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V J Cunningham

Publications and source records attributed to V J Cunningham.

At least 73 records · Page 4Linked to original sources
PubMed1987

Uncoupling of cerebral glucose supply and utilization after hexane-2,5-dione intoxication in the rat.

Chronic administration of hexane-2,5-dione (2,5-HD) to rats causes an accumulation of neurofilaments within axons that may lead to their degeneration. This occurs in both the CNS and PNS. It has been suggested that one of the effects of 2,5-HD is an impairment of glucose utilization arising from an inhibition of specific glycolytic enzymes. This hypothesis is based principally on evidence obtained in vitro. In the present study, glucose utilization, glucose transport across the blood-brain barrier, and blood flow have been measured in vivo in brain regions of control rats and in three groups of rats treated with 2,5-HD as (a) a single intragastric dose (500 mg/kg of body weight), (b) high chronic doses of 500 mg/kg of body weight for 15 days, or (c) low chronic doses of 250 mg/kg of body weight for 21 days. Group b showed overt signs of neuropathy, whereas groups a and c did not. The results indicate two independent effects of 2,5-HD in the CNS: a dose-dependent inhibition of glucose utilization and an effect on glucose supply and transport across the blood-brain barrier, which is apparent only after chronic treatment.

Animals↗
PubMed1986

Studies on the relationship between cerebral glucose transport and phosphorylation using 2-deoxyglucose.

Regional rates of blood-brain glucose transfer and phosphorylation have been measured in anaesthetized fasted and conscious fed and fasted rats using a dual-label 2-deoxyglucose technique that exploits differences in the early-time distribution of analogue and native glucose between blood and brain. Regional cerebral blood flow was also measured in comparable groups of rats. Estimates of glucose influx in the anaesthetized group were compared with those calculated from previously published kinetic constants obtained using [14C]D-glucose as tracer. The close agreement of these two sets of results served to validate estimates of influx obtained using the glucose analogue. Comparisons between all three groups showed that regional rates of glucose influx were maintained at levels appropriate to the rate of cerebral glucose phosphorylation. This occurred despite wide variations in plasma glucose concentration. The results indicate that at least two factors are involved in the adaptation of glucose supply to meet metabolic demand. One is related to blood flow, and probably reflects changes in the surface area of the capillary endothelium perfused. The second involves changes in the blood-brain barrier permeability to glucose and could reflect changes in the density of functioning glucose transporters within capillary endothelial cell membranes.

Animals↗
PubMed1986

Regional blood-brain glucose transfer in the rat: a novel double-membrane kinetic analysis.

Regional blood-brain glucose transfer was studied in pentobarbitone-anaesthetized rats using a programmed intravenous infusion technique that maintained steady levels of unlabeled (up to 55 mM) and tracer D-glucose in the circulating plasma. Regional cerebral blood flow, glucose phosphorylation rate, and tissue glucose content were also measured under comparable conditions. Data were analysed in terms of irreversible Michaelis-Menten kinetics assuming independent influx and efflux (Type I) and reversible Michaelis-Menten kinetics (Type II) across both the luminal and the abluminal membranes of the endothelial cell. The latter analysis corresponds to simple stereospecific membrane pores. The mathematical model allowed for changes in tissue glucose content and back-diffusion of tracer during the experiments. Type I analyses gave Kt values of approximately 6.6 mM, whereas those by Type II were consistently lower. Interregional differences were not significant using either scheme. Comparison of Type II with Type I analyses revealed a possible explanation for discrepancies in the estimates of nonsaturable glucose transfer by different methods and highlighted the importance of tissue glucose measurements in studies of unidirectional glucose influx. Since the experimental data may be described equally well by either scheme and some interaction between influx and efflux across the endothelial cell might be expected, consideration of this alternative approach is suggested.

Animals↗
PubMed1985

Hypothermia produced by tributyl S,S,S-phosphorotrithioate (DEF).

Tributyl S,S,S-phosphorotrithioate (DEF) produces profound hypothermia in rats, mice and guinea pigs by inhibition of thermogenesis. Its actions on heat conservation and motor control are, however, minimal. It is effective against both shivering and non-shivering thermogenesis and completely blocks the increase in body temperature evoked by anterior hypothalamic stimulation. A number of other measures indicated that this is unlikely to be due to a lack of peripheral thermogenic capacity: thus plasma concentrations of glucose, free fatty acids, and ketone bodies remained normal or rose after DEF, and in vitro noradrenaline-stimulated lipolysis was normal in the presence of DEF. The metabolic response to the uncoupler, 2,4-dinitrophenol was unchanged by DEF, and the increase in temperature of brown fat evoked in vivo by nerve stimulation or noradrenaline was also unaffected. It is suggested that DEF (or more likely a DEF metabolite) acts selectively on a central thermogenic control process.

Acclimatization↗
PubMed1985

Kinetics of saturable transport across the blood-brain barrier.

This article is concerned with the extension of the Renkin-Crone model to a case of saturable transport across the blood-brain barrier, i.e., when the apparent permeability-surface area product is concentration dependent. A well-mixed tissue compartment is assumed, together with a simple symmetric saturable transport system. A computation scheme, or algorithm, is described that allows the calculation of arteriovenous differences and net influx rates for parent substance and tracer in terms of arterial and tissue concentrations of each, the transport maximum Tmax, the half-saturation constant Kt, and plasma flow rate. The scheme was devised initially for the analysis of experiments in which the parent substance was not in a steady state and in which tracer backflux from tissue to capillary was significant.

Blood-Brain Barrier↗
PubMed1984

Characterization of Na+,K+-ATPase in cultured and separated neuronal and glial cells from rat cerebellum.

The activities of certain properties of sodium, potassium-activated adenosine triphosphatase (Na+,K+-ATPase; EC 3.6.1.3) were examined in cultures and perikarya fractions enriched in rat cerebellar nerve cells or astrocytes, in comparison with preparations from whole immature and adult rat cerebellum and derived synaptosomal fractions, as well as nonneural tissue such as the kidney. The specific activity of Na+,K+-ATPase was markedly higher in the freshly isolated astrocytes than in the nerve cells (3-15-fold greater depending on neuronal cell type). In contrast, the specific activity of the enzyme was about twice as high in the primary neuronal as in the astrocytic cultures after 14 days in vitro. In membrane preparations from the whole cerebellum, synaptosomal fractions, and total perikarya suspensions the inhibition of enzyme activity by ouabain indicated complex kinetics, which were consistent with the presence of two forms of the Na+,K+-ATPase (apparent Ki values of about 10(-7) M and 10(-4)-10(-5) M, respectively), the high-affinity form accounting for 60-75% of the total activity. The interaction of the enzyme with ouabain was apparently similar in perikarya preparations of granule neurones, Purkinje cells, and astrocytes. Differences were, however, observed in the properties of the Na+,K+-ATPase of cultured neurones and astrocytes. The latter contained predominantly, but not exclusively, an Na+,K+-ATPase with low affinity for ouabain (73% of the total) that is similar to the single enzyme form in the kidney. This form constituted a significantly smaller proportion of the Na+,K+-ATPase in the cultured neuronal preparations (55%). It would appear, therefore, that in membrane fractions from preparations enriched in different separated and cultured neural cell types both the high- and the low-affinity forms of the enzyme, in terms of interaction with ouabain, are expressed. Depending on the class of cells these enzyme forms constituted a different proportion of the total activity, but both forms seemed to be present in every type of cell examined, even after taking into account the contribution in the enriched preparations of the contaminating cell types. In contrast with the results on the Na+,K+-ATPase activity determined under optimal conditions in preparations derived from disrupted cells, differences could not be detected between the cultured cell types when the effect of ouabain on the uptake of 86Rb into "live cells" was estimated as a measure of in situ ion pump activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphatases↗
PubMed1983

Hydrolysis of oleylanilide in the rat.

The fate of oleylanilide, administered as a single intragastric dose in rape oil, has been studied in Porton Wistar rats. Following a dose of oleyl[U-14C]anilide approximately 60% of the label was recovered in the faeces over a 3 day period, and identified principally as unchanged anilide. Most of the remainder of the dose was recovered in urine as hydrophilic metabolites. p-hydroxyacetanilide, which is a major metabolite of aniline in the rat was identified in the hydrolysed samples of urine from anilide treated rats. Following administration of [9,10(n)-3H]oleyl[U-14C]-anilide to rats which had been fitted with a cannula in the thoracic lymph duct the [3H] label which was absorbed was recovered principally in triglycerides showing that extensive hydrolysis of the anilide occurs prior to or during uptake from the gut. Oleylanilide was identified in lymph by gas chromatography but amounted to less than 6% of the dose.

Acetanilides↗
PubMed1983

Relationships between extraction and metabolism of glucose, blood flow, and tissue blood volume in regions of rat brain.

Studies were made on the relationships between the rate of glucose metabolism, the transport of glucose between plasma and brain, cerebral blood flow, and blood content. Conscious control rats were compared with rats with intense tremors induced with cismethrin. The influence of plasma glucose concentration was studied by fasting some animals overnight prior to the induction of tremors. Mean plasma glucose was 8.83 mM in controls, 12.57 mM in fed rats with tremors, and 4.94 mM in rats fasted overnight prior to induction of tremors. Of 12 brain regions studied, nine showed an increased rate of glucose utilization in both fed and fasted trembling rats. Cerebellum had the highest percentage increase (200%). Rates of unidirectional glucose influx in fed trembling rats were significantly greater than those in controls in eight regions. In fasted animals, rates were the same as in controls, except in cerebellum, where it was 1.6 times higher. These high rates of glucose influx at low plasma glucose concentrations were indicative of a change in kinetic parameters of glucose transport. Unidirectional glucose influx rates were transformed to estimates of maximal transport rates (Tmax), based on the Michaelis-Menten equation. Average plasma glucose concentrations in regional capillaries (c) were calculated and shown to be maintained at values close to arterial plasma glucose concentrations (Ca), in all brain regions of each group. In trembling rats, Tmax for each brain region was higher than that in controls. In fasted rats with tremors, Tmax was higher in several brain regions than in fed rats. Tmax in cerebellum was 3.37, 4.71, and 7.89 mumol g-1 min-1 in control, fed trembling, and fasted trembling rats, respectively. Blood flow increased significantly in all regions in rats with tremors and was higher in fasted than in fed animals. There was only a weak correlation between blood flow and Tmax. Blood content of several regions increased in rats with tremors, and there was a strong correlation between Tmax and tissue blood volume. Results are consistent with localized regulatory links between blood flow, capillary surface area, and glucose transport in response to metabolic demand and hypoglycaemia. These involve changes in the linear velocity of blood through capillaries and in the extent of capillary recruitment.

Animals↗
PubMed1982

Inhibition, by 2-oxo acids that accumulate in maple-syrup-urine disease, of lactate, pyruvate, and 3-hydroxybutyrate transport across the blood-brain barrier.

Data are presented in support of the transport of (-)-D-3-hydroxybutyrate across the blood-brain barrier (BBB) being a carrier-mediated process. The kinetic parameters in 21-day-old pentobarbital-anaesthetized rats were Vmax 2.0 mumol.g-1.min-1, Km 29 mM, and KD 0.024 ml.g-1.min-1. The value for Vmax was the same as that for L-lactate and pyruvate transport in animals of the same age. The transport of all three substrates was sensitive to inhibition by low concentrations of either 2-oxo-3-methylbutanoate or 2-oxo-4-methylpentanoate, the 2-oxo acids that can accumulate in patients with maple-syrup-urine disease. The Ki values for the 2-oxo acids were severalfold lower than the respective Km values. 2-Oxo-3-phenylpropionate was a poor inhibitor. The relative affinities of the various monocarboxylic acids for the transport system of the BBB distinguished it from similar systems described in brain, heart, and liver mitochondria; human erythrocytes; and Ehrlich ascites-tumour cells.

3-Hydroxybutyric Acid↗
PubMed1981

A method for the simultaneous estimation of regional rates of glucose influx and phosphorylation in rat brain using radiolabeled 2-deoxyglucose.

A procedure is described which allows the simultaneous estimation of the rate of glucose influx from blood to brain and of the rate of glucose phosphorylation in discrete brain regions of the rat. The method is applicable over an experimental period of 5 min and involves sequential i.v. injections of [14C]2-deoxyglucose and [3H]2-deoxyglucose. Arterial blood samples are collected over the experimental period. After 5 min the rat is killed by microwave irradiation to the head and the brain dissected. The data obtained on glucose, 2-deoxyglucose and 2-deoxyglucosephosphate concentrations in plasma and brain are analyzed in terms of a model which relates the kinetics of 2-deoxyglucose uptake and phosphorylation to those of glucose. The model is based on measurements made of the relative rates of unidirectional influx of glucose and 2-deoxyglucose and of their relative fractional rates of phosphorylation.

Animals↗
PubMed1981

A study of the kinetic behaviour of glucose based on simultaneous estimates of influx and phosphorylation in brain regions of rats in different physiological states.

Results from the application of a procedure that allows simultaneous estimation of the rates of glucose transport from blood and of glucose phosphorylation in discrete regions of the brain are given for groups of rats displaying chemically induced motor disturbances. The procedure is based on sequential injections of [14C]- and [3H]-2-deoxyglucose followed a few minutes later by focused microwave irradiation to the head. Control conscious rats were used and rats displaying either whole body tremors, hind-limb rigidity or choreoathetotic movements induced by synthetic pyrethroid compounds. For individual rats estimates of 5 parameters were obtained in up to 16 brain regions. In addition brain tissue and plasma glucose concentrations were determined. The 5 parameters were: (1) rate of total glucose influx from plasma; (2) rate of glucose phosphorylation (equivalent to net influx); (3) rate of glucose efflux; (4) half-life of free glucose in brain; and (5) PS-product expressed as the ratio of the rate of glucose influx to plasma glucose concentration. For each parameter significant differences between regions were found in all groups of animals including conscious controls. The mean values for the somatosensory cortex of control rats were parameter: (1) 2.02 mumol/g/min; (2) 1.11 mumol/g/min; (3) 0.91 mumol/g/min; (4) 0.94 min; and (5) 0.196 ml/g/min. A high correlation was observed between the rate of total glucose influx and the rate of glucose phosphorylation for all brain regions in all groups of rats. This finding is discussed in terms of a synchronized regulatory mechanism on the glucose transport carrier of capillary endothelial cells and on the functional hexokinase Vmax activity within brain cells.

Animals↗
PubMed1980

Variation in the hepatotoxic effects of carbon disulphide between different strains of rat.

The hepatotoxic effects of carbon disulphide have been investigated in an outbred (Porton) strain of rat and in 8 inbred strains. Carbon disulphide (1.38 mmoles/kg body weight) was administered intraperitoneally to rats which had been pretreated with phenobarbitone and starved. Livers were taken for analysis 24 h later. A considerable genetic variation in the response of rats to carbon disulphide was observed. The extent of centrilobular hydropic degeneration varied greatly between strains and was accompanied by a high incidence of focal coagulative necrosis in the most susceptible rats. Analysis of variance of the accompanying changes in liver weight and water content and in total liver cytochrome P450 content gave statistical confirmation of a strain effect in the response to carbon disulphide. Highly significant strain x treatment interactions for these parameters were attributable to changes after carbon disulphide treatment rather than variation between phenobarbitone pretreated starved controls. The experiments were repeated in two blocks, 3 months apart. Block effects and interactions were significant in some cases but were quantitatively small and did not obscure a ranking based on histological assessment. AGUS rats were least affected by carbon disulphide whereas PVG and LEW rats showed extensive liver damage. Other strains (WA, Porton, F344, BDIX, WAG) showed a gradation of response between these extremes.

Animals↗