg/kg) prolonged the gasping duration or the survival time in a dose-dependent manner. 2) Ischemic brain edema induced by bilateral carotid arterial occlusion (BLCO) in rats: Administration of eptazocine just after BLCO treatment significantly prevented the incidence of ischemic seizures, lethality and an increase in cerebral water content. 3) Acute ischemic changes in cerebral energy metabolism in mice: 2-min BLCO treatment decreased the cerebral contents of phosphocreatine and ATP, and it increased the contents of AMP and lactate, resulting in a 34% decrease in energy charge potential and an increase in lactate/pyruvate ratio. Such changes were improved by eptazocine (3, 10 mg/kg) and ethylketocyclazocine (3 mg/kg), a kappa-agonist. 4) Respiratory function in mouse brain mitochondria preparations: Eptazocine increased the State 3 respiration and respiratory control index (RCI:State 3/State 4), and it prevented a decrease in RCI induced by 3-min ischemia. These results suggest that eptazocine may improve cerebral ischemic disorders through an activation and/or protection of mitochondrial energy-producing systems.

Response of isolated perfused heart to ischemia after long-term treatment of spontaneously hypertensive rats with diltiazem.

The effects of long-term treatment with diltiazem on the heart in normotensive (WKY) and spontaneously hypertensive rats (SHR) were studied. Diltiazem was added to the drinking fluid (900 mg/liter) and given ad libitum from 19 to 26 weeks of age, whereas tap water was given to the control animals. Although diltiazem did not decrease blood pressure in SHR, it decelerated the increase in their left ventricular weight (p less than 0.01). Hearts were removed and perfused by the working heart technique for 15 min, and then global ischemia was induced for either 10 or 30 min. The ischemic heart was reperfused for 30 min. The extent of recovery of coronary flow after reperfusion, following 30 min of ischemia in the diltiazem-treated SHR, was higher than that in the control SHR (p less than 0.01). The levels of adenosine triphosphate (ATP), creatine phosphate (CrP), and energy charge potential in the SHR heart reperfused after 30 min of ischemia were lower than those in the reperfused WKY heart (p less than 0.01, respectively). Diltiazem improved the restoration of ATP and CrP and prevented the decrease in energy charge potential in SHR after reperfusion following 30 min of ischemia (p less than 0.01, respectively). In conclusion, long-term treatment of SHR with diltiazem may protect the myocardium when myocardial ischemia occurs.

Effects of Eptazocine, a Novel Analgesic, on KCN-Induced Changes in the Cerebral Contents of Glycolytic Metabolites and High-Energy Phosphates in Mice

Effects of eptazocine on cerebral metabolic changes due to a sublethal dose of KCN were investigated in mice. KCN (2 mg/kg, i.v.) induced a temporary loss of consciousness being moderated by eptazocine (1-10 mg/kg) in a dose-dependent manner. The KCN injection decreased the contents of phosphocreatine (PCr), ATP and glucose and increased the contents of AMP and lactate, resulting in a 34% decrease in energy charge potential (ECP) and an increase in lactate/ pyruvate (L/P) ratio. Such changes were improved by eptazocine (10 mg/kg) and EKC (3 mg/kg), but not by pentazocine (10 mg/kg) and morphine (3 mg/kg), and the improving effect of eptazocine was completely inhibited by MR-2266 (3 mg/kg), a relatively selective opioid κ-receptor antagonist. On the other hand, eptazocine (3, 10 mg/kg) was found to increase the glucose content in normal mice, but not to give significant changes in the contents of glycolytic metabolites and high-energy phosphates. These results suggest that eptazocine may improve anoxic changes in cerebral energy metabolism.

Metabolic changes associated with iso-osmotic regulation in brain cortex slices.

Abstract— The metabolism of single, first cortical rat brain slices was studied in response to incubation in media of various osmolalities. There was an inverse relationship between osmolality and the magnitude of the increase in tissue water content, and a direct relationship between osmolality and inulin space. Brain sodium varied directly with the media sodium, but hyperosmolal sucrose and glucose resulted in a drop in brain sodium. Brain potassium was constant in hyperosmolal sodium media, but it fell in hypo‐osmolal media and hyperosmolal sucrose and glucose media.Hypo‐osmolality depressed the oxidation of [14C]glucose to 14CO2 whereas hyperosmolality obtained with sodium, sucrose, or glucose stimulated glucose oxidation. Lactate production was enhanced only by sodium hyperosmolality. Hypo‐osmolality caused a 70% drop in phosphocreatine and a minor decrease in energy charge potential, analagous to the effects of hypoxia. Hyperosmolality had no effect on energy metabolism.The total amino acid nitrogen released into the media was suppressed by hypo‐osmolality but was increased by hyperosmolal incubation. Hyperosmolality also increased production of ammonia fourfold.The time course of the change in tissue osmolality and ion content following incubation in hyperosmolal sodium media showed the tissue osmolality reached the media osmolality within 5 min, but it took 30 min for the tissue sodium to reach equilibrium with the media sodium. This indicates that unidentified or‘idiogenic osmoles’are induced transiently by hyperosmolality associated with changes in amino acid and ammonia metabolism.