1 Department of Kinesiology and Applied Physiology, University of Colorado at Boulder, Boulder 80309; 2 Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262; and 3 Department of Medicine, University of Arizona Health Sciences Center, Tucson, Arizona 85724
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ABSTRACT |
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The sympathetic nervous system (SNS)
plays an important role in the regulation of energy expenditure.
However, whether tonic SNS activity contributes to resting metabolic
rate (RMR) in healthy adult humans is controversial, with the majority
of studies showing no effect. We hypothesized that an intravenous
propranolol infusion designed to achieve complete -adrenergic
blockade would result in a significant acute decrease in RMR in healthy
adults. RMR (ventilated hood, indirect calorimetry) was measured in 29 healthy adults (15 males, 14 females) before and during complete
-adrenergic blockade documented by plasma propranolol concentrations
100 ng/ml, lack of heart rate response to isoproterenol, and a
plateau in RMR with increased doses of propranolol. Propranolol
infusion evoked an acute decrease in RMR (
71 ± 11 kcal/day;
5 ± 0.7%, P < 0.0001), whereas RMR was
unchanged from baseline levels during a saline control infusion
(P > 0.05). The response to propranolol differed from
the response to saline control (P < 0.01). The
absolute and percent decreases in RMR with propranolol were modestly
related to baseline plasma concentration of norepinephrine
(r = 0.38, P = 0.05; r = 0.44, P = 0.02, respectively). These findings provide direct evidence for the concept of tonic sympathetic
-adrenergic support of RMR in healthy nonobese adults.
sympathetic nervous system; resting energy metabolism; -adrenergic blockade
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INTRODUCTION |
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THE SYMPATHETIC NERVOUS
SYSTEM (SNS) plays an important role in the regulation of energy
expenditure. Sympathetic -adrenergic stimulation evokes an increase
in metabolic rate (i.e., thermogenesis) under basal fasted conditions
(4, 13, 14). Similarly, it has been shown that the SNS is
largely responsible for the facultative component of the thermic effect
of acute energy intake in humans (1, 2, 7, 15).
Although it is clear that stimulation of the SNS has a thermogenic
effect, the possible role that tonic SNS activity plays in the support
of resting metabolic rate (RMR) in healthy adult humans remains
controversial. The results of studies to date are inconclusive, with
most (2, 3, 7, 9, 12, 15, 16, 19), albeit not all
(5, 8, 21, 22), failing to provide evidence for a
significant contribution of the SNS. In all cases, RMR was
measured before and after nonselective -adrenergic receptor blockade
by use of either oral or intravenous propranolol. A significant reduction in RMR with propranolol has been interpreted as evidence for
tonic sympathetic
-adrenergic support of RMR, whereas lack of change
in RMR has been interpreted as lack of tonic SNS support.
Careful review of the literature cited above, however, reveals
at least two potential methodological explanations for the inconsistent
findings. First, there was substantial variation in the dose of
propranolol used, such that failure to achieve complete -adrenergic
blockade could account for a negative result. The effective blocking
dose, both oral and intravenous, and respective plasma concentrations
of propranolol required to achieve complete
-adrenergic blockade
have been established (6). A plasma concentration of
100
ng/ml with intravenous infusion or 40 ng/ml with oral administration is
necessary. These are typically achieved with a minimum dose of 20 (infusion) or 80 mg (oral). Most studies did not document complete
-adrenergic receptor blockade. Second, the number of normal healthy
subjects studied has generally been small (mean n = 8 per investigation). This leaves open the possibility of insufficient
power to demonstrate a statistically significant effect should one be
present (type II error).
Accordingly, the aim of the present study was to determine
whether there is a tonic SNS -adrenergic contribution to RMR in healthy adult humans. We hypothesized that an intravenous propranolol infusion designed to achieve complete
-adrenergic blockade would result in a statistically significant acute decrease in RMR in an appropriately sized group of healthy men and women.
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METHODS |
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Subjects. Twenty-nine healthy young (27 ± 1 yr, mean ± SE) men (n = 15) and women (n = 14) were studied. All subjects were nondiabetic, normotensive (systolic/diastolic blood pressure <140/90 mmHg), free of known cardiovascular and metabolic disease, nonobese (body mass index <28), and otherwise healthy as assessed by medical history and focused physical examination. Subjects were nonsmokers and were not taking any regular medications. The nature, purpose, and risks of the study were explained to each subject before written informed consent was obtained. The experimental protocol was approved by the Human Research Committee at the University of Colorado at Boulder and by the Colorado Multiple Institutional Review Board.
Protocol.
Subjects reported to the laboratory on three separate occasions. The
first visit involved a physical exam, health history screening,
measurement of resting heart rate and blood pressure, and body
composition analysis. The second and third visits were the experimental
and control sessions for determination of SNS -adrenergic support of
RMR. The order of these latter two sessions was randomized. For the
experimental session, RMR was measured before and during
-adrenergic
receptor blockade (iv infusion of propranolol: 0.25 mg/kg bolus
followed by continuous infusion at 0.004 mg · kg
1 · min
1). For the
control condition, saline was infused at the same volume rate as for
propranolol. All measurements were made in the morning after a 12-h
fast. Subjects were studied under quiet resting conditions in the
semirecumbent position. Females were tested during the follicular phase
of their menstrual cycle (days 1-10). Measurements were
performed between 0600 and 0900 in a dimly lit room at a comfortable
temperature (~23°C).
Measurements.
For the experimental and control sessions, subjects were instrumented
for measurement of heart rate (ECG) and blood pressure (finger
photoplethysmography, Finapres BP monitor, model 2300, Ohmeda,
Englewood, CO). A catheter was introduced into an antecubital vein that
was kept patent with a slow saline drip for intravenous infusions and
blood sampling. After a 30-min rest period, a 45-min measurement of
baseline RMR was begun. The first 15 min were considered an habituation
period, after which oxygen consumption
(O2) and carbon dioxide production
(
CO2) were averaged each minute
for 30 min using a ventilated hood, indirect calorimetry system as described previously (18) (DeltaTrac Metabolic Monitor,
SensorMedics, Yorba Linda, CA). RMR was then calculated from the
average of the 30-min period using the Weir formula (20).
The hood was then removed, while an intravenous bolus was given of
either propranolol or saline (0.25 mg/kg). After the bolus, continuous
infusion of propranolol or saline (0.004 mg · kg
1 · min
1) was given,
during which the second RMR measurement was performed. For this second
measurement, there was a 5-min habituation period, followed by a 30-min
sampling period from which average RMR was calculated.
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Data analysis and statistics.
A two-way repeated-measures analysis of variance (ANOVA) was used to
identify changes in RMR with the infusion of propranolol or saline and
differences between the control and experimental conditions. To
determine whether effective -blockade was achieved, 1)
propranolol concentrations at each time point and the overall average
were assessed to ensure that levels were
100 ng/ml; 2) differences between heart rate responses to isoproterenol before compared with during
-adrenergic receptor blockade also were identified using a two-way repeated-measures ANOVA; and 3)
linear regression analysis of dose-response gain and repeated-measures ANOVA were performed to assure that RMR did not decrease with each
incremental dose of propranolol. Univariate correlation analysis was
performed to determine the relation between baseline plasma catecholamine concentrations and sympathetic support of RMR. The level
of statistical significance was set at P < 0.05. Data
are expressed as means ± SE.
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RESULTS |
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Selected subject characteristics are shown in Table
1. Table 2
shows documentation that complete -adrenergic receptor
blockade was achieved, as indicated by serum propranolol concentrations of
100 ng/ml and a lack of heart rate response to the intravenous isoproterenol infusion. The results of incremental dose-rate
experiments revealed no consistent or significant dose response as
assessed by linear regression analysis (P = 0.64).
Furthermore, the magnitude of decrease in RMR from baseline was similar
regardless of the dose (P = 0.26).
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SNS -adrenergic support of RMR.
Figure 2 shows the change in RMR with
propranolol and saline infusions. Propranolol infusion evoked an acute
decrease in RMR (1,555 ± 26 vs. 1,484 ± 26 kcal/day;
5%,
P < 0.0001), whereas RMR was unchanged from baseline
levels during saline infusion (1,559 ± 29 vs. 1,544 ± 29 kcal/day; P > 0.05). The response to propranolol
differed from the response to saline (P < 0.01). The respiratory exchange ratio (RER) was unchanged with propranolol (mean
change =
0.0072 ± 0.0082; r =
0.06 to
0.08). Figure 3 presents the
minute-by-minute values for RMR,
O2, and
CO2 during baseline and propranolol
infusion.
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Relations between SNS -adrenergic support of RMR and plasma
catecholamine concentrations.
The absolute and percent decreases in RMR with propranolol were
modestly related to baseline plasma concentration of norepinephrine (r =
0.38, P = 0.05;
r =
0.44, P = 0.02, respectively).
The change in RMR was not significantly related to baseline plasma epinephrine concentration (r =
0.32,
P = 0.13; r =
0.30, P = 0.14).
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DISCUSSION |
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The primary finding from the present study is that -adrenergic
receptor blockade induces an acute reduction in RMR. This finding
provides direct evidence for the concept of tonic sympathetic
-adrenergic support of RMR in healthy, nonobese adults. To obtain this evidence, we developed a propranolol infusion protocol that was
designed specifically to achieve complete
-adrenergic blockade. Complete blockade was documented using three approaches: plasma concentrations of propranolol, the absence of a heart rate
response to the
-adrenergic receptor agonist isoproterenol, and lack
of dose response with incremental infusion dose rates of propranolol.
These data have at least three important implications. First, our
results emphasize that it is necessary to achieve complete -adrenergic blockade to properly interpret the contribution of the
SNS to metabolic rate. Only one of the previous studies using an
intravenous propranolol infusion measured plasma propranolol concentration (9). The mean propranolol concentration in
that study was 60 ng/ml, a lower concentration than what has been shown to be necessary to achieve complete
-adrenergic blockade (100 ng/ml). As such, in that study, RMR did not change significantly. No
other propranolol infusion studies reported any documentation of
complete
-adrenergic blockade. Furthermore, all but one study (7) used infusion rates that were less than one-half of
what is necessary to achieve a plasma concentration of 100 ng/ml,
according to previous pharmacology studies (6) and our
pilot research. Only one of these studies found a reduction in RMR
(5), which, although reported as statistically
significant, was much less than that found in the present study with
complete
-adrenergic blockade (1.6 vs. 5% in the current study). In
the studies involving long-term oral propranolol (ranging from 5 to 15 days), none documented complete
-adrenergic blockade (8, 21,
22). However, based on previous pharmacology literature
(6), in each case the dose was likely to have achieved
complete blockade. Among these studies, each reported a significant
decrease in RMR. Thus future studies in which intravenous propranolol
infusion is used to quantify the SNS
-adrenergic contribution to RMR
should be designed with careful attention to the dose of propranolol
given, with the goal of complete
-adrenergic blockade.
Second, clarification that there is, in fact, significant
-adrenergic support of RMR contributes to our understanding of energy balance in humans. Although many factors can influence RMR, and
some are known to play a very important role (e.g., fat-free mass),
there remains large unexplained interindividual variability in RMR.
Because individuals with low RMR are predisposed to body weight gain
and obesity (10), an understanding of potential factors
that could be related to low RMR (i.e., low tonic SNS
-adrenergic
support) is important in developing strategies for reducing obesity.
In this context, we wish to emphasize the physiological importance of
the contribution of this mechanism to overall energy expenditure. On
average, SNS -adrenergic support of RMR in this population accounts
for 71 kcal/day. Hence, in the absence of SNS
-adrenergic support,
one would have to compensate ~26,000 kcal/year through decreased
energy intake or increased energy expenditure by use of non-SNS
mechanisms to prevent weight gain. Thus this may be an important
contributor to the maintenance of energy balance over time and the
prevention of obesity.
Third, -adrenergic blockers are widely used in the treatment of
cardiovascular diseases such as hypertension. Weight loss is often
recommended as well in such patients. Thus clinicians should recognize
that
-blocker therapy might present a challenge to weight
loss/maintenance by reducing energy expenditure. In fact, long-term
propranolol treatment is associated with weight gain (11).
Appropriate adjustments in energy intake and physical activity-related
energy expenditure may be necessary to counteract the potentially
adverse effects of
-adrenergic blocker therapy on energy balance.
In conclusion, we have shown that there is tonic SNS -adrenergic
support of RMR in healthy adult humans. We developed an appropriate
methodology to achieve complete
-adrenergic blockade to eliminate
the interpretative confounding of partial (incomplete) blockade. These
findings are important for our understanding of the role of the SNS in
the regulation of metabolic rate and long-term energy balance, as well
as in designing future studies using this methodology.
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ACKNOWLEDGEMENTS |
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We thank Mary Jo Reiling for administrative and technical assistance and Jason Lashbrook for technical assistance.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants HL-39966, AG-13038, AG-06537, AG-00828, and DK-07658 and by American Heart Association Grants 9920445Z and CWFW-0298.
Address for reprint requests and other correspondence: P. P. Jones, Dept. of Kinesiology and Applied Physiology, Campus Box 354, Univ. of Colorado, Boulder, CO 80309 (E-mail: pamela{at}spot.colorado.edu).
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. Section 1734 solely to indicate this fact.
Received 25 May 2000; accepted in final form 15 January 2001.
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