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Objective: To investigate the effect of SR141716, a selective CB1 receptor antagonist, on energy expenditure and on glucose uptake in isolated soleus muscle of Lep(ob)/Lep(ob) mice., Design: Female Lep(ob)/Lep(ob) mice (8-10 weeks old) were treated with SR141716 (10 mg/kg, i.p. once daily) or vehicle for 7 days., Measurements: Oxygen consumption, daily food and water intake, body weight and glucose uptake in isolated soleus muscle., Results: SR141716 (10 mg/kg, i.p. once daily) resulted in a significant reduction of daily food intake (P<0.01) and body weight (P<0.05) 5 days after daily treatment. Body weight continued to be lower for the rest of the treatment period (P<0.05). There was no significant difference in body weight between the pair-fed and vehicle-treated animals. A 7-day treatment with SR141716 (10 mg/kg, i.p. once daily) caused 37% increase in basal oxygen consumption compared to that of vehicle-treated (90 min mean; P<0.01), and a significant 68% increase in glucose uptake in isolated soleus muscle preparations., Conclusion: It is concluded that SR141716 has a direct effect on energy expenditure suggesting that the antiobesity effect of SR141716 is due to activation of thermogenesis in addition to the initial hypophagia. The increase in soleus muscle glucose uptake with SR141716 treatment may contribute to the improved glycaemia seen in the previous studies.

Objective: To investigate whether the Agouti-related protein (Agrp), the melanocortin receptor antagonist, alters oxygen consumption, as a measure of energy expenditure., Design: A 7-day intracerebroventricular administration of Agrp (1 nmol/day) in rats., Measurements: Oxygen consumption was determined in closed-circuit respirometers on days 1 and 8. BRL-35135, a beta3-adrenoreceptor agonist known to activate the brown adipose tissue (BAT) thermogenesis directly and increase core temperature, was administered i.p. (40 microg/kg) on day 9 to challenge functionally the BAT., Results: Agrp treatment caused a 54% increase in daily food intake and a 12% increase in body weight. An 8% decrease in VO(2) measurements was observed following ICV Agrp treatment on day 1. A similar decrease (7%) was observed on day 8. BRL-35135 stimulated colonic temperature in control rats. However, in the rats that had previously been treated with Agrp this effect was significantly blunted., Conclusion: Chronic CNS administration of Agrp decreases oxygen consumption and decreases the capacity of BAT to expend energy. The obesity observed following CNS administration of Agrp is the result of decreased energy expenditure and increased food intake.

Objective: To determine if oxygen consumption (VO2) calculated using the Fick relationship (calculated VO2) determines total body VO2 accurately and precisely enough to employ this method during clinical assessment of oxygen transport., Design: Methods comparison, using repeated measures during four physiologic states: normal heart/normal lungs, heart failure/normal lungs, normal heart/acute lung injury, heart failure/acute lung injury., Setting: University research laboratory., Subjects: Thirteen adult Yucatan pigs., Interventions: Oleic acid-induced acute lung injury; heart failure was induced with a continuous infusion of esmolol., Measurements and Main Results: Calculated VO2 was determined by multiplying thermodilution cardiac output by the arterialvenous oxygen content difference in anesthetized, spontaneously breathing animals. Conditions were tightly controlled so that calculated VO2 would be as accurate as possible. "True" VO2 was measured simultaneously with a water-sealed spirometer (spirometry VO2). Calculated VO2 and spirometry VO2 were determined and analyzed during the four physiologic states listed above. Pooled data also were evaluated. Mean spirometry VO2 and calculated VO2 differed significantly during all four physiologic states and when data were pooled (spirometry VO2 273 +/- 70, calculated VO2 178 +/- 58 mL/min; p < .01). Calculated VO2 consistently underestimated spirometry VO2, as demonstrated by the large, positive bias in pooled data (95 +/- 59 mL of oxygen/min) and in the four physiologic states. Linear regression of data from all four states yielded slopes that were indistinguishable from 1, but y intercepts that varied from -152 to +182. For pooled data, the following equation was used: calculated VO2 = 0.5 x (spirometry VO2 + 46); r2 = .35. Precision in pooled data was 22% of the mean spirometry VO2. Data analysis for the four physiologic states demonstrated results similar to those results obtained when data were pooled., Conclusions: Even in a tightly controlled, clinical simulation in the laboratory, calculated VO2 from the Fick relationship systematically underestimated VO2 measured with a water-sealed spirometer. If true VO2 changes, the magnitude and direction of change will be reflected by calculated VO2 but with approximately 20% error in the absolute value. Heart failure, acute lung injury, and their combination did not affect the accuracy of calculated VO2. Therefore, calculating VO2 using the Fick relationship is too inaccurate to be used for research purposes. Because assessment of the directional change of VO2 may be clinically useful, calculated VO2 can be employed with discretion during clinical oxygen transport evaluation, bearing in mind the calculation's inherent imprecision.

Objective: The objective of our study was to derive a linear approximation to Brody's equation for oxygen consumption as a simpler alternative for the clinician., Methods: The approximation was derived by using calculus to construct a line tangent to Brody's equation at 81 kg., Results: The linear approximation was derived to be: VO2 = (2.5w + 67.5) ml/min, where w is the subject's weight in kilograms. The error introduced by this linear approximation is 10.9% at 30 kg and 1.35% at 120 kg., Conclusions: This linear equation may have utility for approximating oxygen consumption when an approximation is required, as in closed circuit anesthesia. The utility of this equation is that it is linear and produces a result similar to Brody's equation.

The effects of acute heart failure on lung mechanics and oxygen consumption (VO2) during normocarbic spontaneous ventilation were studied in 21 anesthetized pigs. Heart failure severe enough to double oxygen extraction (O2ex) was induced with intravenous esmolol boluses and infusion. Compared to normal, the inspiratory elastic work of breathing (Wel) increased from 335 +/- 371 (mean +/- SD) to 559 +/- 48 mm Hg.ml (p less than 0.003) during heart failure, lung compliance (CL) fell from 121 +/- 144 to 22 +/- 15 ml/mm Hg (p less than 0.05), and respiratory power climbed from 140 +/- 200 to 245 +/- 214 mm Hg.ml.min-1 (p less than 0.002). These mechanical changes were accompanied by a decrease in both VO2 (221 +/- 61 to 191 +/- 50 mlO2/min, p less than 0.05) and oxygen delivery (DO2) (680 +/- 240 to 260 +/- 90 mlO2/min, p less than 0.004). The VO2/DO2 ratio doubled (p less than 0.0002), confirming increased O2ex. In conclusion, severe acute heart failure decreased CL, and increased Wel and respiratory power significantly. The depressed cardiac output limits both DO2, and to some extent, VO2. However, a greater proportion of the delivered O2 is consumed, supplying indirect evidence which suggests that the respiratory muscles' VO2 increases as a consequence of increased power expenditure.

Resting oxygen consumption (VO2) and mitochondrial GDP binding were measured in hypothyroid and euthyroid rats after administration of selective and nonselective beta-adrenoceptor agonists (BRL 35135A and Isoprenaline--BRL, ISO). Resting VO2, VO2 increment and mitochondrial GDP binding after beta-agonists were lower in hypothyroid rats than in the euthyroid group. The reduced response was more marked for ISO than for BRL. These results suggest that BRL is acting on a beta-adrenoceptor which differs from beta-1 and beta-2 adrenoceptors, responsible for the effect of ISO. Activation of thermogenesis via this beta-3 adrenoceptor seems to be less dependent on permissive levels of thyroid hormones than on activation via beta-1 and/or beta-2 adrenoceptors.

Oxygen consumption (VO2) and mitochondrial guanosine diphosphate (GDP) binding of interscapular brown adipose tissue (BAT) were measured in hypothyroid, hyperthyroid and euthyroid rats after stimulations with selective and nonselective beta-adrenoceptor agonists: BRL 35135A (BRL) and Isoprenaline (ISO). Resting VO2, VO2 increment and mitochondrial GDP binding after beta-adrenergic stimulations were lower in hypothyroid rats than in the euthyroid group. The reduced responses were more marked for ISO than for BRL. Restion VO2 and VO2 increment after beta-adrenergic stimulations were higher in hyperthyroid rats than in the eurthyroid group; the increment was more marked for BRL than for ISO. In hyperthyroidism, mitochondrial GDP binding after BRL and after ISO was in the same magnitude; it was higher in the hyperthyroid than in the euthyroid group after BRL but not after ISO. The different thermogenic responses after ISO and BRL stimulations suggest that BRL is acting on a beta-adrenoceptor differing from the beta-1 and beta-2 adrenoceptors responsible for the effects of ISO. Activation of thermogenesis via the beta-3 adrenoceptor seems to be less dependent on the permissive levels of thyroid hormones than activation via beta-1 and/or beta-2 adrenoceptors. The beta-3 adrenoceptor may be more sensitive to increased levels of thyroid hormones.

The effects of histamine antagonists on noradrenaline-stimulated metabolic rate, tissue blood flow (estimated from the distribution of radiolabelled microspheres) and brown adipose tissue (BAT) oxygen extraction were studied in male anaesthetised rats. Injection of cimetidine (H2-receptor antagonist), reduced the noradrenaline-stimulation of metabolic rate and the increase in blood flow to BAT, but did not affect blood flow to white adipose tissue, skin, leg muscle, kidney, brain, or testes. Following noradrenaline, in vivo oxygen consumption of BAT, estimated from blood flow and oxygen extraction was depressed to 31% of control values by treatment with cimetidine, blood pressure was unaffected. Injection of the histamine (H1-receptor) antagonist, mepyramine, did not affect tissue blood flow or metabolic rate. In conscious animals, cimetidine did not affect resting oxygen consumption, but depressed the thermogenic responses to noradrenaline. These data suggest that the stimulation of BAT blood flow and thermogenesis by noradrenaline may be mediated in part by histamine acting on an H2-type receptor.

Heart ventricles from chick embryos incubated in 60% O2 (hyperoxia) on the 16th through the 18th days of incubation were 21% heavier than those from control embryos maintained in 21% O2 (normoxia). Heart ventricles from embyros incubated in 15% O2 (hypoxia) were 8% lighter than controls. Changes in ventricular weight were accompanied by proportional changes in protein content (21% more in hyperoxic ventricles; 8% less in hypoxic ventricles). Ventricular tissue DNA content showed a significant increase in hyperoxia. Tissue protein/DNA ratios were significantly higher in hyperoxia and lower in hypoxia. These data suggest that increased O2 availability led to hypertrophy of chick embryo ventricular cells and an increase in the level of DNA synthesis. Cytochrome oxidase activity per mg DNA was 15-25% higher in hyperoxic ventricles than in hypoxic ventricles. This result is consistent with our previous findings that alterations in O2 availability affect the O2 consumption rate of the chick emryo in ovo, and it provides direct evidence that a phenomenon repeatedly observed in vitro is of importance in vivo. In contrast to the heart, O2 availability did not affect the wet weight, protein or DNA contents, or cytochrome oxidase activity of the chick embryo brain.

A single injection of ACTH stimulated metabolic rate in the rat, and this effect was enhanced in hyperphagic cafeteria-fed rats. Chronic treatment with ACTH significantly reduced body weight, energy gain and energetic efficiency in stock-fed rats. Thermogenic responses to noradrenaline and a single meal, and purine nucleotide (GDP) binding to brown adipose tissue (BAT) mitochondria were also increased. Cafeteria feeding induced hyperphagia, increases in metabolic rate, acute thermogenic responses and BAT activity, and depressed energetic efficiency. ACTH had no additional effects on energy balance, thermogenic responses or brown fat in cafeteria-fed rats. These data indicate that stimulation of thermogenesis and BAT activity by ACTH resembles that induced by hyperphagia, and this effect may be partly responsible for the changes in energy balance after adrenalectomy seen in previous studies. However, acute and chronic responses to ACTH depend upon the nutritional status of the animal.

Growth of the chick embryo is accelerated by brief (72-hr) exposure to 60% O2 beginning on day 16 of incubation, and acute (2-3 hr) hyperoxia stimulates oxygen consumption (VO2). However, the increment in VO2 that accompanies acute exposure to 60% O2 is only about half that required to account for the degree of growth acceleration observed during 72 hr of hyperoxia. We tested the hypothesis that the magnitude of the oxygen-induced change in embryonic metabolism depends on the length of exposure by making daily measurements of embryonic VO2 during brief (72-hr) exposure to 60% or 15% O2. White leghorn eggs were incubated in 21% O2 for 15 days. On day 16 the experimental eggs were switched to 60% or 15% O2; control eggs were maintained in 21% O2. Oxygen consumption and CO2 production (VCO2) were measured daily. Embryo and organ weights were compared on day 18. Wet and dry weights of briefly hyperoxic embryos were significantly greater than those of normoxic controls. The relative increase in wet weight was significant for the heart and liver but not the brain. Oxygen consumption increased 7% relative to control after 24 hr of hyperoxia and 17% after 72 hr; VO2/gm embryo was 9% greater than control on day 18. Normal growth deceleration was exaggerated by hypoxia; mean wet and dry weights of the briefly hypoxic embryos were significantly less than those of controls. Organ wet weights also showed growth retardation, although the relative decrease in brain weight was not significant. Body water concentration increased in briefly hypoxic embryos. Oxygen consumption was 13% less than control after 24 hr and 17% less after 72 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

The rise in resting oxygen consumption (VO2) during the 2-3 h following intragastric feeding (50 kJ [12 kcal]) was significantly greater in hyperphagic cafeteria-fed rats and hyperthyroid rats, but was markedly reduced in 3-day fasted and genetically-obese Zucker rats, compared to their respective stock-fed controls. In control and hyperthyroid animals this response was almost completely abolished by administration of propranolol. In another group of rats, resting VO/ was elevated by 8 per cent after 12 h of cafeteria feeding and was maximally increased by 20 per cent after 2.5 days on the diet. In rats previously cold-adapted (15 days at 5 degrees C) the maximal response (20 per cent) to cafeteria feeding was seen after only 12 h on the diet. These results suggest that the acute thermic response to food involves a sympathetic activation of thermogenesis, similar to that induced by chromic hyperphagia and cold-exposure, and can be influenced by genetic background plane of nutrition and thyroidal status.

Metabolic rate and tissue blood flow were measured by indirect calorimetry and the radioactive microsphere technique, respectively, in anaesthetized pigs aged 10, 17, and 28 days during infusions of saline or noradrenaline. Noradrenaline produced a rise in oxygen consumption in all pigs but the magnitude of the response declined with age in Large White pigs (percent increase: 10 days old, 29.5 +/- 3.3; 17 days old, 15.3 +/- 3.2; 28 days old, 5.4 +/- 0.17) and was less in 10-day-old Minipigs (9.1 +/- 5.1). Regional blood flow per gram of tissue was similar for pigs of all ages and noradrenaline produced increases in flow to heart and skin, and small reductions in blood flow to skeletal muscle. Noradrenaline increased average blood flow to adipose tissue (four sites) by 21-fold in 10-day-old Large White pigs, but had less effect in 10-day-old Minipigs (9.5-fold) and in older Large White pigs (9-fold), where the effect on metabolic rate was diminished. It is calculated that adipose tissue could be responsible for the increase in metabolic rate during infusion of noradrenaline. Macroscopically there are no gross differences between various adipose tissue depots in the pig but those which showed the greatest response to noradrenaline correspond to areas where brown adipocytes have previously been identified by electron microscopy.

Oxygen consumption was monitored in fed and fasted, lean and obese mice of the ob/ob strain before and after subcutaneous injections of norepinephrine (NE). The increase in oxygen consumption after NE was of a similar magnitude in both lean and obese fed mice, but of a longer duration in the obese. Prior fasting caused a diminution of the response in the lean but was associated with an enhanced response in the obese mice. Fasting also resulted in a significant depression of the resting oxygen consumption of the obese mice but not of the lean. The relevance of these findings to the inability of the obese mouse to withstand cold exposure and to the maintenance of the obese state is discussed.

An apparatus suitable for the continuous measurement of oxygen consumption of rats and mice is described. The system uses a motorized syringe dispenser to deliver fixed volumes of oxygen to a closed animal chamber. The dispenser is controlled by a micro-differential pressure switch to maintain chamber pressure slightly above ambient. The rate of oxygen consumption is determined by timing the interval between successive operations of the dispenser. The system has proved suitable for a range of experimental conditions and treatments.

Acute lung injury causes a restrictive pulmonary defect, decreases lung compliance, and increases the work of breathing. We wished to determine the oxygen cost of the increased elastic work of breathing associated with acute lung injury. Extracorporeal venous circulation with a membrane lung was used to extract CO2 and to induce apnea in 14 anesthetized pigs. Data were collected during 4 experimental states: during spontaneous ventilation and apnea when the animals' lungs were normal, and after acute lung injury developed because of oleic acid administration. Acute lung injury decreased lung compliance from 101 +/- 79 (mean +/- SD) to 52 +/- 25 ml/cm H2O (p less than 0.04), and increased the elastic work of breathing from 700 +/- 590 to 1,060 +/- 630 ml.cm H2O (p = 0.01). During spontaneous ventilation, the increases in total O2 consumption and the O2 cost of breathing caused by acute lung injury were sufficiently small as to be undetectable, and, therefore, less than 3 to 4% of basal O2 consumption despite markedly increased elastic work and ventilatory power requirements. The increase in O2 consumption imposed by acute lung injury was small enough (less than 3 to 4% of total O2 consumption) that it appears to be clinically insignificant.

Methyl isocyanate (MIC) was evaluated for sensory and pulmonary irritation in mice. MIC was found to be both a potent sensory and pulmonary irritant in this species. From these results, a safe level of exposure for a period of 8 hr was estimated to be about 0.02 ppm for humans. Guinea pigs were also exposed to MIC for a single 3-hr exposure at a concentration of 37 ppm. During exposure to MIC, coughing was observed in all animals. Pulmonary function was evaluated immediately following exposure and intermittently on the next 35 days using CO2 challenges and flow-volume loops. Highly abnormal responses to CO2 were observed immediately after exposure in all animals. Six of the eight animals exposed to MIC died. In the two survivors, an apparent recovery was seen during the 5 days following exposure, but a worsening effect was observed at days 21 and 28, with a partial recovery at day 35. The data clearly demonstrated that the primary pulmonary effect of MIC was one of airways obstruction. Oxygen uptake and carbon dioxide output were also measured in the guinea pigs following exposure to MIC. No evidence of a cyanidelike effect was observed, in contrast to a severe depression of oxygen uptake following exposure to hydrogen cyanide.