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Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This two-part investigation compared the ergogenic and metabolic effects of theophylline and caffeine. Initially (part A), the ergogenic potential of theophylline on endurance exercise was investigated. Eight men cycled at 80% maximum O2 consumption to exhaustion 90 min after ingesting either placebo (dextrose), caffeine (6 mg/kg; Caff), or theophylline (4.5 mg/kg Theolair; Theo). There was a significant increase in time to exhaustion in both the Caff (41.2 ± 4.8 min) and Theo (37.4 ± 5.0 min) trials compared with placebo (32.6 ± 3.4 min) (P < 0.05). In part B, the effects of Theo on muscle metabolism were investigated and compared with Caff. Seven men cycled for 45 min at 70% maximum O2 consumption (identical treatment protocol as in part A). Neither methylxanthines (MX) affected muscle glycogen utilization (P > 0.05). Only Caff increased plasma epinephrine (P < 0.05), but both MX increased blood glycerol levels (P < 0.05). Muscle cAMP was increased (P < 0.05) by both MX at 15 min and remained elevated at 45 min with Theo. This demonstrates that both MX are ergogenic and that this can be independent of muscle glycogen.
adenosine antagonism; ergogenic; methylxanthines; adenosine 3',5'-cyclic monophosphate; catecholamines
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MANY STUDIES EXAMINING THE mechanism behind the ergogenic effect of caffeine have focused on the methylxanthine-induced increase in circulating plasma epinephrine and the metabolic changes that occur with exercise (12, 15, 19). However, recent studies have provided evidence that the original hypothesis by Costill et al. (12) may not be the critical mechanism behind the effects of caffeine in all exercise conditions. For example, an ergogenic effect of caffeine has been demonstrated without an increase in plasma epinephrine (20, 35). In addition, an increase in free fatty acid (FFA) mobilization without a corresponding catecholamine response has been demonstrated, indicating a direct effect of caffeine on fat cells (28, 35). Carbohydrate metabolism has been shown to be unaltered when epinephrine was infused to mimic the caffeine-induced epinephrine response (10). Glycogen sparing has not always been found during exercise after caffeine ingestion (9), and an increase in performance has been observed in exercise situations in which muscle glycogen is not the limiting factor and when no glycogen sparing was observed (23). A direct effect of caffeine on the central nervous system has also been postulated to explain the ergogenic effect of this methylxanthine; however, it has been demonstrated that this is not a critical mechanism (28).
Three possible mechanisms through which the methylxanthines may exert their metabolic effects include increased intracellular Ca2+ release (4), inhibition of cAMP phosphodiesterase (6), and antagonism of adenosine receptors (32). It is now established that adenosine receptor antagonism is the most relevant mechanism in vivo (17) because pharmacological doses of methylxanthines (mM) rather than physiological doses (µM) are needed to elicit a Ca2+ or phosphodiesterase inhibition effect (7, 33).
Methylxanthines are nonselective adenosine receptor antagonists at A1 and A2 receptors, and in vitro theophylline, a dimethyxanthine, is a more potent adenosine receptor antagonist than caffeine (5). Biaggioni et al. (3) demonstrated an attenuation of adenosine-induced cardiovascular effects after theophylline administration. In addition, Costa and Biaggioni (11) reported that adenosine administration increases muscle sympathetic nervous system activity and that this increase was dampened by theophylline infusion, providing evidence of a methylxanthine-induced antagonism of adenosine receptors in various human tissues.
Recently, Vergauwen et al. (37) found that adenosine receptor antagonism by caffeine stimulated rather then inhibited net glycogenolysis in a contracting isolated rat hindlimb perfusion. This study demonstrated that adenosine inhibits glycogenolysis in contracting oxidative muscle fibers and may be a potential modulator of carbohydrate metabolism. Furthermore, Raguso et al. (30) used stable isotopes and indirect calorimetry to determine the effect of theophylline on substrate metabolism during 30 min of moderate submaximal exercise. Glucose rate of disappearance was less after theophylline administration, suggesting that adenosine antagonism decreased glucose uptake during exercise. Estimation of muscle glycogen utilization, based on respiratory exchange ratio (RER) data, led to the conclusion that adenosine may play a role in regulating carbohydrate metabolism by decreasing glycogenolysis in contracting skeletal muscle. These studies suggest that methylxanthines should increase muscle glycogen use via adenosine antagonism, yet previous investigations of exercising humans demonstrated a glycogen sparing effect of caffeine (14, 15, 34).
The purpose of this study was twofold: 1) to investigate the ergogenic potential of theophylline on endurance exercise (part A) and 2) to examine the effects of this compound on muscle metabolism and compare it to the effects of caffeine (part B). We hypothesized that theophylline would elicit an ergogenic effect and would stimulate a greater net glycogenolysis compared with placebo and caffeine because of its higher affinity for adenosine receptors.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Eight healthy, active male volunteers [mean maximum O2 consumption (
O2 max) = 57.5 ± 2.7 ml · kg
1 · min1] served as
subjects for part A, whereas seven male subjects (mean O2 max = 56.3 ± 3.5 ml · kg1 · min1)
volunteered for part B. All were physically active with no
history of respiratory problems. The experimental procedures and
possible risks of the study were explained, and informed written
consents were given by all subjects. The study was approved by the
University of Guelph Ethics Committee.
Preexperimental Protocol
Each subject reported to the laboratory on two occasions before the actual experimental trials. On the first visit, the subjects performed an incrementalO2 max test
on an electrically braked cycle ergometer (Quinton Excalibur Sport).
The second visit served as a practice ride for the subjects. For
part A, subjects cycled for ~15-20 min at a power
output selected to elicit ~80-85%
O2 max. Subjects involved in
part B cycled for 30-40 min at a power output selected
to elicit ~65-70% O2 max.
These sessions served to habituate the subject to the cycle ergometer
and to confirm that the chosen power output was appropriate.
Experimental Protocol
Subjects reported to the laboratory three times in a postprandial state. Each trial was separated by ~1 wk. For a given subject, all trials were conducted at the same time of day. Subjects were asked to maintain their normal training schedule and diet throughout the duration of the study and were instructed to prepare for each trial as they would for competition, i.e., have a high-carbohydrate meal and be well rested. In addition, subjects were asked to abstain from all sources of caffeine and theophylline for 48 h before each testing session.At the start of each test, a catheter was placed into the medial
anticubital vein, and a normal saline drip was started to maintain
catheter patency. A resting blood sample was obtained (referred to as
90 min), and the subject ingested a gelatin capsule containing either
placebo (dextrose; Pl), caffeine (6 mg/kg; Caff), or theophylline (4.5 mg/kg Theolair; Theo). Preliminary work demonstrated that these doses
of caffeine and theophylline resulted in similar plasma methylxanthine
concentrations. Treatment was administered in a random, double-blind
fashion. Peak blood levels of theophylline are reached 90 min after the
ingestion of Theolair (31); thus after 90 min of resting
quietly a second blood sample was obtained (0 min). Subjects warmed up
with light stretching and cycling. The warm-up was accurately recorded
during the first trial, and subjects performed the same routine in each
subsequent trial.
Subjects involved in part A then cycled at a power output
that required ~80-85% O2 max
to a point of voluntary exhaustion (Exh) (inability to maintain pedal
cadence above 40 rpm, i.e., the lower limit of the electronically
braked bicycle). Blood and expiratory gas samples were obtained every
15 min and within 5 min of Exh. All samples were taken while subjects
were exercising. During the trials, subjects were given no external
cues regarding time and were verbally encouraged to cycle to Exh in all trials.
Subjects involved in part B of this study were required to
cycle for 45 min at ~65-70%
O2 max. Blood samples and expiratory gas measurements were taken at 15, 30, and 45 min, and muscle biopsies
were taken from the vastus lateralis immediately before exercise, 15 min into exercise, and at the end of the 45-min exercise period. The
exercise intensity used in part A was chosen so that the
results found in this study could be compared with previous work from
our laboratory (20). In part A, Exh occurred at
a different time for each trial, making comparison of metabolism difficult; therefore, a workload of 65-70%
O2 max was used in part B
to ensure steady-state metabolism to permit comparisons at defined time
points and for comparison with the work conducted by Raguso et al.
(30).
Analyses
Expired air samples were analyzed for fractions of O2 and CO2 with an Applied Electrochemical S-3A O2 analyzer and a Sensormedics LB-2 CO2 detector, respectively. The analyzers were calibrated with gases of known concentrations. Blood samples were immediately separated into two aliquots: 3 ml were transferred to a nontreated tube for serum, and 7 ml were transferred to a sodium-heparinized tube. Hematocrit was measured in duplicate from the latter sample by using high-speed centrifugation. A modest hemoconcentration occurred in the exercise samples, but there was no difference among trials. A 100-µl aliquot of blood was added to 500 µl of 0.6 M perchloric acid. A solution of 120 µl of 0.24 M EGTA and reduced glutathione was then added to the remaining blood.In part B, The EGTA- and glutathione-treated plasma was
analyzed in duplicate for epinephrine and norepinephrine concentrations by HPLC (Waters) as described by Weiker (39). Plasma
caffeine, paraxanthine, theophylline, and theobromine were measured by
using fully automated HPLC (Waters). An aliquot of 150 µl of plasma was added to ~40 mg ammonium sulfate and 50 µl 0.05% acetic acid. After the addition of 25 µl of an internal standard solution
[7-(
-hydroxypropyl)theophylline] and 3 ml chloroform-isopropyl
alcohol (85:15 vol/vol) extracting solvent, the mixture was vortexed
for 30 s and centrifuged for 10 min at 2,500 rpm. The organic
phase was transferred and dried under oxygen-free N2 and
resuspended in HPLC mobile-phase solvent (3% isopropanol-0.05% acetic
acid-0.5% methanol), and 100 µl were injected into a Beckman
Ultrasphere IP C18 5-µl column. Methylxanthines were
measured at 282-nm wavelength. Reagents for standards were obtained
from Sigma Chemical. The blood-acid extracts were analyzed enzymatically in duplicate for lactate, glucose, and glycerol (2). Serum was analyzed enzymatically in duplicate for FFA (26).
The muscle biopsy samples in part B were immediately frozen
in liquid N2, removed from the needle, and stored at
80°C. The entire biopsy was then freeze dried and powdered to
dissect out all nonmuscular elements. Two aliquots of powered muscle
(3-4 mg) were used for the enzymatic determination of glycogen
(22). An additional aliquot was extracted with 0.5 M
perchloric acid (1.0 mM EDTA), neutralized with 2.2 M
KHCO3, and analyzed enzymatically for muscle citrate,
lactate, and glucose 6-phosphate (G-6-P) (2). Muscle was extracted and analyzed for acetyl-CoA by using a
radiolabeled technique (8). A final aliquot of muscle was
extracted and analyzed for AMP concentration by using a
radioimmunoassay (18). A portion of the biopsy was also
extracted for the determination of total creatine on each muscle sample
(16). All muscle metabolite contents were corrected to the
highest total creatine content for each individual's biopsies. All
muscle data are expressed per kilogram dry muscle (dm) weight.
Statistics
RER data, performance time to Exh, and the change in muscle glycogen levels between time points were compared by using a one-way ANOVA for repeated measures. All blood and muscle data were analyzed by using a two-way ANOVA (time by treatment) for repeated measures. If significance was found (P < 0.05), the Tukey test was performed as the post hoc analysis. Data are reported as means ± SE.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Part A
Performance.
The most important finding in part A of the study was an
increase (P < 0.05) in time to Exh in both the Caff
and Theo trials compared with Pl (Fig.
1). All eight subjects rode longer after Caff ingestion vs. Pl, whereas six of the eight subjects rode longer
after Theo ingestion vs. Pl. This represents a 22% increase in Exh
after Caff ingestion and a 14% increase after Theo administration. There was no significant difference (P > 0.05) in Exh
between the Caff and Theo trials. Subjectively, two subjects complained of nausea and dizziness after Theo ingestion. This is a common complaint of individuals who are sensitive to this drug.
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Plasma methylxanthines. Subjects had low levels of caffeine (0.2 ± 0.1 µM) and undetectable levels of theophylline before each trial, confirming their compliance to abstain from methylxanthine-containing substances. A dose of 4.5 mg/kg Theolair administered in the Theo trial resulted in a plasma theophylline concentration of 34.1 ± 1.5 µM with low levels of caffeine (0.18 ± 0.1 µM), paraxanthine (0.03 µM), and theobromine (2.89 ± 1.7 µM) when measured 15 min into the exercise session. At the same time point, after the ingestion of 6 mg/kg of Caff, plasma caffeine levels were 33.7 ± 2.2 µM with the following dimethyxanthine concentrations: 3.6 ± 0.5 µM paraxanthine, 3.3 ± 1.9 µM theobromine, and 0.62 ± 0.1 µM theophylline. Thus plasma theophylline levels in the Theo trial were almost identical to plasma caffeine levels in the Caff trial.
Pulmonary data.
Mean RER data were not different (P > 0.05) in any of
the three experimental conditions: Pl, 1.0 ± 0.03; Theo,
0.99 ± 0.02; and Caff, 1.0 ± 0.02. Similarly, mean
O2 consumption was also similar among treatments: Pl,
80.3 ± 0.5% O2 max;
Theo, 81.4 ± 0.4% O2 max; and
Caff, 79.7 ± 0.7% O2 max.
Blood-borne metabolites.
A summary of the data for blood glucose, lactate, glycerol, and serum
FFA are presented in Table 1. Blood
glucose concentrations were similar at rest in all three treatments and
increased slightly (P > 0.05) during exercise.
Although there was a significant increase (P < 0.05)
in blood glucose concentrations at Exh in the Caff and Theo trials
compared with Pl, this is difficult to interpret physiologically as Exh
represents different time points for each trial.
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Part B
Plasma methylxanthines. As in part A, subjects arrived at the laboratory with low methylxanthine concentrations before each trial. Fifteen minutes into exercise in the Theo trial, plasma levels of theophylline were 30.3 ± 1.6 µM. Plasma caffeine concentrations in the Caff trial were 32.0 ± 2.9 µM.
Plasma catecholamines.
Before capsule ingestion, plasma epinephrine levels were similar in all
trials (Fig. 2). However, 90 min after
the ingestion of Caff, plasma epinephrine concentration was
significantly higher (P < 0.05) compared with that for
Pl and Theo. Theo ingestion resulted in concentrations very similar to
those with Pl. At 30 and 45 min of exercise, epinephrine concentration
was statistically higher in the Caff trial compared with Pl. Although
there was a trend for higher epinephrine values after Caff ingestion at these time points compared with Theo, this was not statistically significant (P > 0.05). As expected, plasma
epinephrine levels increased (P < 0.05) in all trials
as a result of exercise. There was no effect of Caff or Theo ingestion
on plasma norepinephrine levels compared with that of Pl. At the onset
of exercise, norepinephrine concentration increased (P < 0.05) and remained elevated throughout the exercise session in all
trials (Fig. 3).
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Muscle glycogen and blood glucose.
There was no effect (P > 0.05) of Theo or Caff on
muscle glycogen net utilization at any time point throughout the
exercise protocol (Fig. 4). Glycogen
levels decreased (P < 0.05) by 102 ± 19 mmol
glycosyl units/kg dm in the Pl trial within the first 15 min of
exercise. Similar reductions also occurred in the Theo trial (115 ± 22 mmol glucosyl units/kg dm) and Caff trial (116 ± 31 mmol
glucosyl units/kg dm). As expected, the net rate of glycogenolysis was
reduced (P < 0.05) in the subsequent 30 min by about
50%. Overall net glycogen utilization was also similar among trials.
Neither Theo or Caff ingestion had any statistically significant effect
(P > 0.05) on blood glucose at any time throughout the
exercise protocol compared with the Pl trial (Table
2).
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Muscle and blood lactate.
Muscle lactate concentration (Table 3)
was not significantly (P > 0.05) affected by
methylxanthine ingestion. However, at 15 min of exercise, there was a
trend (P = 0.07) for higher lactate levels in the Caff
and Theo trials compared with Pl. This trend was maintained at 45 min
in the Theo trial. As expected, blood lactate levels increased
(P < 0.05) with exercise; however, there was no effect
of treatment on this metabolite (Table 2).
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Muscle G-6-P. There was no effect of Caff or Theo ingestion on G-6-P concentrations compared with Pl (Table 3). Intramuscular G-6-P concentrations were significantly higher (P < 0.05) at 15 and 45 min of exercise compared with rest.
Muscle citrate. There was no statistically significant effect of Theo or Caff on citrate values compared with Pl at any time point throughout the protocol (Table 3). Exercise resulted in an increase (P < 0.05) in citrate levels by 15 min, which was maintained throughout the end of exercise when compared with resting concentrations.
Acetyl-CoA. Neither Caff nor Theo had any effect on acetyl-CoA concentrations at rest or during exercise compared with Pl (Table 3). In all three trials, acetyl CoA concentrations increased significantly (P < 0.05) over resting values during exercise.
Muscle cAMP.
Caff and Theo ingestion resulted in a significant increase
(P < 0.05) in muscle cAMP concentration 15 min into
the exercise protocol compared with Pl (Fig.
5). This elevation in cAMP levels was
maintained in the Theo trial so that by 45 min, cAMP concentration in
the Theo trial was significantly higher (P < 0.05)
compared with that in the Caff and Pl trials.
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Respiratory data.
RER was significantly higher (P < 0.05) in the Caff
trial compared with Theo (0.91 ± 0.02 vs. 0.87 ± 0.02),
whereas neither treatment was different (P > 0.05)
compared with Pl (0.90 ± 0.02). This represented a 13% decrease
in carbohydrate utilization in the Theo compared with Caff trial. As in
part A, the mean O2 consumption was not
different (P > 0.05) for any of the experimental
conditions: Pl, 67.9 ± 0.5%
O2 max, Theo, 69.5 ± 0.7% O2 max, and Caff, 68.1 ± 0.6% O2 max.
Blood glycerol and FFAs. There was a trend (P = 0.08) for higher blood glycerol concentrations 90 min after Theo ingestion vs. Pl (0.53 ± 0.08 vs. 0.32 ± 0.03 mM) (Table 2). Once exercise began, blood glycerol levels were significantly higher (P < 0.05) in both the Theo and Caff trials compared with Pl and remained elevated over Pl levels until the end of the exercise period. In addition, blood glycerol concentrations were significantly higher (P < 0.05) in the Theo trial compared with the Caff trial at 45 min. There was no effect of treatment on plasma FFA concentrations. At the end of exercise, FFA levels were significantly higher (P < 0.05) compared with other time points at rest and during exercise. (Table 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This two-part study examined the effect of theophylline on whole
body endurance exercise performance and skeletal muscle metabolism. The
major finding in part A of this investigation was an
ergogenic benefit of theophylline on exercise performance. These
results are in agreement with the only other study to examine the
effect of theophylline on skeletal muscle endurance and metabolism
(25). In a limited study (n = 3), Marsh et
al. (25) investigated the effect of theophylline on the
metabolism of wrist flexor muscles during a progressive
O2 max exercise test (~16 min) and
concluded that a therapeutic dose of theophylline significantly
increased the endurance of forearm musculature. The present study is
the first to examine the potential ergogenic effect of theophylline on
whole body endurance exercise and the first to compare its effects to
those elicited by caffeine. Subjects rode on average 5 min longer in
the Theo trial vs. Pl and 9 min longer after Caff ingestion compared
with Pl. The dose of Theo used in the present study (4.5 mg/kg
Theolair, resulting in plasma theophylline levels of 34.1 ± 1.5 µM) was chosen to be at the low end of the therapeutic range
(31). However, even at this low dose of Theo, two of the eight subjects in part A experienced nausea and dizziness.
Subsequently, one of these two subjects rode longer on the Pl vs. Theo.
None of the eight subjects reported any adverse effects after Caff ingestion. These results do support our hypothesis that theophylline is
an ergogenic aid, and, as discussed below, some of the data from
part B support the theory that theophylline is a more potent adenosine receptor antagonist compared with caffeine.
A major finding of part B was the lack of a glycogen-sparing
effect of Theo or Caff compared with Pl during 45 min of cycling at
70% O2 max. Chesley et al.
(9) found no influence of caffeine on net glycogenolysis
during 15 min of cycling at 85%
O2 max in 13 untrained men. This is
in contrast to several earlier investigators (15, 16, 34),
who reported glycogen sparing after caffeine ingestion during endurance
exercise. However, other investigations have reported an increase in
the rate of glycogenolysis in active skeletal muscle after
methylxanthine administration (30, 37). Whereas the
results of Vergauwen et al. (37) may not be directly applicable to the present data, as they used a perfused rat hindlimb preparation, Raguso et al. (30) suggested similar findings
in human subjects.
Under similar exercise conditions (subjects cycled for 30 min at
~70-75% O2 max) and plasma
theophylline concentrations (~30 µM), Raguso et al.
(30) observed a reduction in the glucose rate of
disappearance with no change in RER and concluded that adenosine
antagonism may play a role in regulating glucose uptake and
glycogenolysis in contracting skeletal muscle. The increase in muscle
glycogen utilization reported by Raguso et al. is in contrast to the
negligible effect of methylxanthines on carbohydrate metabolism found
in the present study. It is quite apparent from the conflicting results
in the literature that there must be interacting factors that determine
the effect of methylxanthines on muscle carbohydrate metabolism, and,
as will be discussed below, the specific distribution of adenosine
receptors may be critical.
One possible explanation for the conflicting results for the glycogen sparing effects of caffeine could be different fiber types used in different exercise intensities. Vergauwen et al. (36, 37) provide functional evidence for the existence of the adenosine receptor subtype A1-dependent mechanism of action in stimulating insulin-dependent glucose transport in slow-twitch skeletal muscle, whereas our laboratory has presented preliminary evidence demonstrating the physical presence of A2 adenosine receptors in rat slow-twitch skeletal muscle (21). Furthermore, skinned, slow-twitch human fibers have been shown to be about two to three times more sensitive to caffeine compared with fast-twitch fibers (27).
To our knowledge, this is the first study to measure the effects of methylxanthines on cAMP concentration in human muscle. The low dose of caffeine used in the present experiment exerts most, if not all, of its physiological action via inhibition of cellular A1 and A2 receptors (17). This implies that A1-receptor antagonism by Caff and Theo resulted in an elevation of muscle cAMP concentration during exercise. Both methylxanthines resulted in elevated cAMP 15 min into exercise compared with Pl. This elevation was maintained in the Theo trial so that, by 45 min, cAMP concentration was significantly higher compared with that in the Caff and Pl trials. This is consistent with theophylline being a more potent adenosine receptor antagonist compared with caffeine (5). These data demonstrating an elevation in cAMP levels after adenosine receptor antagonism are consistent with what has previously been reported (36) and provide additional functional evidence for the existence of A1 receptors in skeletal muscle.
The negligible effect of theophylline ingestion on epinephrine is similar to the study by Raguso et al. (30) yet is in contrast to other studies (38). The caffeine-induced increase in plasma epinephrine is similar to what has previously been reported (20). However, these investigators concluded that the increase in plasma epinephrine levels as a result of caffeine ingestion had no detectable effect on metabolism. This is consistent with van Soeren et al. (35) and Mohr et al. (28), who reported caffeine-induced metabolic effects without an increase in catecholamines in tetraplegic patients. Furthermore, the data in the present study suggest that theophylline and caffeine affect central nervous system regulation of the sympathetic nervous system differently.
Inherent in the mechanisms that have been proposed to explain the glycogen-sparing effect of caffeine is the assumption that fat oxidation is increased after caffeine ingestion. Because adenosine is a potent inhibitor of lipolysis in vivo (29), adenosine antagonism by methylxanthines should stimulate lipolysis. Our data from part B are in agreement with this hypothesis because both caffeine and theophylline resulted in increased blood glycerol levels. Furthermore, 45 min into exercise in part B, blood glycerol concentration was higher in the Theo trial vs. Caff and Pl. This supports further the hypothesis that adenosine may be involved in the regulation of lipid metabolism, because theophylline is a more potent adenosine receptor antagonist than caffeine (5). These data provide additional support for the argument that various metabolic responses to methylxanthines are not always related to a catecholamine-induced mechanism.
It has been suggested that increases in skeletal muscle citrate and acetyl-CoA concentrations may inhibit phosphofructokinase and pyruvate dehydrogenase reactions, resulting in decreased muscle glycogenolysis (13, 40), and that this could be enhanced by methylxanthines as a result of an increase in fat metabolism. In the present study, there was no significant effect of methylxanthine ingestion on intramuscular acetyl-CoA, citrate, or G-6-P concentrations, which is internally consistent with the lack of glycogen sparing observed. These data are also in general agreement with Spriet et al. (34). Although they reported a glycogen sparing effect of caffeine early in the exercise, muscle citrate and acetyl CoA concentrations remained similar between treatments.
Theo ingestion resulted in an increase in blood lactate levels at all
time points during exercise compared with Pl when subjects were cycling
at 80% O2 max (part A),
whereas the only effect of Caff on blood lactate concentration vs. Pl
was at Exh. Only one study has examined the effect of caffeine on
muscle lactate levels (23). That study reported an
increase in muscle lactate concentration during exercise bouts of fixed
power output (100% O2 max) and
duration (2 min) after caffeine ingestion. Muscle lactate in the
present study was not significantly affected by methylxanthine
ingestion; however, the exercise intensity was much lower (~70%
O2 max).
The significant increase in muscle cAMP and the tendency for an
increase in muscle lactate illustrated in part B both imply that muscle glycogenolysis may have been enhanced, even though our
glycogen data do not support this. Given the variability (~10%) (1) encountered when muscle glycogen utilization is
quantified by using the muscle biopsy technique, a small, but perhaps
significant, effect of Theo and/or Caff on glycogen use could have been
missed. Furthermore, it is possible that the exercise intensity used in part B (~70% O2 max)
was too low to show an effect of adenosine receptor antagonism on
muscle glycogenolysis. That is, antagonizing adenosine receptors and
tighter coupling between the activation of -receptors and cAMP
production may only affect muscle glycogen use when catecholamine
(epinephrine) and adenosine concentrations are especially high, such as
in intense exercise. This possibility is supported by the observation
that blood lactate levels were significantly elevated by Theo when
subjects were cycling at ~80% O2 max (part A).
In conclusion, the ingestion of Theo resulted in a 14% increase in
performance during whole body cycling exercise at 80%
O2 max. One practical application of
this finding is that theophylline should be considered an ergogenic
aid. Presently, theophylline is not a banned or controlled substance by
the International Olympic Committee; however, our results support the
hypothesis that theophylline is an ergogenic aid. These data also
illustrate that muscle glycogen sparing is not always observed after
the ingestion of caffeine or theophylline. Furthermore, the lack of
epinephrine increase as a result of theophylline ingestion demonstrates
that methylxanthines do not always assert their metabolic effects
through catecholamine-induced mechanisms. In addition, adenosine
receptor antagonism in both adipose tissue and skeletal muscle by the
methylxanthines may be involved in the regulation of substrate
metabolism during exercise. The former is evidenced by an increase in
glycerol, and the latter by an increase in muscle cAMP. These data
indicate that adenosine is an important regulator of metabolism in
these tissues.
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ACKNOWLEDGEMENTS |
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The authors thank P. Sathasivam for excellent technical assistance.
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FOOTNOTES |
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This study was supported by Natural Sciences and Engineering Research Council of Canada and a Graduate Student Gatorade Award.
Address for reprint requests and other correspondence: T. E. Graham, Dept. of Human Biology and Nutritional Sciences, Univ. of Guelph, Guelph, Ontario, Canada N1G 2W1 (E-mail: terrygra{at}uoguelph.ca).
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 3 August 1999; accepted in final form 17 July 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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