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Effect of salbutamol on muscle strength and endurance performance in nonasthmatic men

van BAAK, MARLEEN A.; MAYER, LEON H. J.; KEMPINSKI, ROGER E. S.; HARTGENS, FRED

Medicine & Science in Sports & Exercise: July 2000 - Volume 32 - Issue 7 - p 1300-1306
Applied Sciences: Physical Fitness And Performance
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van BAAK, M. A., L. H. J. MAYER, R. E. S. KEMPINSKI, and F. HARTGENS. Effect of salbutamol on muscle strength and endurance performance in nonasthmatic men. Med. Sci. Sports Exerc., Vol. 32, No. 7, pp. 1300–1306, 2000.

Purpose The ergogenic effect of acute β2-adrenergic agonist administration in nonasthmatic individuals has not been clearly demonstrated. Therefore, the acute effects of oral administration of the β2-adrenergic agonist salbutamol (4 mg) on muscle strength and endurance performance were studied in 16 nonasthmatic men in a double-blind randomized cross-over study.

Methods Peak expiratory flow (Mini Wright Peakflowmeter), isokinetic strength of the knee extensors and knee flexors at four angular velocities (Cybex II dynamometer), and endurance performance in a cycle ergometer test until exhaustion at 70% of maximal workload were measured.

Results Peak expiratory flow increased from 601 ± 67 L·min1 to 629 ± 64 L·min1 after salbutamol (P < 0.05). Peak torque was higher after salbutamol than after placebo (4.4% for the knee extensors, 4.9% for the knee flexors) (P < 0.05). Mean endurance time increased from 3039 ± 1031 s after placebo to 3439 ± 1287 s after salbutamol (P = 0.19). When four subjects complaining about adverse side effects were excluded from the analysis, the increase in endurance time (729 ± 1007 s or 29%) was statistically significant (P < 0.05). Salbutamol did not affect O2, respiratory exchange ratio, heart rate, and plasma free fatty acid and glycerol concentration during exercise; plasma lactate and potassium concentrations were increased (P < 0.05).

Conclusions Under the conditions of this study, oral salbutamol appears to be an effective ergogenic aid in nonasthmatic individuals not experiencing adverse side effects.

Department of Human Biology, Maastricht University, Maastricht, THE NETHERLANDS; and Netherlands Centre for Doping Affairs, Rotterdam, THE NETHERLANDS

Submitted for publication November 1998.

Accepted for publication October 1999.

Address for correspondence: Dr. Marleen A. van Baak, Department of Human Biology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands; E-mail: m.vanbaak@hb.unimaas.nL.

Salbutamol and other β2-adrenergic agonists are widely used as bronchodilators for the prevention and treatment of (exercise-induced) asthma. Asthma is a very common condition in the general population, and many recreational and competitive athletes suffer from an asthmatic condition (37). Approximately 10% of the athletes participating in the Olympic Games have asthma (22). The use of β2-adrenergic agonists by competitive athletes is strictly regulated in many sport disciplines. The reason is the assumed ergogenic action of β2-adrenergic agonists. Competitive athletes, therefore, have to take care not to violate antidoping rules with the treatment of their asthma. The International Olympic Committee allows the use of three β2-adrenergic agonists (salbutamol, salmeterol, and terbutaline) by inhaler when their use is previously certified by a respiratory or team physician (10). Other β2-adrenergic agonists and the administration of the aforementioned β2-adrenergic agonists in other than the inhalatory form are not allowed.

Because of their alleged ergogenic capacity, β2-adrenergic agonists may also be used by nonasthmatic athletes (4,9). However, the evidence for an acute ergogenic effect of β2-adrenergic agonists in nonasthmatic individuals is not very convincing. A number of studies have investigated the effect of varying doses of β2-adrenergic agonists in the aerosol/nebulized form on maximal oxygen consumption (O2max) in trained nonasthmatic men. In none of these studies was a significant effect on O2max found (4,5,9,14,21,23,24). With respect to submaximal endurance exercise performance, results are thus far inconsistent. Norris et al. (24) found no effect of salbutamol administration on time needed to complete a 20-km time trial. On the other hand, Bedi et al. (1) showed that sprint time till exhaustion after a 1-h submaximal exercise bout was increased by pretest albuterol inhalation. In contrast, a study by Cayton et al. (3) suggests that endurance performance is significantly impaired in nonasthmatic men after salbutamol. Other investigators looked at the effects of β2-adrenergic agonists on parameters of anaerobic performance. In the majority of studies, no effects were seen (15,20,21,23,24), and in only one study was a positive effect found (30). The acute effect of β2-adrenergic agonists on muscle strength has only been studied for the respiratory muscles by measuring maximal inspiratory pressure during intravenous salbutamol infusion. No effect was found (35).

Because of the relative scarcity and inconsistency of data on the acute effects of salbutamol administration on muscle strength and aerobic endurance performance, we decided to study these parameters after administration of a single oral dose of salbutamol. It is unlikely that the bronchodilatory action of salbutamol has an ergogenic effect, because in nonasthmatic subjects bronchodilation is not a performance-limiting factor. We therefore assume that salbutamol has to reach the systemic circulation in order to display its possible ergogenic action. Systemic plasma concentrations are much lower after clinically relevant aerosol doses than after typical oral doses (37). If salbutamol has an ergogenic effect, it is therefore more likely that such an effect can be demonstrated after an oral dose than after aerosol administration.

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METHODS

Subjects

Subjects were 16 healthy male volunteers (age = 23.3 ± 2.1 yr, body mass index = 22.4 ± 1.6 kg·m2, O2max = 55.9 ± 7.2 mL·kg1·min1, maximal workload (Wmax) = 351 ± 27 W; mean ± SD). Based on the answers to a brief questionnaire, all subjects were considered free of asthma, exercise-induced asthma, chronic bronchitis, or other respiratory diseases. None of them had ever used bronchodilating drugs. All subjects were active in sports at least two times per week (track and field, fitness training, hockey, soccer, or cycling). Subjects were asked not to change their habitual sports activities during the study. The protocol of the study was approved by the Ethics Committee of Maastricht University, and all subjects gave written informed consent before entering the study.

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Study Design

Subjects were familiarized to all testing procedures on a separate day, before the study. In addition, Wmax and O2max was determined in each individual before the start of the study. The study was performed according to a double-blind, randomized cross-over design. Two trials were performed with an interval of approximately 1 wk. Each subject took either a single oral dose of 4-mg salbutamol or placebo 1.5 h before they came to the lab. An oral dose of 4-mg salbutamol is in the normal therapeutic range for the treatment of asthma but is higher than the therapeutic dose of salbutamol given by inhalation (0.2–0.4 mg). Inhalation is the most common route of administration for relief of bronchospasms in asthmatic patients. All tests were performed between 1.5 and 4 h after intake of salbutamol, the period of peak plasma concentrations (26). In each individual, the two trials were performed at the same time of the day. Subjects were asked to follow the same activity and meal pattern for 24 h before the two trials to ensure that the trial conditions were as comparable as possible. On the trial days, muscle strength, peak expiratory flow, and endurance time were determined successively.

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Measurements

Maximal workload (Wmax).

In each subject Wmax (in W) was determined on an electromagnetically braked cycle ergometer (Lode, Groningen, The Netherlands) using an incremental workload protocol. Starting at 100 W for 5 min, workload was increased by 30 W every 3 min until volitional fatigue. During the test, oxygen consumption, carbon dioxide production and min ventilation were determined by a Sensormedics 2900 system (Sensormedics Corporation, Yorba Linda, CA). Respiratory exchange ratio at exhaustion was ≥ 1.10 in all subjects.

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Maximal isokinetic muscle strength.

Maximal isokinetic muscle strength of the knee flexors and knee extensors was measured at four angular velocities (180 °·s1, 120 °·s1, 60 °·s1, and 30 °·s1) on a Cybex II isokinetic dynamometer (Ronkonkoma, NY) after a warm-up of 5 min on a cycle ergometer. Chair dimensions were standardized for each subject, and straps were used to fixate the pelvic region and thigh. Peak torque at each angular velocity was the highest torque during five flexions or extensions at that velocity. Two minutes of rest were given between the measurements at different angular velocities. The strength measurements were performed between 1.5 and 2 h after drug ingestion.

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Peak expiratory flow.

Peak expiratory flow (PEF) was measured in sitting position, approximately 2 h after drug administration, with a Mini Wright Peakflowmeter (Airmed, UK). Peak expiratory flow was defined as the highest value out of three forced expirations.

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Endurance performance.

Immediately after the measurement of peak expiratory flow, the endurance test was started. Subjects cycled to exhaustion on a cycle ergometer at a workload representing 70% of their Wmax. After a warm-up of 5 min at 50% Wmax, the workload was increased to 70% Wmax, and the subjects continued to cycle until exhaustion, i.e., when they were no longer able to maintain the pedaling rate above 40 revolutions·min1. During the endurance test, gas exchange and heart rate were measured and a venous blood sample was collected after 10, 20, and 30 min of exercise. It was decided not to measure gas exchange later during the test, because it was feared that this might interfere with performance, which was the primary outcome parameter of the endurance test. In addition, heart rate was measured and blood was sampled at the moment of exhaustion and after 10 min of recovery. Subjects were not given feedback about the duration of the tests.

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Blood analyses.

Blood samples were transferred to 1.5-mL Eppendorf vials containing 30 μL EDTA (7.5% weight/volume). The vials were centrifuged immediately for 1 min in a high-speed Eppendorf centrifuge. Plasma was transferred to Cobas vials and frozen in liquid nitrogen. Frozen plasmas were stored at −80°C until analysis.

Plasma lactate (lactate dehydrogenase method (7)), glycerol (Triglyceride kit no. 644200, Boehringer Mannheim, Germany) and nonesterified fatty acid (NEFA test kit no. 994–75409, Wako Chemicals, Germany) concentrations were determined in duplicate on a COBAS-Fara centrifugal spectrophotometer (Roche, Switzerland). The plasma potassium concentrations were determined by means of an electrolyte analyzer (AVL, Graz, Austria).

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Statistical analysis.

Data are presented as mean ± SD. Two-way repeated measures ANOVAs (drug × angular velocity) were used to analyze the isokinetic strength measurements. The areas under the curve (AUCs) of the plasma concentrations of nonesterified fatty acids, lactate, and potassium (0–30 min) were calculated and two-tailed Student t-tests for paired data were used to analyze the differences between the placebo and salbutamol AUCs. Differences in plasma concentrations at exhaustion or during recovery were also analyzed by paired t-tests. P < 0.05 was considered to be statistically significant.

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RESULTS

Four subjects spontaneously complained about side effects, such as nausea, dizziness, and nervousness, after taking their medication. They nevertheless agreed to perform the tests. After unblinding of the medication, it turned out that all four subjects had received salbutamol on that occasion.

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Peak Expiratory Flow

Peak expiratory flow was 601 ± 67 L·min1 after placebo and 629 ± 64 L·min1 after salbutamol (P < 0.05).

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Muscle Strength

After salbutamol, the mean peak torques were in all test conditions higher than after placebo (Fig. 1). Two-way repeated measures ANOVA (drug × angular velocity) showed that peak torque of the knee flexors and knee extensors decreased significantly with increasing angular velocity (P < 0.01) and was higher after salbutamol than after placebo (P < 0.05). No statistically significant interaction effects were found. The average difference in peak torque between placebo and salbutamol was 4.4% for the knee extensors and 4.9% for the knee flexors.

Figure 1

Figure 1

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Endurance Test

Figure 2 shows the individual endurance times after placebo and salbutamol. Endurance time increased after salbutamol in 10 subjects, was reduced in 3 subjects, and was unchanged in another 3 subjects. The mean endurance time was 3039 ± 1031 s after placebo and 3439 ± 1287 s after salbutamol. This difference of 400 ± 1160 s or 19 ± 46% (range −47 to 150%) failed to reach statistical significance (P = 0.19). However, when the four subjects who complained about side effects (see Fig. 2) were removed from the analysis, mean endurance time increased from 3004 ± 1029 s after placebo to 3743 ± 1300 s after salbutamol. This increase of 729 ± 1007 s or 29 ± 45% (range −11 to 150%) was statistically significant (P < 0.05).

Figure 2

Figure 2

Salbutamol had no statistically significant effects on heart rate, oxygen uptake, carbon dioxide production, or respiratory exchange ratio (RER) during exercise (P > 0.4). At 30 min of exercise heart rate was 165 ± 11 beats·min1 during salbutamol and 163 ± 9 beats·min1 during placebo (P = 0.83); RER was 0.96 ± 0.03 and 0.97 ± 0.05, respectively (P = 0.45). Salbutamol also did not affect plasma glycerol or nonesterified fatty acid concentrations during exercise, exhaustion, or during recovery (Fig. 3) (P > 0.8), but it increased plasma lactate concentration during exercise (AUC 0–30 min) (P < 0.05) (Fig. 4). Plasma concentrations of lactate at exhaustion (P = 0.18) or during recovery (P = 0.85) did not differ statistically significantly between the placebo and salbutamol trial. The average plasma potassium concentration during exercise (AUC 0–30 min) (P < 0.05) and at exhaustion (0.05 <P < 0.06) were lower after salbutamol (Fig. 5).

Figure 3

Figure 3

Figure 4

Figure 4

Figure 5

Figure 5

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DISCUSSION

β-Adrenergic stimulation of various organs plays an important role in the adaptation of the human body to exercise. Increased transport capacity by an increase in cardiac output, increased availability of substrates for energy metabolism by increases in lipolysis and glycogenolysis and increased skeletal muscle contractility associated with increased activity of the sympathetic nervous system are all, at least partly, mediated by β-adrenergic receptor stimulation.

In this study, the acute effects of additional pharmacological β2-adrenergic receptor stimulation on skeletal muscle strength and aerobic endurance performance were investigated. Despite the double-blind design of the study, we cannot fully exclude the possibility that subjects were aware of the treatment they received, because of certain side effects experienced. This raises the possibility that voluntary test performance was biased by this knowledge. However, only half of the subjects correctly guessed when they had taken salbutamol.

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Peak Expiratory Flow

The main therapeutic application of β2-adrenergic agonists is as a bronchodilator in the treatment of patients with asthma. A dose of 4 mg of the β2-adrenergic agonist salbutamol administered orally increased peak expiratory flow of the nonasthmatic subjects in our study. We only checked our subjects for the absence of asthma by medical history and not by a more reliable bronchial provocation test to rule out bronchial hyperresponsiveness. We therefore cannot completely rule out the presence of some bronchial hyperreactivity in our study population. However, most other authors who did determine airway reactivity and only included subjects with normal reactivity also found increases in lung function parameters after β2-adrenergic agonist administration (1,14,15,23,24).

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Skeletal Muscle Strength

In our study, isokinetic muscle strength increased slightly (4–5%), but statistically significantly, after acute administration of salbutamol. Acute β-adrenergic stimulation is known to increase tension production in fast twitch skeletal muscle fibers in a variety of animal species (39). The mechanism of this positive inotropic effect has not been fully elucidated but is likely to involve increased sarcoplasmatic Ca2+-release (2,39). Very few data are available on the acute effects of β-adrenergic stimulation in human skeletal muscle. Marsden and Meadows (18) showed that infusion of epinephrine in physiological amounts had no effect on peak tension of the calf muscle and the adductor pollicis. Lanigan et al. (13) found that acute oral administration of the β2-adrenergic agonist terbutaline increased maximal voluntary contraction of the calf muscles by 3 and 6% in the nonfatigued and fatigued dominant leg, respectively, in this study. These changes were described as not statistically significant; however, the study included only four subjects (13). Chronic treatment with the β2-adrenergic agonist salbutamol for 2–3 wk has been shown to significantly increase voluntary strength of the quadriceps and hamstrings in humans (7–22% depending on muscle group and duration of treatment) (19). The authors were unable to ascertain the mechanism by which salbutamol enhanced muscle strength but suggest that, in addition to any acute effects of salbutamol, muscle hypertrophy and a change of slow to fast muscle fiber types may contribute to the increase in muscle strength with chronic treatment (19).

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Endurance Performance

Although an average increase in endurance performance of 19% was found after salbutamol administration, this difference was not statistically significant due to the large interindividual variation in response, ranging from −47 to +150%. However, four subjects spontaneously complained about not feeling fit before one of the tests. It turned out that they had taken salbutamol on that occasion. Two of them performed worse after salbutamol than after placebo, in one performance was unchanged, and in one performance was slightly increased after salbutamol compared with placebo. When these subjects were excluded from the analysis, the increase in endurance time was 29% in the remaining subjects and was statistically significant. This suggests that adverse side effects of salbutamol, which are experienced by only part (in this study 25%) of the subjects, may mask its ergogenic effect during endurance exercise. Cayton et al. (3) studied the effects of 5-mg salbutamol administered by nebulizer in nonasthmatic men using an identical exercise test. They reported a 27% reduction in performance after salbutamol. Because this study has only been reported in abstract form, it is not clear whether this impaired performance is related to side effects in this group of subjects. Norris et al. (24) have also investigated the effect of β2-adrenergic agonist administration on endurance performance. They used a 20-km bicycle ergometer time trial but were unable to demonstrate an effect of inhalation of 400-μg salbutamol on time trial performance. A time trial test has a higher reproducibility than the exercise test until exhaustion in well-trained athletes (11) and therefore should be able to pick up changes in performance more easily. A likely explanation for the different results between the study by Norris et al. (24) and this study is the dose and route of salbutamol administration in the two studies: 400 μg by inhalation in the study by Norris and coworkers (24) and 4 mg orally in this study. In these dose ranges oral administration results in higher plasma concentrations than inhalation (37). It is therefore likely that the systemic actions of the β2-adrenergic agonist, rather than its bronchial actions, are involved in its ergogenic effect.

Of the metabolic parameters measured during exercise in this study, only plasma lactate and potassium concentration were significantly affected by salbutamol. Plasma lactate concentration was increased, whereas plasma potassium was lowered after salbutamol. Increased lactate concentrations in plasma after systemic salbutamol administration have been found in other studies as well, both at rest (8,36) and during exercise (3,8). The increased lactate concentration may reflect an increased β2-adrenergic receptor-mediated glycolytic flux in skeletal muscle, as has also been reported after intravenous epinephrine administration (27). On the other hand, oxygen uptake, CO2 production, and respiratory exchange ratio during exercise were unaffected, suggesting the absence of an important change in carbohydrate oxidation during exercise. We cannot explain this apparent discrepancy, but it should be realized that both plasma lactate concentration and respiratory exchange ratio are indirect measures of glycolytic flux and carbohydrate oxidation and other factors (changes in disappearance of lactate, changes in oxidation of other macronutrients) may affect these variables as well. Salbutamol has been shown to increase plasma free fatty acid and glycerol concentrations at rest (26,36), indicative of β2-adrenergic stimulation of adipose tissue lipolysis. The effect of salbutamol or other β2-adrenergic agonists on lipolysis during exercise has, to our knowledge, not been studied before. Our results suggests that additional β2-adrenergic stimulation by salbutamol during exercise does not increase lipolysis, because plasma concentrations of free fatty acids and glycerol were unchanged during and after exercise.

Salbutamol and other β2-adrenergic agents lower plasma potassium concentration at rest (6,8,17,26) and during exercise (6,8,28), which was also found in this study. Despite this lowering of plasma potassium concentration, the loss of potassium from the exercising muscles is not reduced by β2-adrenergic stimulation and may even be increased (8,26). These findings are compatible with a stimulation of potassium uptake in nonactive tissues by β2-adrenergic agonists (26). Several investigators have associated the exercise-induced reductions in intracellular potassium concentration in active skeletal muscle and increases in plasma potassium concentration, resulting in decreased skeletal muscle membrane potential and reduced excitability, with fatigue during high intensity as well as prolonged exercise (16,29,31,32). In agreement with this hypothesis, β2-adrenergic antagonists such as propranolol increase plasma potassium concentration and impair endurance exercise performance (12,33,34), whereas caffeine and salbutamol reduce plasma potassium concentration and improve endurance exercise performance (16,25, this study). However, a causative effect of changes in potassium homeostasis on fatigue during exercise remains to be shown.

In conclusion, a single oral dose of 4 mg of the β2-adrenergic agonist salbutamol causes a small (4–5%) increase in isokinetic muscle strength of the knee flexors and extensors (P < 0.05). The average increase in endurance performance of 19% was not statistically significant. However, adverse side effects of salbutamol in a limited number of subjects may have influenced this result. If those subjects are excluded, the increase in endurance performance after salbutamol was statistically significant. We therefore conclude that, under the conditions of our study, oral salbutamol appears to be an effective ergogenic aid in nonasthmatic individuals not experiencing adverse side effects. Whether this also holds for better trained competitive athletes, for performance in actual competition and for other routes of administration of salbutamol remains to be studied.

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Keywords:

ERGOGENIC AGENT; EXHAUSTION; POTASSIUM; LACTATE; MUSCLE CONTRACTILITY

© 2000 Lippincott Williams & Wilkins, Inc.