Bronchodilators taken before physical activity, especially inhaled beta2-agonists, are the most commonly used treatments for the management of exercise-induced asthma (3). Because asthma prevalence is high among athletes (21), beta2-agonists are widely used among them. Moreover, because of their alleged ergogenic effects, these drugs are also used by athletes without asthma to improve their physical performance. Because of the sympathomimetic and anabolic properties of beta2-agonists, concerns have been raised relative to the potential unfair competitive advantage provided by these drugs. As a result, the use of beta2-agonists is forbidden in athletes according to the prohibited list of the World Anti-Doping Agency, except formoterol, salbutamol, salmeterol, and terbutaline that are permitted by inhalation for athletes with a therapeutic use exemption.
Many studies have been performed to assess the effect of inhaled beta2-agonists on exercise performance (19). Their potential ergogenic effect was mainly investigated by measuring the effect of prior drug inhalation on performance during an incremental exercise test, a constant-load endurance test or a sprint session (e.g., Wingate test). The large majority of these studies reported no ergogenic effect after inhalation of therapeutic or supratherapeutic doses of beta2-agonists (19). In animal models however, beta2-agonists were shown to greatly increase muscle contractility (38), to reduce muscle fatigue (7) and to improve force recovery (27). Oral beta2-agonist administration in human has also substantial effects on muscle function (9,24,37) and exercise performance (10,11). Doses of inhaled beta2-agonists such as salbutamol are 10 to 20 times smaller than oral doses and mainly act locally within the airways. However, salbutamol inhalation was also shown to have systemic effects able to modify the resting metabolic rate (1) or the exercise metabolic response (36). Therefore, some part of the inhaled dose may potentially reach the peripheral muscles and/or the motor centers of the brain. This might explain the increased exercise capacity reported in some studies after beta2-agonist inhalation (4,34,36). However, assessing the effect of inhaled beta2-agonists on whole-body exercise performance as in previous studies may not be sensitive enough to evaluate specific changes in peripheral muscle function.
Therefore, based on the above results, we hypothesized that salbutamol inhalation may increase peripheral muscle contractility, may reduce fatigue and improve force recovery after a high-intensity exercise. Moreover, because beta2-agonists may also affect the central nervous system (CNS) (5,13,31), we assessed the effect of salbutamol inhalation on the level of muscle activation during voluntary contraction before and after exercise. We evaluated the effects of both a therapeutic (200 μg) and a supratherapeutic (800 μg) dose of salbutamol because the latter would still result in negative urine doping test (18).
MATERIALS AND METHODS
Fourteen healthy, nonsmoking male subjects gave their written informed consent to participate in the study. The mean ± SD of age was 23.3 ± 3.2 yr, the mean ± SD of height was 179 ± 8 cm, and the mean ± SD of weight was 70.1 ± 9.2 kg. The subjects were physically active (mean exercise activity = 5.9 ± 2.0 h·wk−1), had no history of atopy, asthma, or other cardiorespiratory disorders. They were not allowed to perform any physical exercise on the day before the test and to eat or drink any caffeinated products on the day of the test. They had to keep their training activity constant during the whole testing period, and they took a high-carbohydrate meal at least 2 h before each test to load their carbohydrate stores. Nine subjects took part to one part of the study only (i.e., the cycling test or the leg extension test; see later), whereas five subjects performed both parts of the study (i.e., both exercise tests). During a preliminary visit to the laboratory, subjects were familiarized with the equipment and procedures. The study was approved by the local ethics committee (Comité de Protection des Personnes Sud Est) and performed according to the Declaration of Helsinki.
A prospective double-blind, randomized, three-way crossover design was used to compare two dose levels of salbutamol (200 and 800 μg) and a placebo, administered by inhalation before three identical cycling (n = 10) or leg extension (n = 9) exercise tests. Two types of exercise tests were used to assess the effect of inhaled salbutamol on muscle fatigue and recovery after different fatiguing tasks, i.e., a whole-body exercise and an isolated exercise. Each session was performed at least 72 h apart, within a period of no more than 3 wk. Salbutamol (Ventolin 100 μg; GlaxoSmithKline, Marly-le-Roi, France) or placebo were administered using a meter-dose inhaler with an inhalation chamber (Volumatic; GlaxoSmithKline). One or four puffs of salbutamol or placebo were introduced into the chamber, and then the subject performed five respiratory cycles inside. This procedure was repeated twice. To ensure blinding, the technician who gave the random order treatments was not involved in the other parts of the protocol. Lung function [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and forced expiratory flow at 25-75% of FVC (FEF25-75)] was assessed 10 min after treatment administration (SensorMedics V max 229; SensorMedics Corporation, Yorba Linda, CA).
The exercise test was performed on an electromagnetically braked bicycle ergometer (Ergometer 900; Ergoline, Germany). Saddle and handlebar heights were individually adjusted to the subject and kept similar all over the protocol. Resting lung function, ventilation, gas exchange, and heart rate during exercise were measured with an ergospirometric device (SensorMedics V max 229; SensorMedics Corporation). Twenty-five minutes after treatment inhalation, subjects started cycling at 80 W, and subsequently, the load was increased by 20 W·min−1 until subjects were exhausted or not able to sustain their individual target pedaling frequency. Subjects chose their preferred pedaling frequency (between 70 and 100 rpm) at the beginning of the first incremental test, and it was then held constant during this and the following exercise test. Quadriceps force (see below) was assessed before exercise (15 min after treatment inhalation) and 30 and 60 min after the end of the exercise.
Leg extension test.
Subjects lay supine on a table, the left leg fixed with a knee joint angle of 90° of flexion and the ankle attached just superior to the malleoli to a strain gauge (Dempo Technology Co, Trevisio, Italy). The protocol was similar to the one used by Mador et al. (23) but adapted for healthy, active subjects to produce sufficient muscle fatigue. Subjects performed five sets of ten 5-s maximal voluntary contractions (MVC), with 2-min rest between sets and 5-s rest between contractions. Quadriceps force (see below) was assessed before exercise (15 min after treatment inhalation), after the first, third, and fifth sets of contraction and 30 and 60 min after the end of the exercise, except for voluntary activation and recruitment profile (see below), which were assessed before and after exercise only to avoid interfering with the task.
Quadriceps force measurement.
Subjects lay supine on a table, the left leg fixed with a knee joint angle of 90° of flexion, and the ankle attached just superior to the malleoli to a strain gauge (Dempo Technology Co; range 0-3000 N; sensitivity 0.2 mV·N−1). Before the initial quadriceps force measurement, a standardized warm-up consisting in quadriceps contractions at increasing intensities was performed. Isometric quadriceps force was measured (i) during voluntary contractions and (ii) during magnetic femoral nerve stimulations (twitch force) by using a 45-mm figure-of-eight coil powered by a Magstim 200 stimulator (MagStim, Whitland, UK). The stimulating coil head was positioned high in the femoral triangle just lateral to the femoral artery. The best spot allowing maximal force was determined with minor adjustments and then marked on the skin with an antiallergenic permanent pen. The subjects were instructed to keep the mark on the skin to replicate the positioning from one session to another.
First, the interpolated twitch technique was used to assess voluntary activation of the quadriceps contraction. Subjects were told to perform five 5-s submaximal voluntary contractions of increasing intensity, at approximately 15%, 30%, 50%, 70%, and 90% MVC and a 5-s maximal contraction (100% MVC). The force produced during a superimposed twitch (TwQsup) delivered 2 s after the beginning of each voluntary contraction was used to calculate the recruitment fraction as follows:
where TwQpeak is the peak force evoked during a potentiated twitch (see below).
The recruitment fraction obtained at 100% MVC was defined as the maximal voluntary activation. In addition, each recruitment fraction at submaximal voluntary contractions was plotted against the corresponding level of voluntary force and a linear regression was performed. The slope and the intercept of the linear regression were used to characterize the recruitment profile as previously described (39).
Then, quadriceps twitch force was measured 2 s after a 5-s MVC of the quadriceps to obtain potentiated twitch (TwQ). Force recordings from a representative subject during MVC and TwQ are shown in Figure 1. The use of potentiated twitch to assess peripheral fatigue after exercise eliminated the confounding effects of contractile history of a muscle. In addition, changes in potentiated twitch have been shown to be more sensitive for detecting fatigue compared to unpotentiated twitch (20). Five potentiated twitches were obtained at each time, the smallest and the highest values were excluded and the mean of the three remaining twitches was analyzed. The following parameters were then calculated at each time point: peak force (TwQpeak); contraction time (CT), i.e., the time elapsed between the twitch onset and the peak force; maximal rate of force development (MRFD), i.e., maximal value of the first derivative of the mechanical signal before reaching peak force; maximal rate of force relaxation (MRFR), i.e., maximal value of the first derivative of the mechanical signal after reaching peak force; and one-half relaxation time (RT0.5), i.e., the time elapsed between peak force and half the peak value. Stimulation supramaximality was tested on each visit by performing additional twitches with 98%, 95%, and 90% of the maximal output of the stimulator (five twitches at each power output): supramaximality was confirmed on every occasion by reaching a plateau in quadriceps force at submaximal intensity of the stimulator. Test-retest measurements of TwQpeak indicated a within-session (1 h apart) variability level of 2.9 ± 2.1% (range 0.5-7.7%; interclass correlation coefficient r = 0.992, P < 0.001; n = 10) and a between-session (24-48 h apart) variability level of 4.2 ± 8.0% (range 0.9-16.4%; interclass correlation coefficient r = 0.928, P< 0.001; n = 10).
Maximum quadriceps force during voluntary contraction was calculated at each time point (before and after exercise) as the highest peak value obtained during the five MVC performed before TwQ measurement. Strong verbal encouragement was given to the subjects during each MVC.
Quadriceps force and lung function measurements before exercise were compared between treatments as absolute values with all subjects pooled together (n = 14). The amount of fatigue after each exercise test (cycling test, n = 10; leg extension test, n = 9) was compared between treatments by calculating the percentage reduction in quadriceps force from before exercise. During the cycling test, ventilation and gas exchange were compared between treatments by calculating the average values (i) during the last 15 s of the test and (ii) during the last 15 s of the 1-min stages performed at 60% and 80% of the lowest maximal power output reached in the three treatment conditions (i.e., at the same absolute power output).
Data were analyzed for the effects of time and treatments using two-way ANOVA with repeated measures in combination with t-test and Bonferroni correction for post hoc analysis. All statistical analyses were performed using standard statistical software (Statview 5.0; SAS Institute, Cary, NC). All results are presented as mean ± SD, and P < 0.05 was considered to be statistically significant.
No adverse effects after treatment inhalation were reported by the subjects.
Lung function and exercise response.
Lung function variables after salbutamol or placebo inhalation are shown in Table 1. A slight bronchodilatation was observed after salbutamol inhalation compared with after placebo inhalation: FEF25-75 was significantly increased (P = 0.009), whereas FEV1/FVC tended to be improved (P = 0.071).
Cardiorespiratory variables and power output during the cycling tests are shown in Table 2. No significant difference between treatments was observed at any time of the test. Total exercise time did not differ significantly between treatments (placebo: 763 ± 115 s, 200 μg: 747 ± 120 s, 800 μg: 759 ± 120 s; P = 0.268).
Averaged force during the leg extension test was similar between the three treatments (placebo = 428 ± 89 N, 200 μg = 439 ± 136 N, 800 μg = 426 ± 104 N; P = 0.837). The linear slope of the reduction in force throughout the 50 contractions was not significantly different between the three treatments (placebo = −2.8 ± 1.0 N per contraction−1, 200 μg = −3.2 ± 1.3 N per contraction−1, 800 μg = −2.8 ± 1.5 N per contraction; P = 0.518).
Quadriceps force and voluntary activation before exercise.
MVC (placebo = 597 ± 146 N, 200 μg = 629 ± 141 N, 800 μg = 610 ± 148 N; P = 0.328), TwQpeak (placebo = 215 ± 83 N, 200 μg = 227 ± 69 N, 800 μg = 250 ± 84 N; P = 0.238), CT, MRFD, MRFR, and RT0.5 (results not shown; all P > 0.05) before exercise were not significantly different between treatments. However, slightly higher TwQpeak values were observed after salbutamol inhalation, with 8 of 14 subjects having TwQpeak with 800 μg >120% of placebo values (Fig. 2). Maximal voluntary activation (placebo = 92 ± 3%, 200 μg = 94 ± 5%, 800 μg = 94 ± 3%; P = 0.227), slope, and intercept of the recruitment regression lines (placebo: slope = 0.19 ± 0.08, intercept = 35.3 ± 16.2, r 2 = 0.87 ± 0.09; 200 μg: slope = 0.21 ± 0.11, intercept = 37.0 ± 16.0, r 2 = 0.85 ± 0.12; 800 μg: slope = 0.22 ± 0.14, intercept = 33.3 ± 17.4, r 2 = 0.89 ± 0.10; all P > 0.05) calculated before exercise were not significantly different between treatments.
Quadriceps force and voluntary activation after exercise.
MVC, contractile parameters of TwQ, and maximal voluntary activation before and after the cycling test are provided in Table 3 as absolute values. Changes in MVC and TwQpeak are shown in Figure 3 as percentage values. MVC, TwQpeak, MRFD, and MRFR were significantly reduced after exercise, whereas no significant change in CT, RT0.5, maximal voluntary activation, and recruitment regression lines (results not shown) was observed. No significant difference between treatments in quadriceps force and activation was observed at any time of the protocol
MVC, contractile parameters of TwQ, and maximal voluntary activation before, during, and after the leg extension test are provided in Table 4 as absolute values. Changes in MVC and TwQpeak during and after the leg extension test are shown in Figure 4 as percentage values. Slope and intercept of the recruitment regression lines before and after the leg extension test are shown in Table 5. MVC, TwQpeak, MRFD, MRFR, RT0.5, maximal voluntary activation, and slopes of recruitment regression lines were significantly reduced after exercise, whereas intercepts of recruitment regression lines were significantly increased. No significant difference between treatments in quadriceps force and activation was observed at any time of the protocol.
To our knowledge, no studies has investigated the effect of salbutamol inhalation on peripheral muscle contractility and fatigue after exercise. The results of this study showed that acute inhalation of therapeutic (200 μg) or supratherapeutic (800 μg) doses of salbutamol did not modify significantly the quadriceps contractility or exercise-induced fatigue assessed by femoral nerve magnetic stimulation. This was demonstrated by similar voluntary and evoked force as well as similar exercise-induced force reduction after salbutamol and placebo inhalation. Moreover, salbutamol inhalation did not modify quadriceps voluntary activation both before and after whole-body or isolated exercises.
Critique of methods.
When using magnetic nerve stimulation to assess muscle strength and fatigue, it is critical that muscle stimulation is supramaximal. In the present study, we confirmed for each subject on every occasion that magnetic nerve stimulation allowed supramaximal stimulation of the quadriceps as previously described in our laboratory (40). Moreover, we also confirmed that twitch quadriceps force measurement during femoral nerve magnetic stimulation is highly reproducible (40), with a mean test-retest variability level of 2.9 ± 2.1% within the day and 4.2 ± 8.0% between days. Therefore, we believe that the use of magnetic nerve stimulation in the present study allows us to assess the effect of salbutamol inhalation on muscle strength and fatigue.
Muscle fatigue was assessed after two types of exercise, an incremental cycling test on the one hand, and a one-leg knee extension test on the other. Because mechanisms of muscle fatigue depend on the task characteristics (6), the effect of beta2-agonists inhalation on muscle fatigue after a whole-body exercise or an isolated exercise test may differ. Therefore, both exercise tests were performed in the present study to investigate potential effects of salbutamol on muscle function. The significant reduction in quadriceps force observed after both types of exercise indicated that muscle fatigue was successfully induced, whereas the changes in maximal voluntary activation and recruitment profile after the isolated exercise (Tables 4 and 5) suggested that central fatigue was present after this type of exercise (15). The quadriceps was specifically assessed as it is a primary locomotor muscle. However, because the effect of salbutamol on muscle may differ depending on fiber-type composition (24), the results of the present study remain to be confirmed for other muscle groups. Similarly, although the present results were obtained in healthy, moderately trained men, the potential effect of salbutamol inhalation on muscle function in populations with different training status or in patients requires additional investigations.
Effect of salbutamol on lung function and exercise response.
A slight increase in lung function (FEF25-75 and FEV1/FVC) was found after salbutamol inhalation, as previously shown (4,8,29,34,36). This result confirms the bronchodilating effect of beta2-agonists inhalation in normal subjects and, therefore, indirectly suggests that salbutamol was efficiently administered. However, despite this increase in airway caliber after salbutamol administration, no change was observed in ventilation during the cycling test as previously reported (8). It should be emphasized that, although statistically significant, this bronchodilating effect may be of minor clinical significance in these normal subjects and without overt consequence on exercise performance.
Similarly to previous studies (8,25,26,28), we did not find any effect of salbutamol inhalation on maximal power output and cardiorespiratory parameters during the incremental cycling test. Also, salbutamol inhalation did not modify mean quadriceps force during the leg extension test. These results not only confirm that inhalation of therapeutic or supratherapeutic (800 μg) doses of salbutamol has no ergogenic effect during incremental whole-body exercise but also indicate that no ergogenic effect is present during isolated exercise where muscle contractility and/or activation rather than cardiorespiratory parameters are the major limiting factors (2).
Effect of salbutamol inhalation on muscle function.
Although most studies having evaluated the effect of beta2-agonist inhalation on exercise performance showed no ergogenic effect, several results still suggest that these treatments may alter the exercise response. First, some studies indicated that beta2-agonist inhalation can indeed improve exercise performance: Bedi et al. (4) and Signorile et al. (34) reported an increase in sprint capacity after inhalation of therapeutic dose (180 μg) of salbutamol, whereas van Baak et al. (36) showed recently an increase in time-trial cycling performance after inhalation of supramaximal dose (800 μg) of salbutamol. Second, several studies reported a significant effect of salbutamol inhalation on the exercise response, for example, changes in heart rate (14), free fatty acids, glycerol, lactate, and potassium (36), indicating that inhaled beta2-agonists can act beyond the airways and potentially reach the peripheral muscles. Third, oral beta2-agonist administration was shown to have substantial effects on exercise performance (10,11) and muscle function (9,24,37), although this is not a universal finding (22). Fourth, in animal models, beta2-agonists were shown to increase muscle contractility (38) and to improve fatigue resistance (7) and recovery (27). These effects on muscle function after beta2-adrenergic administration may result from an increased Ca2+ release from the sarcoplasmic reticulum and/or from an increased Ca2+ sensitivity (17,34).
In the present study, however, we did not find any significant effect of salbutamol inhalation on voluntary or evoked muscle force before exercise as well as on muscle fatigue and recovery after exercise. Also, treatments did not modify contractile parameters of TwQ. There was, nonetheless, a slight but nonsignificant increase in quadriceps twitch force before exercise after salbutamol compared with placebo inhalation (200 μg = +12 ± 32%; 800 μg = +22 ± 34%; Fig. 2). The apparent discrepancy between these results and previous results regarding salbutamol effects on muscle function in animal models or after oral intake in human may be explained by the amount of drug reaching the peripheral muscles. Pharmacokinetics measurements after a single oral dose of 4 mg of salbutamol indicated that peak plasma concentrations reached 10-20 μg·L−1 (16). Studies having shown a significant effect of salbutamol on contractile properties of muscle fibers also used similar salbutamol concentrations (38). On the other hand, plasma concentration of salbutamol after inhalation of 200 μg of salbutamol was shown to be <0.5 μg·L−1 (29), that is, 20-40 times less than after a 4-mg salbutamol oral intake. Therefore, although the relationship between plasma and muscle salbutamol concentrations is only speculative, the amount of salbutamol reaching the peripheral muscles may be insufficient after acute inhalation of therapeutic or supratherapeutic (800 μg) doses to modify muscle function similarly to oral administration. However, when plasma salbutamol concentration was measured after administration of an identical single dose of 1.2 mg of salbutamol either by inhalation (meter-dose inhaler) or orally (oral solution), similar maximal concentrations were observed (3.4 ± 1.1 vs 3.9 ± 1.4 μg·L−1) although with a different kinetics (maximal concentrations were reached after 0.22 and 1.8 h, respectively) (12). These results, in addition to the slight but nonsignificant dose-effect of salbutamol inhalation on quadriceps twitch force in the present study (Fig. 2), suggest that higher doses of inhaled salbutamol might affect muscle function similarly to oral administration (9,24,37). Moreover, chronic salbutamol inhalation may induce higher plasma concentration than acute administration (29). Chronic beta2-adrenergic (fenoterol) administration was shown to improve muscle strength and total protein content of frog sartorius muscle (33), suggesting that chronic administration of the drug may increase its effect on muscle force production (34). Therefore, although the present results indicate that acute inhalation of 200 or 800 μg of salbutamol does not significantly modify muscle contractility, further studies are needed to evaluate the effect of higher doses or chronic administration on muscle function.
In addition to their potential effects on muscle contractility, beta2-agonists may also affect exercise performance and muscle function through their effects on the CNS (30). It has been hypothesized that the ergogenic effect of oral salbutamol intake might be due, at least in part, to a stimulatory effect on the CNS (11). Beta2-receptors are indeed numerous within the brain and beta2-agonist administration was used for example as a treatment of depression, probably through an increase in serotoninergic activity (5,13,35). In the present study, we evaluated whether the central motor command may be modified after salbutamol inhalation by using the interpolated twitch technique. Voluntary activation was assessed both during maximal and submaximal contractions to evaluate any change in central command dependant on the level of force. Because the relationship between recruitment fraction and force is considered to be linear at submaximal force level (32,39), voluntary activation at submaximal intensities was characterized through linear regressions as previously described (39). Quadriceps voluntary activation during both maximal and submaximal voluntary contractions was not modified after salbutamol inhalation. Moreover, whereas the changes in voluntary activation during submaximal and maximal contractions after the isolated exercise are compatible with central fatigue (15), these changes were similar after placebo and salbutamol inhalation. Therefore, these results suggest that salbutamol inhalation does not modify muscle activation both before and after high intensity exercise.
In conclusion, the present results indicate that inhalation of therapeutic (200 μg) and supratherapeutic (800 μg) doses of salbutamol did not significantly modify quadriceps contractility and fatigue after a whole-body or an isolated exercise. Moreover, treatments did not modify muscle activation during voluntary contraction both before and after exercise. Therefore, an improvement in muscle function after acute therapeutic salbutamol inhalation susceptible to provide an unfair competitive advantage cannot be confirmed. It remains, however, to evaluate whether inhalation of higher doses or chronic inhalation may improve muscle function and therefore have a potential performance-enhancing effect.
The authors thank the subjects for their time and effort dedicated to this study, the "Agence française de lutte contre le dopage" for financial support and Isabelle Vivodtzev for her assistance with this project. The authors state that the results of the present study do not constitute endorsement of the product by themselves or ACSM.
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Keywords:©2008The American College of Sports Medicine
BETA2-AGONIST; MUSCLE; STRENGTH; EXERCISE; PERFORMANCE