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J Appl Physiol 87: 977-981, 1999;
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Vol. 87, Issue 3, 977-981, September 1999

Dobutamine as selective beta 1-adrenoceptor agonist in in vivo studies on human thermogenesis and lipid utilization

S. L. H. Schiffelers, V. J. A. van Harmelen, H. A. J. de Grauw, W. H. M. Saris, and M. A. van Baak

Nutrition Toxicology and Environment Research Institute Maastricht, Department of Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The use of dobutamine as selective beta 1-adrenoceptor agonist in in vivo studies on human thermogenesis and lipid utilization was investigated in 20 men. At 2.5, 5, and 10 µg · kg-1 · min-1, dobutamine induced significant increases in energy expenditure, lipid oxidation, and lipolysis. The beta 1-adrenoceptor antagonist atenolol (bolus: 42.5 µg/kg, infusion: 1.02 µg · kg-1 · min-1) blocked all dobutamine-induced effects on thermogenesis and lipid utilization. All parameters remained at levels comparable to those during saline infusion. The dose of atenolol used did not inhibit beta 2-adrenoceptor-specific changes in energy expenditure, lipid oxidation, and lipolysis during salbutamol infusion (85 ng · kg-1 · min-1). This indicates that atenolol was specific for beta 1-adrenoceptors and did not camouflage concomitant beta 2-adrenoceptor stimulation during dobutamine infusion. Therefore, we conclude that dobutamine can be used as a selective beta 1-adrenoceptor agonist at dosages <= 10 µg · kg-1 · min-1 in in vivo studies on human thermogenesis and lipid utilization.

atenolol; salbutamol; lipid oxidation; lipolysis


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

THE SYMPATHETIC NERVOUS system plays an important role in the regulation of human thermogenesis. Sympathetic nervous system activity is mainly stimulated in response to food digestion and physical exercise but can also be triggered by cold exposure or pathogenic stimuli. In response to these stimuli, catecholamines are released that subsequently induce thermogenesis (14). This increase in energy expenditure is due to stimulation of both beta 1- and beta 2-adrenoceptors of the sympathetic nervous system (4). alpha 1-Adrenoceptors probably do not play a role (4, 6, 17). The effect of beta 3-adrenergic stimulation on human thermogenesis is, at the moment, still debatable (4, 11, 23), because the available agonists appear to be only weak partial agonists in humans (1). In rodents beta 3-agonists induce significant effects, but this might be explained by the pharmacological differences between human and rodent beta 3-adrenoceptors (10, 15).

In obese men nonselective beta -adrenergic stimulation leads to a reduced increase in thermogenesis and lipid utilization compared with in lean men (3). Therefore, it is interesting to know whether these impaired responses might be due to a defect in the beta 1- or the beta 2-adrenoceptor. The most selective beta 1-adrenoceptor agonist for in vivo use in humans is dobutamine. In lean healthy volunteers dobutamine increases oxygen consumption, indicating an increase in thermogenesis (2, 7), decreases respiratory exchange ratio (RER), suggesting an increase in lipid oxidation, and increases plasma glycerol and nonesterified fatty acids (NEFA) concentrations, indicating an increase in lipolysis (7).

However, both in vitro (15, 16) and in vivo (12, 13) animal studies have shown that dobutamine also has alpha 1- and beta 2-adrenoceptor agonistic properties. Because alpha 1-adrenoceptors are not important for human thermogenesis, their role was not further investigated. The selectivity of dobutamine for beta 1- and beta 2-adrenoceptors in studies on human thermogenesis and lipid utilization was elucidated in this study. Therefore, we evaluated the effect of atenolol, a predominantly beta 1-adrenoceptor antagonist, on dobutamine-induced increases in energy expenditure, lipid oxidation, and lipolysis. Addition of atenolol should block all beta 1-adrenoceptor-mediated effects and reveal all other effects of dobutamine. In a control test, the selective beta 1-adrenoceptor-blocking properties of atenolol at the dose used were verified. Addition of atenolol should have no effect on the increases in thermogenesis and lipid utilization induced by the selective beta 2-adrenoceptor agonist salbutamol.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects. Twenty lean male volunteers participated in this study. Mean age and body mass index were 22.0 yr (range: 18-27 yr) and 21.9 kg/m2 (range: 19.4-25.3 kg/m2), respectively. The subjects were healthy and took no medication at the time of the study. They gave written informed consent before participating in the study. The study protocol was reviewed and approved by the Ethics Committee of Maastricht University.

Experimental protocol. The study protocol consisted of four tests. In the dobutamine test, a 30-min baseline period was followed by consecutive infusions of 2.5, 5, and 10 µg · kg-1 · min-1 dobutamine (selective beta 1-adrenoceptor agonist; Dobax, Byk, Zwanenburg, The Netherlands), each dose administered during 30 min. This test intended to measure all dobutamine-mediated effects. The saline test consisted of a 30-min baseline period followed by three times a 30-min period of saline infusion (0.6 ml/min) to study the regular changes in thermogenesis and associated metabolic processes over this period of fasting. In the dobutamine plus atenolol test, dobutamine was given (as described above) in combination with the beta 1-adrenoceptor antagonist atenolol (Tenormin, Zeneca, Ridderkerk, The Netherlands) to reveal possible beta 2-adrenoceptor-mediated effects of dobutamine. Therefore, a priming dose of 42.5 µg/kg atenolol was administered intravenously within 5 min at the start of the baseline period, after which a continuous infusion of atenolol (1.02 µg · kg-1 · min-1) was started for the remainder of the test. The salbutamol plus atenolol test consisted of a 45-min baseline period, after which the beta 2-adrenoceptor agonist salbutamol (Ventolin, GlaxoWellcome, Zeist, The Netherlands) was given for 90 min at an infusion rate of 85 ng · kg-1 · min-1. During the last 45 min, atenolol was added to the salbutamol infusion at the same dose as described above to study possible beta 2-adrenoceptor-blocking effects of atenolol. The infusion periods were prolonged during the last test, because thermogenesis did not reach steady state within 30 min during salbutamol infusion, as it did during dobutamine infusion. Twenty subjects participated in the dobutamine test, 10 subjects in the saline test, 14 subjects in the dobutamine plus atenolol test, and 10 subjects underwent the salbutamol plus atenolol test. Each of the 20 subjects participated in 2 or 3 trials. There were no statistically significant differences in subject parameters between tests. The study design was single blind, and the order of tests was randomized.

The subjects came to the laboratory at 8:30 AM, with at least 2 days between tests. All individuals were fasted for at least 10 h (overnight) and came to the laboratory by car or by bus to minimize the amount of physical activity before the tests. At the beginning of each test, a catheter was inserted into a forearm vein for drug infusion and blood sampling. During the tests, energy expenditure and RER were continuously measured, and, at the end of each 30- or 45-min interval, a blood sample was obtained. For safety reasons the infusion was stopped when heart rate had increased >30 beats/min and/or mean blood pressure had risen more than 30 mmHg. After these criteria, one subject was not tested at the highest dose of 10 µg · kg-1 · min-1 dobutamine. Room temperature was kept between 23 and 25°C.

Methods. An open-circuit ventilated-hood system was used for measurement of whole body energy expenditure and RER. The volume of air drawn through the hood was measured by a dry-gas meter (Schlumberger, Dordrecht, The Netherlands), and the composition of the inflowing and outflowing air was analyzed by a paramagnetic O2 analyzer (Servomex, Crowborough, UK) and an infrared CO2 analyzer (Hartmann and Braun, Frankfurt, Germany). Airflow rate and the O2 and CO2 concentrations of the inflowing and outflowing air were used to compute O2 consumption (coefficient of variation 2.4%) and CO2 production (coefficient of variation 3.1%) on-line every 2 min through an automatic acquisition system interfaced with a personal computer. Energy expenditure was calculated according to the formula of Weir (21). Energy expenditure and RER values were averaged over the last 10 min of each infusion step, during which their values were stable, and their means were used in the data analysis. Blood pressure was measured by an automated blood pressure device (Tonoprint, Speidel & Keller, Jungingen, Germany, and UA 731, Takeda Medical, Rotterdam, the Netherlands) during the last 10 min of each period. The mean of four measurements per interval was computed and used for further analysis. Heart rate was monitored continuously by conventional electrocardiogram and was recorded at the end of every 5-min period. The values over the last 10 min were averaged and used for further analysis.

Analytic methods. Blood samples for glycerol and NEFA determination were preserved in sodium-EDTA. All samples were immediately centrifuged for 1 min at 7,280 g. Plasma was transferred to microtest tubes, rapidly frozen in liquid nitrogen, and stored at -70°C until further analysis. Plasma glycerol concentrations were measured with a glycerol kit (Boehringer 148270, Mannheim, Germany), and plasma NEFA concentrations were measured with the NEFA C kit (Wako NEFA C kit 99475409, Neuss, Germany), both on a Cobas-Fara analyzer (Roche Diagnostica, Basel, Switzerland). In each run, standard samples with known concentrations were included for quality control.

Data analysis. All values are presented as means ± SE. The differences in outcome between the dobutamine, the saline, and the dobutamine plus atenolol tests were analyzed with a split-block incomplete-block factorial ANOVA. In this design, categories are made for treatment and subject to account for missing values. Post hoc testing between studies was done according to Bonferroni's inequalities. The effects within studies were analyzed with repeated-measurements ANOVA. Post hoc testing between time points was done with a paired t-test, corrected according to Bonferroni's inequalities. All statistical tests were performed two sided. P < 0.05 was regarded as statistically significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Dobutamine, saline, and dobutamine plus atenolol tests. Energy expenditure increased significantly during dobutamine infusion (P < 0.001) (Fig. 1). During saline infusion there was no significant change in energy expenditure. Simultaneous administration of atenolol completely prevented the dobutamine-induced increase in energy expenditure. Energy expenditure remained at a similar level as during the saline test. RER decreased significantly in all three tests (dobutamine, saline: P < 0.001; dobutamine plus atenolol: P < 0.01) (Fig. 1). During the second and third infusion period of dobutamine, RER was significantly lower than during the corresponding infusion periods with saline (both P < 0.001). Atenolol infusion prevented the more pronounced reduction in RER at the higher dobutamine dosages. RER decreased to a comparable level as during saline infusion.


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  		Fig. 1.   Energy expenditure (top) and respiratory exchange ratio (bottom) during infusion of saline (; n = 10 subjects), dobutamine (triangle ; n = 20 subjects), or dobutamine plus atenolol (dob+at; ; n = 14 subjects). Values are means ± SE. Repeated-measurements ANOVA: ## P < 0.01; ### P < 0.001. Unpaired t-test: dobutamine vs. saline, * P < 0.05, *** P < 0.001; dobutamine vs. dobutamine plus atenolol: ++ P < 0.01, +++ P < 0.001.

Plasma glycerol and NEFA concentrations increased significantly with dobutamine (both P < 0.001), saline (glycerol: P < 0.01, NEFA: P < 0.001), as well as dobutamine plus atenolol (glycerol: P < 0.01, NEFA: P < 0.001) (Fig. 2). In all infusion periods glycerol and NEFA concentrations were significantly higher in the dobutamine test compared with the saline and dobutamine plus atenolol tests. During atenolol administration, glycerol and NEFA levels remained similar to those during saline infusion.


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  		Fig. 2.   Plasma glycerol (top) and nonesterified fatty acid (NEFA) concentration (bottom) during infusion of saline (; n = 10 subjects), dobutamine (triangle ; n = 20 subjects), or dobutamine plus atenolol (; n = 14 subjects). Values are means ± SE. Repeated-measurements ANOVA: ## P < 0.01, ### P < 0.001. Unpaired t-test: dobutamine vs. saline, * P < 0.05, *** P < 0.001; dobutamine vs. dobutamine plus atenolol: ++ P < 0.01, +++ P < 0.001.

During the last infusion period, heart rate was significantly higher with dobutamine than with saline (P < 0.001) (Fig. 3). Heart rate did not change during saline infusion. Atenolol lowered heart rate at baseline and completely inhibited the increase in heart rate by dobutamine. Systolic blood pressure increased significantly (P < 0.001), and diastolic blood pressure remained unchanged in the dobutamine test (Fig. 3). Saline infusion caused no changes in systolic and diastolic blood pressure. Atenolol inhibited most of the increase in systolic blood pressure, but there was still a significant increase (P < 0.001). Diastolic blood pressure did not change during dobutamine plus atenolol infusion.


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  		Fig. 3.   Heart rate (top) and systolic (middle) and diastolic (bottom) blood pressure during infusion of saline (; n = 10 subjects), dobutamine (triangle ; n = 20 subjects), or dobutamine plus atenolol (; n = 14 subjects). Values are means ± SE. Repeated-measurements ANOVA: # P < 0.05, ### P < 0.001. Unpaired t-test: dobutamine vs. saline, ***P < 0.001; dobutamine vs. dobutamine plus atenolol: + P < 0.05, ++ P < 0.01, +++ P < 0.001; saline vs. dobutamine plus atenolol: @ P < 0.05.

Salbutamol test. Energy expenditure significantly increased during salbutamol infusion (P < 0.001) and remained at this level after the addition of atenolol (Table 1). RER remained unchanged during the whole test. Plasma glycerol and NEFA concentrations increased significantly during salbutamol infusion (glycerol: P < 0.01, NEFA: P < 0.001) and decreased after the addition of atenolol (glycerol: P < 0.05, NEFA: P < 0.001). However, plasma glycerol and NEFA levels remained significantly higher with salbutamol plus atenolol compared with baseline (both P < 0.01). Heart rate and systolic blood pressure increased significantly with salbutamol (both P < 0.001) and decreased significantly after the addition of atenolol (heart rate: P < 0.001, systolic blood pressure: P < 0.01). Heart rate remained significantly higher during salbutamol plus atenolol infusion compared with baseline (P < 0.001), but systolic blood pressure did not differ from baseline during salbutamol plus atenolol administration. Diastolic blood pressure did not change during the test.

                              
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  		Table 1.   Parameters at baseline, during salbutamol infusion, and during salbutamol plus atenolol infusion


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

This study was performed to examine whether dobutamine can be used as a selective beta 1-adrenoceptor agonist in in vivo studies on human thermogenesis and lipid utilization. Dobutamine induced significant increases in energy expenditure, lipid oxidation, as measured by a decrease in RER, and lipolysis, as measured by increases in plasma glycerol and NEFA levels. This is in accordance with previous studies (2, 7).

From animal studies it is known that dobutamine has significant alpha 1- and beta 2-adrenoceptor-stimulating properties at higher dosages in vitro (12, 13, 15, 16). Furthermore, Daul et al. (5) showed that these adrenoceptors also play a role in the regulation of dobutamine-induced changes in heart rate and blood pressure at dosages of >= 6 µg · kg-1 · min-1 in vivo in humans. We intended to study the beta 1-adrenoceptor selectivity of dobutamine for changes in thermogenesis and lipid utilization. For that reason, beta 1-adrenoceptor-mediated effects of dobutamine on energy expenditure, lipid oxidation, and lipolysis were blocked with the selective beta 1-adrenoceptor-antagonist atenolol. This design should reveal all beta 2-adrenoceptor-mediated effects of dobutamine, because alpha 1-adrenoceptors play no role in human thermogenesis (4, 6, 17). We found that atenolol completely inhibited the dobutamine-induced increases in energy expenditure and plasma glycerol and NEFA concentrations and the decrease in RER. These parameters remained at levels comparable with those during the saline test, suggesting that dobutamine affects these parameters only via beta 1-adrenoceptor stimulation at the dosages used.

A control test was done to evaluate the selectivity for beta 1- and beta 2-adrenoceptors of the dose of atenolol used. beta 2-Adrenoceptor-mediated effects of salbutamol were compared with those during simultaneous salbutamol plus atenolol infusion. If atenolol blocks beta 2-adrenoceptors, all responses on salbutamol infusion should be impaired after the addition of atenolol. We found that salbutamol-induced changes in energy expenditure and RER were not affected by atenolol. Thus it is unlikely that the diminished increases in thermogenesis and lipid oxidation during simultaneous dobutamine plus atenolol infusion were due to beta 2-adrenoceptor blockade by atenolol at the dosage used. This is also supported by the fact that atenolol has an inhibition constant of 72 ng/ml for beta 1-adrenoceptors and 2,519 ng/ml for beta 2-adrenoceptors (22). Thorne and Wahren (19) reported a plasma atenolol concentration of ~300 ng/ml at a dose of 1.67 µg · kg-1 · min-1. This is comparable with a plasma concentration of ~180 ng/ml for the dose of atenolol we used (1.02 µg · kg-1 · min-1). The affinity of salbutamol for beta 2- and beta 1-adrenoceptors lies only eightfold apart (8). This suggests that concomitant beta 1-adrenoceptor stimulation during salbutamol infusion is more likely to have occurred than beta 2-adrenoceptor blockade during simultaneous atenolol infusion. The significant decreases in plasma glycerol and NEFA concentrations after the addition of atenolol might therefore be due to the blockade of the beta 1-adrenoceptor-mediated effects of salbutamol. Another explanation might be that atenolol blocked the basal beta 1-adrenoceptor-mediated effects of the endogenous catecholamines on lipolysis.

It is still uncertain which processes are responsible for sympathetically mediated thermogenesis and in which tissues these processes are localized. Several authors (9, 18) have suggested that the catecholamine-induced increase in whole body energy expenditure may partly be explained by the increase in myocardial energy expenditure caused by an increase in cardiac output. Myocardial energy expenditure can be estimated by the rate-pressure product (heart rate × systolic blood pressure) (20). In our study, the estimated increase in myocardial energy expenditure would result in an overall increase in energy expenditure of 14% during the dobutamine test and of 2% during the dobutamine plus atenolol test. Whole body energy expenditure, however, increased 33% during the dobutamine test and 5% during the dobutamine plus atenolol infusion. The majority of the increase in energy expenditure, therefore, appeared to result from substrate oxidation in other tissues.

In summary, the results of this study indicate that, at dosages of 2.5, 5, and 10 µg · kg-1 · min-1, the predominantly beta 1-adrenoceptor agonist dobutamine caused significant increases in energy expenditure, lipid oxidation, and lipolysis. The beta 1-adrenoceptor-antagonist atenolol blocked all dobutamine-induced increases in thermogenesis and lipid utilization. All parameters remained at levels comparable with those during saline infusion. The dose of atenolol used was specific for beta 1-adrenergic blockade and therefore did not camouflage concomitant beta 2-adrenoceptor stimulation by dobutamine. Therefore, we conclude that dobutamine can be used as selective beta 1-adrenoceptor agonist at dosages <= 10 µg · kg-1 · min-1 in in vivo studies on human thermogenesis and lipid utilization.


    ACKNOWLEDGEMENTS

The authors thank Jos Stegen and Joan Senden for technical support during analysis of the blood samples and Dr. Arnold Kester for statistical advice.


    FOOTNOTES

This study was supported by Netherlands Organization for Scientific Research, Grant 903-39-138.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: S. L. H. Schiffelers, Dept. of Human Biology, Maastricht Univ., PO Box 616, 6200 MD Maastricht, The Netherlands (E-mail: s.schiffelers{at}hb.unimaas.nl).

Received 16 September 1998; accepted in final form 26 May 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Arch, J. R., and S. Wilson. Prospects for beta 3-adrenoceptor agonists in the treatment of obesity and diabetes. Int. J. Obes. 20: 191-199, 1996.

2.   Bhatt, S. B., R. C. Hutchinson, B. Tomlinson, T. E. Oh, and M. Mak. Effect of dobutamine on oxygen supply and uptake in healthy volunteers. Br. J. Anaesth. 69: 298-303, 1992[Abstract/Free Full Text].

3.   Blaak, E. E., M. A. van Baak, G. J. Kemerink, M. T. Pakbiers, G. A. Heidendal, and W. H. Saris. beta -Adrenergic stimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E306-E315, 1994[Abstract/Free Full Text].

4.   Blaak, E. E., M. A. van Baak, K. P. Kempen, and W. H. Saris. Role of alpha - and beta -adrenoceptors in sympathetically mediated thermogenesis. Am. J. Physiol. 264 (Endocrinol. Metab. 27): E11-E17, 1993[Abstract/Free Full Text].

5.   Daul, A., U. Hermes, R. F. Schafers, R. Wenzel, C. von Birgelen, and O. E. Brodde. The beta -adrenoceptor subtype(s) mediating adrenaline- and dobutamine-induced blood pressure and heart rate changes in healthy volunteers. Int. J. Clin. Pharmacol. Ther. 33: 140-148, 1995[Medline].

6.   DeFronzo, R. A., D. Thorin, J. P. Felber, D. C. Simonson, D. Thiebaud, E. Jéquier, and A. Golay. Effect of beta - and alpha -adrenergic blockade on glucose-induced thermogenesis in man. J. Clin. Invest. 73: 633-639, 1984.

7.   Green, C. J., R. S. Frazer, S. Underhill, P. Maycock, J. A. Fairhurst, and I. T. Campbell. Metabolic effects of dobutamine in normal man. Clin. Sci. (Colch.) 82: 77-83, 1992[Medline].

8.   Kikkawa, H., H. Kurose, M. Isogaya, Y. Sato, and T. Nagao. Differential contribution of two serine residues of wild type and constitutively active beta 2-adrenoceptors to the interaction with beta 2-selective agonists. Br. J. Pharmacol. 121: 1059-1064, 1997[Medline].

9.   Kurpad, A. V., K. Khan, A. G. Calder, and M. Elia. Muscle and whole body metabolism after norepinephrine. Am. J. Physiol. 266 (Endocrinol. Metab. 29): E877-E884, 1994[Abstract/Free Full Text].

10.   Liggett, S. B. Functional properties of the rat and human beta 3-adrenergic receptors: differential agonist activation of recombinant receptors in Chinese hamster ovary cells. Mol. Pharmacol. 42: 634-637, 1992[Abstract].

11.   Liu, Y. L., S. Toubro, A. Astrup, and M. J. Stock. Contribution of beta 3-adrenoceptor activation to ephedrine-induced thermogenesis in humans. Int. J. Obes. 19: 678-685, 1995.

12.   Maccarrone, C., E. Malta, and C. Raper. beta -Adrenoceptor selectivity of dobutamine: in vivo and in vitro studies. J. Cardiovasc. Pharmacol. 6: 132-141, 1984[Medline].

13.   Robie, N. W., D. O. Nutter, C. Moody, and J. L. McNay. In vivo analysis of adrenergic receptor activity of dobutamine. Circ. Res. 34: 663-671, 1974[Abstract/Free Full Text].

14.   Rothwell, N. J. CNS regulation of thermogenesis. Crit. Rev. Neurobiol. 8: 1-10, 1994[Medline].

15.   Ruffolo, R. R., Jr., K. Messick, and J. S. Horng. Interactions of three inotropic agents, ASL-7022, dobutamine and dopamine, with alpha - and beta -adrenoceptors in vitro. Naunyn Schmiedebergs Arch. Pharmacol. 326: 317-326, 1984[Medline].

16.   Ruffolo, R. R., Jr., T. A. Spradlin, G. D. Pollock, J. E. Waddell, and P. J. Murphy. alpha - and beta -Adrenergic effects of the stereoisomers of dobutamine. J. Pharmacol. Exp. Ther. 219: 447-452, 1981[Abstract/Free Full Text].

17.   Seaton, T., S. Welle, S. Alex, U. Lilavivat, and R. Campbell. The effect of adrenergic blockade on glucose-induced thermogenesis. Metabolism 33: 415-419, 1984[Medline].

18.   Simonsen, L., B. Stallknecht, and J. Blow. Contribution of skeletal muscle and adipose tissue to adrenaline-induced thermogenesis in man. Int. J. Obes. 7, Suppl. 3: S47-S51, 1993.

19.   Thorne, A., and J. Wahren. beta -Adrenergic blockade does not influence the thermogenic response to a mixed meal in man. Clin. Physiol. 9: 321-332, 1989[Medline].

20.   Vanoverschelde, J. L., W. Wijns, B. Essamri, A. Bol, A. Robert, D. Labar, M. Cogneau, C. Michel, and J. A. Melin. Hemodynamic and mechanical determinants of myocardial O2 consumption in normal human heart: effects of dobutamine. Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H1884-H1892, 1993[Abstract/Free Full Text].

21.   Weir, J. B. New methods for calculating metabolic rates with special reference to protein metabolism. J. Physiol. (Lond.) 109: 1-9, 1949.

22.   Wellstein, A., D. Palm, and G. G. Belz. Affinity and selectivity of beta -adrenoceptor antagonists in vitro. J. Cardiovasc. Pharmacol. 8, Suppl. 11: S36-S40, 1986.

23.   Wheeldon, N. M., D. G. McDevitt, and B. J. Lipworth. Do beta 3-adrenoceptors mediate metabolic responses to isoprenaline? Q. J. Med. 86: 595-600, 1993[Abstract/Free Full Text].

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E. RAVUSSIN and S. R. SMITH
Increased Fat Intake, Impaired Fat Oxidation, and Failure of Fat Cell Proliferation Result in Ectopic Fat Storage, Insulin Resistance, and Type 2 Diabetes Mellitus
Ann. N.Y. Acad. Sci., June 1, 2002; 967(1): 363 - 378.
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 J. Clin. Endocrinol. Metab.Home page
S. R. Smith, L. de Jonge, M. Pellymounter, T. Nguyen, R. Harris, D. York, S. Redmann, J. Rood, and G. A. Bray
Peripheral Administration of Human Corticotropin-Releasing Hormone: A Novel Method to Increase Energy Expenditure and Fat Oxidation in Man
J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 1991 - 1998.
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 J. Clin. Endocrinol. Metab.Home page
S. L. H. Schiffelers, W. H. M. Saris, F. Boomsma, and M. A. van Baak
{beta}1- and {beta}2-Adrenoceptor-Mediated Thermogenesis and Lipid Utilization in Obese and Lean Men
J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2191 - 2199.
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 J. Appl. Physiol.Home page
K. Collomp, R. Candau, F. Lasne, Z. Labsy, C. Prefaut, and J. De Ceaurriz
Effects of short-term oral salbutamol administration on exercise endurance and metabolism
J Appl Physiol, August 1, 2000; 89(2): 430 - 436.
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