Effect of inhaled terbutaline on substrate utilization and 300-kcal time trial performance

The Journal of Physiology

Kalsen

Ørtenblad

et al. 2014

Key pointsr From animal models, it is well established that β 2 -adrenergic stimulation increases contractile force, rates of Ca 2+ release and uptake from the sarcoplasmic reticulum, and Na + -K + -ATPase activity of skeletal muscles. However, these effects are unexplored in humans.r Here we report that β 2 -adrenergic stimulation with the high dose selective β 2 -adrenoceptor agonist terbutaline elicits positive inotropic and lusitropic effects on non-fatigued m. quadriceps that are associated with enhanced rates of Ca 2+ release and uptake from the sarcoplasmic reticulum in trained men.r However, we also observed that the positive inotropic and lusitropic effects of β 2 -adrenergic stimulation on m. quadriceps were blunted when muscle fatigue developed.r Furthermore, we show that β 2 -adrenergic stimulation counteracts exercise-induced reductions in Na + -K + -ATPase V max (maximum rate of activity) and elevates glycolytic activity during high intensity exercise.r These findings are important for our understanding of the role of β 2 -adreceptor activation in regulation of ion handling and contractile properties of non-fatigued and fatigued skeletal muscles in humans.Abstract The aim of the present study was to examine the effect of β 2 -adrenergic stimulation on skeletal muscle contractile properties, sarcoplasmic reticulum (SR) rates of Ca 2+ release and uptake, and Na + -K + -ATPase activity before and after fatiguing exercise in trained men. The study consisted of two experiments (EXP1, n = 10 males, EXP2, n = 20 males), where β 2 -adrenoceptor agonist (terbutaline) or placebo was randomly administered in double-blinded crossover designs. In EXP1, maximal voluntary isometric contraction (MVC) of m. quadriceps was measured, followed by exercise to fatigue at 120% of maximal oxygen uptake (V O 2 ,max ). A muscle biopsy was taken after MVC (non-fatigue) and at time of fatigue. In EXP2, contractile properties of m. quadriceps were measured with electrical stimulations before (non-fatigue) and after two fatiguing 45 s sprints. Non-fatigued MVCs were 6 ± 3 and 6 ± 2% higher (P < 0.05) with terbutaline than placebo in EXP1 and EXP2, respectively. Furthermore, peak twitch force was 11 ± 7% higher (P < 0.01) with terbutaline than placebo at non-fatigue. After sprints, MVC declined (P < 0.05) to the same levels with terbutaline as placebo, whereas peak twitch force was lower (P < 0.05) and half-relaxation time was prolonged (P < 0.05) with terbutaline. Rates of SR Ca 2+ release and uptake at 400 nM [Ca 2+ ] were 15 ± 5 and 14 ± 5% (P < 0.05) higher, respectively, with terbutaline than placebo at non-fatigue, but declined (P < 0.05) to similar levels at time of fatigue. Na + -K + -ATPase activity was unaffected by terbutaline compared with placebo at non-fatigue, but terbutaline counteracted exercise-induced reductions in maximum rate of activity (V max ) at time of fatigue. In conclusion, increased contractile force induced by β 2 -adrenergic stimulation is associated with enhanced rate of Ca 2+ release in humans....

Section: Discussionmentioning

confidence: 90%

β₂‐Adrenergic stimulation enhances Ca²⁺ release and contractile properties of skeletal muscles, and counteracts exercise‐induced reductions in Na⁺–K⁺‐ATPase V_max in trained men

The Journal of Physiology

Kalsen

Ørtenblad

et al. 2014

“…3,4 Skeletal muscle, the largest tissue of the human body in non-obese individuals, 5 has a high density of beta-adrenoceptors of which the beta 2 -subtype accounts for approximately 90%. 6,7 Stimulation of muscle beta 2 -adrenoceptors with selective agonists modulates myocellular excitation-contraction coupling and metabolism, 8,9 which appear mediated by cAMP/ protein kinase A (PKA)-dependent signaling. [10][11][12] Furthermore, beta 2 -agonists stimulate muscle protein turnover and growth.…”

Section: Introductionmentioning

confidence: 99%

Beta₂‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Drug Testing and Analysis

Narkowicz

Habib

et al. 2019

Self Cite

While studies have demonstrated substantial differences in beta2‐adrenergic agonist enantiomer pharmacology, enantioselective disposition of long‐acting beta2‐adrenergic ligand racemic (rac)‐formoterol in blood is inadequately explored after inhaled therapy given analytical challenges. Furthermore, information on enantioselective disposition and partitioning of beta2‐adrenergic agonist in skeletal muscle is absent despite its promising data on muscle anabolism in humans. Using a sensitive ultra‐high performance liquid chromatography−mass spectrometry (UPLC−MS/MS) assay, we determined disposition of (R,R)‐formoterol and (S,S)‐formoterol in plasma and skeletal muscle samples from 11 non‐asthmatic men who had inhaled rac‐formoterol at therapeutic doses (2 × 27 μg). Mean (SD) concentrations of (R,R)‐ and (S,S)‐formoterol in plasma and in muscle biopsies of the vastus lateralis 1 hour after inhalation of formoterol were 31 (15) and 45 (18) pg × mL−1 for (R,R)‐formoterol and (S,S)‐formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pg × mgwet wt−1, respectively, in muscle. Formoterol exhibited different enantioselective disposition in plasma and muscle (p < 0.0001). In plasma, mean log (R,R):(S,S)‐formoterol ratio was lower than 0 [−0.17(0.07), p < 0.0001], whereas in muscle, mean log (R,R):(S,S)‐formoterol ratio was slightly higher than 0 [0.04(0.07), p < 0.05]. Log (R,R):(S,S)‐formoterol ratio in muscle was related to muscle fiber‐type composition. Furthermore, formoterol induced an approximately two‐fold increase in muscle p‐PKASer/thr phosphorylation (p < 0.01), indicating a substantial beta2‐adrenergic response. Collectively, these findings suggest that formoterol exhibits modest enantioselective disposition in plasma after inhaled therapy in humans, which appear related to a greater (R,R)‐enantiomer disposition in skeletal muscle that may be dependent on fiber‐type composition.

Section: Introductionmentioning

confidence: 99%

“…This is highly relevant for doping control as formoterol is delivered by inhalation for therapeutic use and a threshold for total formoterol (free and glucuronide conjugate) is used. 4 Supratherapeutic dosing of beta2-agonists via the inhaled route has been shown to elicit performance-enhancing effects [11][12][13][14][15] as well as increase fat oxidation. 16 It is clear from the short-acting beta2-agonist (SABA) salbutamol that there are enantioselective differences in metabolism between oral and inhaled routes of administration that have the potential to be exploited for doping control purposes.…”

mentioning

confidence: 99%

Enantioselective disposition of (R,R)‐formoterol, (S,S)‐formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control

Jacobson

Drug Testing and Analysis

Narkowicz

et al. 2019

Self Cite

Formoterol is a long‐acting beta2‐adrenoceptor agonist (LABA) used for the treatment of asthma and exercise‐induced bronchoconstriction. Formoterol is usually administered as a racemic (rac‐) mixture of (R,R)‐ and (S,S)‐enantiomers. While formoterol is restricted by the World Anti‐Doping Agency (WADA), inhalation of formoterol is permitted to a predetermined dose (54 μg/24 hours) and a urine threshold of 40 ng/mL. However, chiral switch enantiopure (R,R)‐formoterol is available, effectively doubling the therapeutic advantage for the same threshold. The aim of this study was to investigate whether formoterol exhibits enantioselective urinary pharmacokinetics following inhalation. Six healthy volunteers were administered a 12 μg inhaled dose of rac‐formoterol. Urine was collected over 24 hours and analyzed by enantioselective ultra‐performance liquid chromatography−tandem mass spectrometry (UPLC−MS/MS) assay. Total (free drug plus conjugated metabolite) median (min‐max) rac‐formoterol urine levels following inhalation were 1.96 (1.05–13.4) ng/mL, 1.67 (0.16–9.67) ng/mL, 0.45 (0.16–1.51) ng/mL, 0.61 (0.33–0.78) ng/mL, and 0.17 (0.08–1.06) ng/mL at 2, 4, 8, 12, and 24 hours, respectively, well below the 2019 urine threshold. The proportion of conjugation differed between enantiomers with glucuronide conjugation much greater for (R,R)‐formoterol (around 30%–60% of total) compared to (S,S)‐formoterol (0%–30%). There was clear evidence of inter‐individual enantioselectivity observed in the ratios of (R,R):(S,S)‐formoterol, where (S,S)‐ was predominant in free formoterol, and (R,R)‐ predominant in the conjugated metabolite. In conclusion, rac‐formoterol delivered by inhalation exhibits enantioselective elimination in urine following single‐dose administration. Enantioselective assays should be employed in doping control to screen for banned beta2‐agonist chiral switch products such as (R,R)‐formoterol, and total hydrolyzed rac‐formoterol is warranted to account for inter‐individual differences in enantioselective glucuronidation.