Objective: Given the therapeutic and non-therapeutic use of the tadalafil, (phosphodiesterase-5 inhibitor, PDE-5i), we examined its effects on anaerobic performance indices.
Methods: In total, 12 well-trained subjects reported to the laboratory on two occasions 1 week apart to perform a 30 s Wingate anaerobic power test (WAnT) on a bicycle ergometer. The day before the WAnT, the subjects were double-blinded to receive an oral dose of tadalafil (20 mg) or placebo. Blood lactate value at rest and 1, 3, 6 and 10 minutes of recovery phase, mean power, peak power, time to peak power and fatigue index were assessed for each WAnT.
Results: Blood lactate values at the 3-min recovery WAnT increased significantly in the tadalafil condition (mean (SD) 13.9 (1.7) v 12.8 (1.3) mmol/l; p<0.05) and time to peak power decreased significantly (6.3 (1.3) v 5.7 (1.5) s; p = 0.05). No differences were observed in any other parameters between the two conditions.
Conclusion: The primary finding of this investigation was that the administration of a single dose of a long-term PDE-5i does not substantially influence anaerobic performance indices. However, results demonstrated both an increase in lactate values at the 3-min point of the recovery phase and a decrease in time to peak power.
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Although several studies have investigated the effects of phosphodiesterase-5 inhibitors (PDE-5i) administration in subjects diagnosed with cardiopulmonary diseases,1 2 few studies have investigated the effects in healthy subjects.3 Kloner et al4 found that tadalafil administration in healthy subjects produces a mild vasodilation causing minimal or small changes in blood pressure. PDE-5i have been shown to be safe when administered in combination with most vasodilator medications.5 Some PDE-5i may increase exercise capacity, both in healthy subjects during hypoxia3 6 7 and in subjects diagnosed with cardiopulmonary diseases.3–11 Of particular interest are studies that have shown that PDE-5i are capable of inducing vasodilation of coronary resistance vessels with an increase in blood flow into the ischaemic myocardial region during exercise.1 12
Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to the corresponding 5-nucleotide monophosphate.13 In total, 11 different PDE families (PDE-1 to PDE-11) have been identified throughout the body.14 These PDEs differ in selectivity for cyclic nucleotides, sensitivity to inhibitors and activators, physiological roles and tissue distribution.9 14 15 The PDE-5i are a class of vasoactive drugs that have been developed for treatment of erectile dysfunction (ED).2 16 17 Three highly selective and potent PDE-5i are mainly used for the treatment of ED: sildenafil, tadalafil and vardenafil. Although these inhibitors are comparable in their ability to inhibit PDE-5, there are some notable differences in their pharmacokinetic properties. In particular, the t1/2 of tadalafil is longer (17–21.6 h) than that of sildenafil and vardenafil (3–5 and 4–5 h, respectively).18
There is widespread use of PDE-5i daily to treat ED and also for recreational purposes in individuals of varying ages.19 We are aware that athletes take PDE-5i, very often for recreational purposes, without knowledge if PDE-5i might positively or negatively influence their physical performance. There is a paucity of information available regarding the effect of long-acting PDE-5i on exercise capacity in healthy trained subjects. No influence on performance parameters during incremental testing for V.O2max has been seen.6 20 In addition, studies on the effects of PDE-5i on anaerobic performance are lacking. Therefore, the purpose of this study was to investigate whether a single dose of a PDE-5i (tadalafil) can influence anaerobic performance indices in healthy, trained subjects.
Based on pilot data and estimates of sample variability available in the literature,23 we estimated that 20 subjects per treatment would be necessary to identify a difference of 8 to 10% between placebo and tadalafil treatment for all dependent variables at α = 0.05 and β = 0.20. In total, 20 healthy trained men were recruited to participate as subjects in this study; their characteristics are presented in table 1.
After explanation of all experimental procedures, participants provided written informed consent according to protocols approved by the university scientific commission and by the university ethics committee. All subjects were students and were involved in educational athletic activity and team sports (soccer, basketball, volleyball). During the time of the study, all subjects maintained their normal diet and sleeping habits. All the subjects were non-smokers. One week before starting the experimental evaluations, all subjects underwent a preliminary clinical pre-participation screening assessment consisting of personal medical history, physical examination, ECG and blood pressure at rest and after step test, spirometry, and urine analyses according to standard procedures, conducted by a sport medicine physician. In addition, a detailed endocrinological/andrological history and an examination of anthropometric and sexual characteristics were conducted.
During the week before the experimental tests all volunteers underwent two pre-testing sessions. During the first pre-testing session height, weight and V.O2max were assessed. Each subject’s V.O2max was determined by means of a continuous graded exercise test until exhaustion on a cycle ergometer (Lode Excalibur Sport, Lode BV, Groninger, Netherlands). After a 3-min rest period in a sitting position on the cycle ergometer for baseline evaluations, the test started with a 1-min unloaded warm-up of unloaded cycling and then the power output was increased 30 W every 3 min until subjects could no longer continue. Before and during the test, oxygen consumption, carbon dioxide production and ventilation were continuously measured breath-by-breath by an oxygen uptake open-circuit system (Quark b2, COSMED, Rome, Italy); this was subsequently smoothened by using a 6-breath moving average and reduced to a 30-s average. V.O2max was identified at the occurrence of a plateau of V.O2 despite further increase in workload or an increase in V.O2 <1 ml/kg/min in comparison with that produced by the previous workload.21 Secondary criteria were also applied to verify the maximum effort, such as attainment of age-predicted maximum heart rate and/or a respiratory exchange ratio >1.15.22 During the second pre-testing session, all volunteers underwent the Wingate exercise test on cycle ergometer in order to become familiar with the experimental protocol and to allow detection further contraindications to exercise.
In the experimental sessions, each subject performed, on two different occasions, using a double-blind design, a 30-s Wingate anaerobic power test (WAnT) on a cycle ergometer, after a single oral administration of one tablet of either placebo or tadalafil (20 mg, Cialis; Ely-Lilly) in the morning. All the subjects received randomly placebo or tadalafil before the first exercise test, then after a week’s wash-out period, received the alternative tablet, before the second exercise test. The study’s crossover design (fig 1) allowed intraindividual comparison of drug effects.
In accordance with the pharmacokinetic properties of tadalafil, all exercise tests were performed in the afternoon, about 7 to 8 h after placebo/tadalafil administration. No physical exercise or sexual intercourse was allowed during the study starting from 24 h before the exercise tests. During the wash-out period, the athletes practised their usual physical activity in order to maintain their normal fitness.
All performance indices were calculated using Lode Wingate V1.0.9 software. Lactate values were also determined at 1, 3, 6 and 10 minutes of recovery phase using an Accusport Lactate Analyzer (Boehringer Mannheim, Mannheim, Germany).24 The WAnT was preceded by a warm-up and followed by a cool-down period. Before the warm-up period, subjects were allowed to adjust the handlebar and saddle height to achieve greatest comfort. Warm-up is considered to be essential for optimum performance25 and consequently this was standardised for each subject before WAnT. Subjects performed a short version of warm-up,26 consisting of 4 minutes of pedalling at 60 RPM with a load flywheel corresponding to 50% of the individual’s V.O2max (subthreshold warm-up), interspersed with three “all-out sprints” each lasting 4 seconds. Subjects then rested for 3 minutes to eliminate any fatigue associated with the warm-up. We provided a verbal countdown at the 10-s mark to give the subject sufficient time to achieve maximum pedal cadence by the beginning of the test. At the end of this countdown period, tension was automatically added by software and each subject pedalled as fast as they could for 30 seconds. Before starting the WAnT test, subjects were required to rise out of the saddle. At the beginning of the WAnT test, each subjects cycled in the standing position for 5 seconds and were then seated until the end of the test. Verbal encouragement was given to each participant throughout the test. After completing the all-out sprint, the participants continued cycling without workload for 10 minutes to aid recovery (cool-down period).
All data are presented as means (SD). The lactate variable was analyzed with a two-way analysis of variance (ANOVA) (treatment administration × time) for repeated measure on one factor (time) followed by appropriate post hoc analysis. Differences in mean power, peak power, minimum power, time to peak power and fatigue index between the two treatments (tadalafil or placebo) were determined by paired Student’s t test. Statistical significance was set at p⩽0.05. Statistical analyses were conducted in SPSS for Windows V14.0.1 (SPSS Inc., Chicago, Illinois, USA)
During each WAnT, peak power output was obtained within the first 10 seconds. As shown in table 2, time to peak power was significantly lower after tadalafil than placebo (5.7 (1.5) v 6.3 (1.3) s, p = 0.05). There were no significant differences between tadalafil and placebo treatment in all other performance indices (table 2).
ANOVA showed a significant effect for time (p<0.0001) and treatment (p = 0.03) on lactate levels, but there was no significant time by treatment interaction effect (p = 0.63). Post hoc analysis revealed significant differences between basal lactate value and lactate values after WAnT (p<0.001). Moreover, there was a significant difference (p = 0.02) between lactate value at 3 minutes and 1 minute during the recovery phase. Blood lactate at 3 minutes after WAnT was significantly higher in tadalafil than placebo condition (13.9 (1.7) v 12.8 (1.9) mmol/l; p = 0.02). Blood lactate values at rest and during recovery period are presented in fig 2.
The primary objective of our study was to determine whether a single dose of a long-term PDE-5i (tadalafil 20 mg) influences anaerobic performance indices (mean power, peak power, minimum power, time to peak power and fatigue index). These indices were examined using the 30-s WAnT. In this study, we observed no significant differences between tadalafil and placebo conditions for mean power, peak power, minimum power and fatigue index. In spite of that, tadalafil administration significantly decreased the time to peak power and significantly increased blood lactate value at the 3-min point of recovery phase. The absence of a significant time × treatment interaction effect indicated that treatment (placebo or tadalafil) did not affect the blood lactate response to the WAnT, which is consistent with previously reported kinetics.26
As previously reported,23 the maximum rate of glycolysis can be expected to be reached between the fifth and tenth seconds of the WAnT, when anaerobic lactic acid metabolism appears to have become the dominant energy source up to the end of the WAnT. During the 30-s WAnT performance, the energy supply is mainly anaerobic, as the energy turnover is derived from anaerobic alactic (31%) and lactic acid metabolism, dominated by glycolysis (50% of the total energy turnover).23 We observed a higher peak blood lactate level (3 min after the end of WAnT), in tadalafil condition, associated with an anticipated time to peak power, but no differences in the other power output indices. This result could mirror variations in time and amount of substrate utilisation without affecting the whole 30-s WAnT performance.
The increase of lactate values at 3 minutes can be explained by two potential factors. First, the decrement of time to peak power may be due to faster utilisation of anaerobic alactic metabolism, which could entail an enhanced utilisation of anaerobic lactic sources.27 Anaerobic alactic metabolism involves breakdown high-energy phosphate stores.27 The potential energy within the creatine phosphate (CP) molecule is released when the bond between the creatine and phosphate molecules is cleaved.27 CP hydrolysis is catalysed by the enzyme creatine kinase. Hassan et al.28 found a positive correlation between cGMP and myocardial creatine kinase activity in rat. Lung and muscle tissues are a rich source of PDEs, including PDE-518 29 the major function of which is acceleration of the decay of cGMP. Therefore the hydrolysis of cGMP due to PDE5i administration could improve the CK activity in muscle and consequently enhance the anaerobic alactic metabolism. Second, Abdollahi et al30 studied the effects of PDE 3, 4 and 5 inhibitors administration on glycogenolysis, and found an increase of glycogenolysis after PDE5i administration. During glycogenolysis, one glucose component at a time is cleaved from the glycogen molecule. Thus, an enhancement of glycogenolysis after PDE5i administration increases glucose units and consequently could increase blood lactate level.
We evaluated the individual exercise performance response to a single bout of an all-out 30-s exercise either after a single therapeutic dose of the PDE-5i tadalafil or placebo in a group of healthy male athletes. Results of the present study demonstrate that tadalafil did not influence the mean and peak power output values. Only time to peak power output was decreased after tadalafil administration. It is difficult to hypothesise if an anticipated peak power (at around 5 seconds) could have any influence on sport performance. Only in a sport that needs to reach the maximum power output in few seconds could tadalafil administration be beneficial to improve performance. Further studies are needed to evaluate if tadalafil administration could improve single short athletic performances and also to assess the effects on repeated trial performance. Furthermore, it also remains to be determined whether prolonged PDE-5i use or treatment and/or higher PDE-5i doses (that is, not therapeutic doses) might function as a “performance-enhancing” drug in athletes, mainly in sport activities performed in particular environments (eg high altitude, hypoxic conditions) and thus whether PDE-5i could be considered substances to be prohibited in some specific conditions.
What is already known on this topic
PDE-5i are a class of vasoactive drugs that have been developed for treatment of erectile dysfunction.
Some PDE-5i may increase exercise capacity, both in healthy subjects during hypoxia and in subjects diagnosed with cardiopulmonary diseases.
There is a paucity of information available regarding the effect of long-acting PDE-5i on exercise capacity in healthy trained subjects.
What this study adds
The effect of a long-acting PDE-5i (tadalafil) on anaerobic performance indices in healthy trained subjects was investigated.
Tadalafil did not influence the mean and peak power output values of a 30-s WAnT. A higher peak blood lactate level (3 minutes after the end of WAnT), associated with an anticipated time to peak power was observed.
These results could mirror variations in time and amount of substrate utilization without affecting the whole 30-s WAnT performance.
Competing interests: None.