Thermogenesis Inhibition in Brown Adipocytes Is a Specific Property of Volatile Anesthetics

2003 ◽  
Vol 98 (2) ◽  
pp. 437-448 ◽  
Author(s):  
Kerstin B.E. Ohlson ◽  
Sten G.E. Lindahl ◽  
Barbara Cannon ◽  
Jan Nedergaard
Keyword(s):  
Oxygen Consumption ◽  
Heat Production ◽  
Specific Property ◽  
Clinical Importance ◽  
Volatile Anesthetics ◽  
Oxygen Electrode ◽  
Inhibitory Effect ◽  
Nonshivering Thermogenesis ◽  
Brown Adipocytes ◽  
Anesthetic Agents

Background This investigation examined the possibility that the inhibitory effect of halothane on nonshivering thermogenesis (heat production) in brown adipocytes is not a universal effect of all anesthetic agents but related to the type of anesthetic. Methods Brown adipocytes from hamster were isolated with a collagenase digestion method and incubated with anesthetic agents. The rate of oxygen consumption was measured with an oxygen electrode. The effect of clinically relevant (and higher) doses of anesthetics of different classes on basal and norepinephrine-induced thermogenesis (oxygen consumption) was tested. Results Two distinct groups of anesthetics could be distinguished: thermogenesis inhibitors and noninhibitors. Thermogenesis inhibitors include volatile anesthetics such as halothane (IC(50), 1.1 mm), ether (IC(50), 20 mm), and chloroform (IC(50), 2.2 mm) (nominal concentrations), but also tribromoethanol (IC(50), 0.6 mm), all inducing inhibition of norepinephrine-induced thermogenesis without affecting the EC for norepinephrine. Thermogenesis noninhibitors include the nonvolatile anesthetics pentobarbital, propofol, ketamine, and urethane, the inhalation anesthetic nitrous oxide, and, notably, also the volatile nonanesthetics (nonimmobilizers) 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane; none of these compounds had any effect on norepinephrine-induced thermogenesis at any concentration tested. Conclusions There are two distinct classes of anesthetics with regard to effects on thermogenesis, thermogenesis inhibitors and thermogenesis noninhibitors. The results are important for the interpretation of studies in thermal biology in general; specifically, they indicate that conclusions concerning regulation of nonshivering thermogenesis during anesthesia depend on the type of anesthetic used. Of clinical importance is that the volatile anesthetics are inhibitory for nonshivering thermogenesis and thus for an alternative heat production when myorelaxants prevent shivering. As the distinction between thermogenesis inhibitors and thermogenesis noninhibitors corresponds to the distinction between volatile and nonvolatile anesthetics, it may be related to the mode of action of the volatile anesthetics.

Halothane Selectively Inhibits Nonshivering Thermogenesis 

1995 ◽  
Vol 82 (2) ◽  
pp. 491-501 ◽  
Author(s):  
Andrea Dicker ◽  
Kerstin B. E. Ohlson ◽  
Lennart Johnson ◽  
Barbara Cannon ◽  
Sten G.E. Lindahl ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Inhibitory Effect ◽  
Nonshivering Thermogenesis ◽  
Halothane Anesthesia ◽  
Control Series ◽  
Mechanically Ventilated ◽  
Anesthetized Rats ◽  
Rate Of Oxygen Consumption ◽  
Spontaneously Breathing ◽  
Thermogenic Response

Background During halothane anesthesia, infants fail to increase oxygen consumption in response to a cold stimulus in the form of an increase in temperature gradient between body and environment. Based on recent observations with isolated brown-fat cells, it seemed feasible that this inability to respond could be due to an inhibition of nonshivering thermogenesis during halothane anesthesia. Methods The rate of oxygen consumption was measured in cold-acclimated hamsters and rats. The rate evoked by norepinephrine injection in hamsters at an environmental temperature of approximately 24 degrees C was used as a measure of the capacity for nonshivering thermogenesis. Anesthesia was induced by 3% halothane and maintained by 1.5% halothane. One experimental series with spontaneously breathing hamsters and a second control series with spontaneously breathing rats and with rats whose lungs were mechanically ventilated were conducted. Results Norepinephrine injection led to a fourfold increase in the rate of oxygen consumption in control hamsters; after this response had subsided, a second injection led to a similar effect. Halothane anesthesia caused an approximately 20% decrease in resting metabolic rate (P < 0.05) and a 70% inhibition of the thermogenic response to norepinephrine (P < 0.001). The halothane concentration yielding half-maximal inhibitory effect was estimated to be less than 1.0%. After the animals had recovered from halothane anesthesia, a completely restored thermogenic response to norepinephrine was observed. The inhibitory effect of halothane also was observed in hamsters maintained at normothermia and was therefore not secondary to the slight hypothermia that otherwise developed during anesthesia. In a series of control experiments, it was confirmed that rats also showed large thermogenic responses to norepinephrine injections, and it was found that, in spontaneously breathing halothane-anesthetized rats, the thermogenic response to norepinephrine was also much inhibited. Further, in halothane-anesthetized rats whose lungs were mechanically ventilated, and where blood gases were kept at virtually normal levels, the thermogenic response to norepinephrine was found to be similarly markedly inhibited. Conclusions A much diminished or abolished thermogenic response to injected norepinephrine was demonstrated in halothane-anesthetized animals. This implies that there would be a diminished ability to elicit nonshivering thermogenesis even when this process is physiologically induced. Such a diminished ability could in part explain the susceptibility of neonates and infants to hypothermia during halothane anesthesia.

Nonshivering thermogenesis in skeletal muscle of seasonally acclimatized mice, Peromyscus

1981 ◽  
Vol 241 (3) ◽  
pp. R185-R189
Author(s):  
S. J. Wickler
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Arterial Pressure ◽  
Flow Rate ◽  
Heat Production ◽  
Major Contributor ◽  
Nonshivering Thermogenesis ◽  
Perfusion System ◽  
Apparent Increase ◽  
Hindlimb Muscle

Nonshivering thermogenesis (NST) is a major contributor to total heat production capabilities of Peromyscus and the magnitude of the NST response increases dramatically in winter-acclimatized animals. To directly assess the contribution from skeletal muscle to this NST, a hindlimb perfusion system was developed for Peromyscus. Oxygen consumption was then measured with and without norepinephrine (the mediator of NST) in freshly captured animals in summer and winter. Norepinephrine (NE) was infused at 0.001, 0.01, and 0.1 micrograms . g hindlimb muscle-1 . min-1. Vascular resistance (VR), calculated as arterial pressure divided by flow rate, increased during all NE infusions. At doses of 0.001 and 0.01, VR stabilized after approximately 10 min, but at 0.1 VR continued to rise. Resting oxygen consumption was 0.817 +/- 0.037 and 0.805 +/- 0.049 mumol O2 . g-1 . min-1 in summer (n = 8) and winter (n = 7) animals, respectively. There was no apparent increase in oxygen consumption with any dosage of NE. It appears that the increase in NST in winter animals is not due to an increased NST in skeletal muscle.

Nonshivering thermogenesis in the newborn lamb

1969 ◽  
Vol 47 (3) ◽  
pp. 249-253 ◽  
Author(s):  
G. E. Thompson ◽  
D. McEwan Jenkinson
Keyword(s):  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Heat Production ◽  
Microscopic Examination ◽  
Early Age ◽  
Nonshivering Thermogenesis ◽  
Newborn Lamb

Microscopic examination of adipose tissue from lambs of varying ages between birth and 20 days showed that most cells were multivacuolar on the first day of life, but most were univacuolar at 10 days of age and older. The oxygen consumption of four lambs aged between 6 h and [Formula: see text] days was approximately doubled after injection with (−)noradrenaline (400 μg/kg subcutaneously) in an environment of 20 °C. Five lambs between [Formula: see text] days and 12 days showed a reduced response or no response. Three lambs between 14 days and 20 days of age showed virtually no change in oxygen consumption after noradrenaline. It is concluded that the mechanism for nonshivering heat production is present in the newborn lamb, but disappears at a relatively early age.

Doxorubicin and epirubicin iron-induced generation of free radicals In vitro. A comparative study

1987 ◽  
Vol 7 (8) ◽  
pp. 653-658 ◽  
Author(s):  
Kjell Grankvist ◽  
Roger Henriksson
Keyword(s):  
Oxygen Consumption ◽  
Free Radicals ◽  
Myocardial Injury ◽  
Oxygen Free Radicals ◽  
Oxygen Electrode ◽  
Inhibitory Effect ◽  
Free System ◽  
A Cell ◽  
Strong Inhibitory Effect

To ascertain any differences in myocardial injury exerted by the anthracyclines doxorubicin and epirubicin, their ability to generate oxygen free radicals when mixed with Fe(II) was examined in vitro using an oxygen electrode. 5–250 μg/ml doxorubicin or epirubicin consumed oxygen when mixed with 50 or 100 μmol/1 Fe(II). Addition of 75 μmol/1 cytochrome C showed that of the consumed oxygen, approximately 80% entered the monovalent pathway of oxygen reduction. The strong inhibitory effect of 250 mg/1 catalase indicates that most of the superoxide radicals generated are further reduced to hydrogen peroxide by both anthracyclines. Addition of metal chelators DTPA (100/μmol/1), or DDTC (50 μmol/1) did not affect oxygen consumption, whereas EDTA (100/μmol/1) or desferrioxamine (100 μmol/1) with anthracyclines and Fe(II) rather stimulated oxygen consumption. It is concluded that there are no significant differences in the amount or proportion of generated oxygen free radicals between doxorubicin and epirubicin when mixed with Fe(II) in a cell-free system in vitro. Thus, the ability of the anthracyclines, in conjunction with iron alone, to generate radicals does not explain the differences of the drugs in causing myocardial injury.

Carteolol is a weak partial agonist on β3-adrenergic receptors in brown adipocytes

1998 ◽  
Vol 76 (4) ◽  
pp. 428-433 ◽  
Author(s):  
Jin Zhao ◽  
Barbara Cannon ◽  
Jan Nedergaard
Keyword(s):  
Oxygen Consumption ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Partial Agonist ◽  
Brown Fat ◽  
Fat Cells ◽  
Nonshivering Thermogenesis ◽  
Brown Adipocytes ◽  
Cgp 12177 ◽  
Brl 37344

The ability of the Beta1/Beta2 partial agonist carteolol to act as an agonist on Beta3-adrenergic receptors was investigated by studying its ability to stimulatethermogenesis (oxygen consumption) in brown fat cells isolated from hamsters. Carteolol wasable to induce thermogenesis, with an EC50 of 5 µM, but it was only a partial(40%) agonist. D,L-Propranolol had a pKB of 5.1 as anantagonist against carteolol in this system, indicating that the carteolol effect was probablymediated via Beta3-receptors. Also in mouse and rat cells, carteolol was a partial agonist withEC50 values around 1 µM. Being a partial agonist, carteolol acted as an antagonistagainst norepinephrine-, BRL-37344-, or CGP-12177-stimulated thermogenesis with apKB of approximately5. The partial agonist effects of carteolol are discussed in relation to the absence of agonisteffect of this compound on guinea-pig taenia cecum Beta3-receptors and in relation to the possible plurality of Beta3-receptors.Key words: carteolol, Beta3-adrenergic receptor, brown fat cells, nonshivering thermogenesis.

Propranolol and pyrogen effects of shivering and nonshivering thermogenesis in rats

1976 ◽  
Vol 230 (3) ◽  
pp. 637-642 ◽  
Author(s):  
BA Horwitz ◽  
GE Hanes
Keyword(s):  
Oxygen Consumption ◽  
Heat Production ◽  
Bacterial Endotoxin ◽  
Nonshivering Thermogenesis ◽  
Beta Adrenergic ◽  
Differential Effects ◽  
Adrenergic Antagonist ◽  
Colonic Temperature ◽  
Beta Adrenergic Antagonist

Injection of bacterial endotoxin (Piromen) into unanesthetized rats elicited increases in shivering and nonshivering thermogenesis as well as in colonic temperature. In animals exposed to 24-25 degrees C, treatment with propranolol (a beta-adrenergic antagonist) markedly diminished the pyrogen-induced increases in oxygen consumption (heat production) and colonic temperature with little change occurring in shivering activity. In contrast, in rats exposed to mild cold (17-18 degrees C), propranolol did not significantly alter the magnitude of the pyrogen-evoked thermogenesis. Rather in these animals, shivering tended to increase when nonshivering thermogenesis was blocked. These data are interpreted as reflecting differential effects of pyrogen on the pathways controlling the two modes of heat production in the rat.

Chamber cold acclimatization in man

1961 ◽  
Vol 16 (6) ◽  
pp. 1011-1015 ◽  
Author(s):  
Thomas R. A. Davis
Keyword(s):  
Oxygen Consumption ◽  
Air Temperature ◽  
Rectal Temperature ◽  
Heat Production ◽  
Cold Exposure ◽  
Technical Assistance ◽  
Exposure Period ◽  
Seasonal Difference ◽  
Nonshivering Thermogenesis ◽  
Cold Acclimatization

In March, ten nude subjects were exposed 8 hr daily for 31 days to an air temperature of 11.8 C. In September, another six subjects were similarly acclimatized to an air temperature of 13.5 C. Measurements were made of the responses of shivering, oxygen consumption, rectal temperature, and skin temperature to a standard cold exposure. By the 14th day, shivering in both groups decreased significantly. Heat production remained unchanged in the winter group but decreased in the summer group. Basal metabolism did not change in either group. In both groups, rectal temperatures were maintained at lower values after the exposure period. In the winter group extremity temperatures were unchanged; those in the summer group were lowered by a small amount. The decrease in heat production and mean surface temperature in the summer group is related to the seasonal difference in cold acclimatization. Failure of cold-elevated metabolism to decrease despite a highly significant decrease in shivering indicates the presence of nonshivering thermogenesis in man. It is concluded that man can be artificially cold acclimatized. Note: With the Technical Assistance of D. R. Johnston, F. C. Bell, W. Rawlings, and L. Lee Submitted on May 8, 1961

Shivering and nonshivering thermogenic responses of cold-exposed rats to hypothalamic warming

1975 ◽  
Vol 228 (5) ◽  
pp. 1519-1524 ◽  
Author(s):  
CA Fuller ◽  
BA Horwitz ◽  
JM Horowitz
Keyword(s):  
Oxygen Consumption ◽  
Heat Production ◽  
Neural Control ◽  
Nonshivering Thermogenesis ◽  
Neural Controllers ◽  
Rate Of Oxygen Consumption ◽  
Exposed Animal ◽  
Unanesthetized Animals ◽  
Shivering Thermogenesis ◽  
Rule Out

The concurrent neural control of two thermoregulatory responses, shivering thermogenesis (ST) and nonshivering thermogenesis (NST), was investigated in chronically implanted cold-exposed rats. The effects of heating the preoptic/anterior hypothalamus (POAH) on shivering and on the rate of oxygen consumption (Vo2) were measured in these unanesthetized animals. With ambient temperature maintained constant (at some value between 10 and 16 degrees C), warming the hypothalamus 2-3 degrees C resulted in a significant decrease in Vo2 (Psmaller than 0.001) and an increase in shivering (Psmaller than .01), these responses being reversed on cessation of hypothalamic warming. These results are consistent with the proposal that, in the cold-exposed animal, elevated POAH temperatures directly inhibit NST even though shivering may increase (possibly as a compensation for the decrease in nonshivering heat production). They also rule out the possibility that, in the rat, signals from cutaneous and hypothalamic thermoreceptors are integrated in an indentical manner by the neural controllers for ST and NST.

scholarly journals No major thermogenic role for (Na+ + K+)-dependent adenosine triphosphatase apparent in hepatocytes from hyperthyroid rats

1982 ◽  
Vol 202 (3) ◽  
pp. 661-665 ◽  
Author(s):  
D G Clark ◽  
M Brinkman ◽  
O H Filsell ◽  
S J Lewis ◽  
M N Berry
Keyword(s):  
Oxygen Consumption ◽  
Oxygen Uptake ◽  
Atpase Activity ◽  
Heat Production ◽  
Adenosine Triphosphatase ◽  
Heat Output ◽  
Liver Parenchymal ◽  
Dependent Atpase ◽  
Parenchymal Cells ◽  
Isolated Liver

(Na+ + K+)-dependent ATPase activity, heat production and oxygen consumption were increased by 59%, 62% and 75% respectively in hepatocytes from tri-iodothyronine-treated rats. Ouabain at concentrations of 1 and 10 mM decreased oxygen uptake by 2-8% in hepatocytes from euthyroid rats and by 5-15% in hepatocytes from hyperthyroid animals. Heat output was decreased by 4-9% with the glycoside in isolated liver parenchymal cells from the control animals and by 11% in the cells from the tri-iodothyronine-treated animals. These results do not support the hypothesis that hepatic (Na+ + K+)-ATPase plays a major role in increased heat production in hepatocytes from hyperthyroid rats.

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