Selective inhibition of glucose oxidation by triethyltin in rat brain in vivo
TL;DR: Changes in glucose metabolism in the brain are shown not to be directly due to hypothermia and some of the advantages of measuring the labelling of intermediates at very short time intervals after the injection of the labelled glucose are demonstrated.
Abstract: Results are reported of a comparative study in vivo of the metabolism of [2-14C]-glucose and [1-14C]acetate in brains of rats intoxicated with triethyltin sulphate. The incorporation of 14C from glucose into glutamate, glutamine, γ-aminobutyrate and aspartate was greatly decreased. The incorporation of 14C from acetate into these amino acids was unaffected. The experimental data indicated that the main action of triethyltin was to decrease the rate at which pyruvate formed from glucose is oxidized. Glycolysis was not inhibited. Changes in glucose metabolism in the brain are shown not to be directly due to hypothermia. Some of the advantages of measuring the labelling of intermediates at very short time intervals after the injection of the labelled glucose are demonstrated.
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TL;DR: According to Ross (1), there are three main areas in which organotin compounds have product and process utility: (1) heat stabilizers; (2) catalytic agents; (3) biocidal compounds.
Abstract: According to Ross (1), there are three main areas in which organotin compounds have product and process utility: (1) heat stabilizers; (2) catalytic agents; (3) biocidal compounds. Organotin derivatives account for the fourth largest production of organometallics amounting to about 3-4 million pounds per year as compared with about 485 million pounds per year for organolead compounds. Originally, organotin compounds were developed as thermal stabilizers for chlorinated hydrocarbons which would be used in those applications for which there was a strong possibility of thermal degradation. However, as the chemistry of organotin compounds became better understood, their application expanded to catalytic and biologically active agents.
254 citations
TL;DR: Data suggest a substantial reduction of brain metabolic rate is achieved in the rat at a barbiturate dosage which may be therapeutically relevant in the human after acute brain ischemia.
Abstract: A new method of determining the rate of glucose utilization in brain regions of individual rats has been used to measure the dose dependency of the reduction of the metabolic activity of the cerebral cortex by pentobarbital. Cerebral cortical glucose utilization is depressed to a basal level of 44% of the control rate when cerebral pentobarbital levels exceed 50 microgram per g of tissue. The major portion of this effect occurs between the cerebral pentobarbital range of 10--20 microgram per g, which can be achieved by 1/5 to 1/10 the normal anesthetic intraperitoneal dosage. If a depression of brain metabolism is responsible for the previously reported protection of the brain from ischemic damage, these data suggest a substantial reduction of brain metabolic rate is achieved in the rat at a barbiturate dosage which may be therapeutically relevant in the human after acute brain ischemia.
158 citations
TL;DR: A method is described by which the rate of glucose utilization by whole brain of conscious rats may be measured through the uptake of 14C derived front [2‐14C] glucose into the acid‐soluble metabolite pool of brain.
Abstract: — A method is described by which the rate of glucose utilization by whole brain of conscious rats may be measured. The basis is the uptake of 14C derived front [2-14C] glucose into the acid-soluble metabolite pool of brain. Catheters are placed in the femoral artery and vein under light ether anesthesia. After full recovery of consciousness a single intravenous injection of [2-14C] glucose is given and arterial blood samples taken at intervals. Simultaneous with the last sample the brain is removed and frozen within 1 s. The accumulation of 14C into the acid-soluble metabilite pool is measured and the rate of glucose utilization is calculated according to the equation:
The integral is calculated from the plasma glucose specific activity curve and evidence is presented to justify this procedure. The rate of glucose utilization measured by this method was 0·62 μmol/min per g in conscious rats and 0·28 μmol/min per g in sodium pentobarbital anesthetized rats.
130 citations
TL;DR: The origin of the acetyl group in acetyl‐CoA which is used for the synthesis of ACh in the brain and the relationship of the cholinergic nerve endings to the biochemically defined cerebral compartments of the Krebs cycle intermediates and amino acids were studied.
Abstract: —The origin of the acetyl group in acetyl-CoA which is used for the synthesis of ACh in the brain and the relationship of the cholinergic nerve endings to the biochemically defined cerebral compartments of the Krebs cycle intermediates and amino acids were studied by comparing the transfer of radioactivity from intracisternally injected labelled precursors into the acetyl moiety of ACh, glutamate, glutamine, ‘citrate’(= citrate +cis-aconitate + isocitrate), and lipids in the brain of rats. The substrates used for injections were [1-14C]acetate, [2-14C]acetate, [4-14C]acetoacetate, [1-14C]butyrate, [1, 5-14C]citrate, [2-14C]glucose, [5-14C]glutamate, 3-hydroxy[3-14C]butyrate, [2-14C]lactate, [U-14C]leucine, [2-14C]pyruvate and [3H]acetylaspartate.
The highest specific radioactivity of the acetyl group of ACh was observed 4 min after the injection of [2-14C]pyruvate. The contribution of pyruvate, lactate and glucose to the biosynthesis of ACh is considerably higher than the contribution of acetoacetate, 3-hydroxybutyrate and acetate; that of citrate and leucine is very low. No incorporation of label from [5-14C]glutamate into ACh was observed. Pyruvate appears to be the most important precursor of the acetyl group of ACh.
The incorporation of label from [1, 5-14C]citrate into ACh was very low although citrate did enter the cells, was metabolized rapidly, did not interfere with the metabolism of ACh and the distribution of radioactivity from it in subcellular fractions of the brain was exactly the same as from [2-14C]pyruvate. It appears unlikely that citrate, glutamate or acetate act as transporters of intramitochondrially generated acetyl groups for the biosynthesis of ACh. Carnitine increased the incorporation of label from [1-14C]acetate into brain lipids and lowered its incorporation into ACh.
Differences in the degree of labelling which various radioactive precursors produce in brain glutamine as compared to glutamate, previously described after intravenous, intra-arterial, or intraperitoneal administration, were confirmed using direct administration into the cerebrospinal fluid. Specific radioactivities of brain glutamine were higher than those of glutamate after injections of [1-14C]acetate, [2-14C]acetate, [1-14C]butyrate, [1,5-14C]citrate, [3H]acetylaspartate, [U-14C]leucine, and also after [2-14C]pyruvate and [4-14C]acetoacetate. The intracisternal route possibly favours the entry of substrates into the glutamine-synthesizing (‘small’) compartment. Increasing the amount of injected [2-14C]pyruvate lowered the glutamine/glutamate specific radioactivity ratio.
The incorporation of 14C from [1-14C]acetate into brain lipids was several times higher than that from other compounds. By the extent of incorporation into brain lipids the substrates formed four groups: acetate > butyrate, acetoacetate, 3-hydroxybutyrate, citrate > pyruvate, lactate, acetylaspartate > glucose, glutamate. The ratios of specific radioactivity of ‘citrate’ over that of ACh and of glutamine over that of ACh were significantly higher after the administration of [1-14C]acetate than after [2-14C]pyruvate.
The results indicate that the [1-14C]acetyl-CoA arising from [1-14C]acetate does not enter the same pool as the [1-14C]acetyl-CoA arising from [2-14C]pyruvate, and that the cholinergic nerve endings do not form a part of the acetate-utilizing and glutamine-synthesizing (‘small’) metabolic compartment in the brain. The distribution of radioactivity in subcellular fractions of the brain after the injection of [1-14C]acetate was different from that after [1, 5-14C]citrate. This suggests that [1-14C]acetate and [1, 5-14C]citrate are utilized in different subdivisions of the ‘;small’ compartment.
121 citations
TL;DR: The brains of 18-day-old rats utilize glucose and ketone bodies and the rates of acetyl-CoA formation from these substrates and of glycolysis were determined in vivo from the labelling of intermediary metabolites after intraperitoneal injection.
Abstract: The brains of 18-day-old rats utilize glucose and ketone bodies. The rates of acetyl-CoA formation from these substrates and of glycolysis were determined in vivo from the labelling of intermediary metabolites after intraperitoneal injection of d-[2-14C]glucose, l(+)-[3-14C]- and l(+)-[U-14C]-lactate and d(−)-3-hydroxy[14C]butyrate. Compartmental analysis was used in calculating rates to allow for the rapid exchange of blood and brain lactate, the presence in brain of at least two pools each of glucose and lactate, and the incomplete equilibration of oxaloacetate with aspartate and of 2-oxoglutarate with glutamate. Results were as follows. 1. Glucose and ketone bodies labelled identical pools of tricarboxylate-cycle metabolites, and were in every way alternative substrates. 2. The combined rate of oxidation of acetyl-CoA derived from pyruvate (and hence glucose) and ketone bodies was 1.05μmol/min per g. 3. Ketone bodies contributed 0.11–0.53μmol/min per g in proportion to their concentration in blood, with a mean rate of 0.30μmol/min per g at 1.24mm. 4. Pyruvate and ketone bodies were converted into lipid at 0.018 and 0.008μmol/min per g respectively. 5. Glycolysis, at 0.48μmol/min per g, was more rapid in most rats than pyruvate utilization by oxidation and lipid synthesis, resulting in a net output of lactate from brain to blood. 6. Rates of formation of brain glutamate, glutamine and aspartate were also measured. Further information on the derivation of the models has been deposited as Supplementary Publication SUP 50034 (18 pages) at the British Library, Lending Division (formerly the National Lending Library for Science and Technology), Boston Spa, Yorks. LS23 7QB, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1973) 131, 5.
118 citations