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Previous studies based on animal models have raised concerns about salbutamol use in ozone air pollution with regard to ozone related lung injury. We conducted a double-blind, randomized, placebo-controlled crossover study including 18 subjects diagnosed with EIB by a eucapnic voluntary hyperpnea (EVH) test. Participants completed 30 min of standardized moderate to vigorous exercise in four conditions: ozone plus salbutamol; room air plus salbutamol; ozone plus placebo medication; and room air plus placebo medication. Spirometry, fraction of exhaled nitric oxide, and symptoms were measured before, immediately after, 30 min after and 1 h after exercise. Measurements between the four conditions were compared using percent change from pre to post exercise. There was a statistically significant difference between the salbutamol and placebo medication groups for spirometric variables including FEV1 (Estimate = 6.3, 95% CI: 4.23-8.37, p < 0.001). No differences were observed between ozone and room air exposures. There were no significant differences in FeNO response between experimental conditions. We found that salbutamol improved pulmonary function in individuals with EIB when exercising in ozone and did not increase eosinophilic airway inflammation as indicated by FeNO. This evidence suggests that it is safe for people with EIB to continue to use salbutamol as proscribed when ozone levels are elevated., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Inhaled beta-2 adrenoceptor agonists (iβ2A) are routinely used as bronchodilators in the treatment of asthma. However, their cardiac effects in athletes are scarcely examined. Thus, the aim of this study was to evaluate the effects of iβ2A on left ventricular (LV) systolic function (SF) by echocardiography in healthy, non-asthmatic female and male endurance athletes. A randomized, double-blinded, placebo-controlled, balanced, 4-way complete block cross-over study was conducted. Twenty-four healthy athletes (12f/12m: 22.9 ± 2.7/24.4 ± 4.6 years) randomly completed 4 study arms (placebo; salbutamol; formoterol; formoterol + salbutamol). After inhalation of the study medication, the participants performed a 10-min time trial (TT) on a bicycle ergometer. After each TT an echocardiography was performed to determine LVSF. Blood samples were collected pre, post, 3 h and 24 h post TT. In females, total serum concentrations for salbutamol and formoterol were higher. LV ejection fraction (LVEF) and LV global longitudinal strain (LVendoGLS) showed a treatment effect for the whole study group (p < 0.0001) and a sex effect on LVEF (p = 0.0085). In women, there was a significant treatment effect for all medication arms (at least p ≤ 0.01) both on LVEF and LVendoGLS. In men only formoterol and formoterol + salbutamol displayed a treatment effect on LVEF (p = 0.0427, p = 0.0330; respectively), whereas on LVendoGLS only formoterol + salbutamol was significant (p = 0.0473). The iβ2A significantly influenced LVSF after an acute bout of exercise in healthy endurance athletes. These effects were even more pronounced when combining both iβ2A that supports a dose-dependent effect on cardiac function. Moreover, female athletes had higher serum concentrations of β2 agonists and stronger effects on LVSF compared to male athletes. This is mainly explained by differences in body weight and related plasma volume and may indicate a potential risk when increasing dose above the tested concentrations. Trial registration: At the European Union Drug Regulating Authorities Clinical Trials (Eudra CT) with the number 201,500,559,819 (registered prospectively on 09/12/2015) and at the German register for clinical studies (DRKS number 00010574 registered retrospectively on 16/11/2021)., (© 2024. The Author(s).)

Objective: To study the changes in dynamic compliance (C dyn ), ventilation/perfusion (V˙/ Q˙) mismatch and haemodynamic variables in hypoxaemic anaesthetized horses whose PaO 2 increased following salbutamol inhalation., Study Design: Retrospective, clinical, cohort study., Animals: A group of 73 client-owned horses treated with salbutamol when PaO 2 <100 mmHg (13.3 kPa) during anaesthesia., Methods: Horses were divided into two groups: responders (R), where PaO 2 after salbutamol ≥1.2 PaO 2 before treatment (i.e. ≥20% increase), and non-responders (NR), where PaO 2 after salbutamol <1.2 PaO 2 before treatment. Demographic data and intraoperative variables before treatment were compared between R and NR. C dyn , arterial to end-tidal carbon dioxide difference [P(a-E´)CO 2 ], estimated ratio of dead space to tidal volume (est.V D /V T ), estimated shunt fraction (F-shunt), heart rate, systolic, mean and diastolic arterial pressure and dobutamine requirements were compared before and after treatment within R and NR. For each variable, the difference (Δ) between values pre- and posttreatment was calculated and compared between groups R and NR. Numerical data were compared using univariate or bivariate analysis and categorical data were compared using chi-square test; p < 0.05., Results: Of the 73 horses 50 were classified as R while 23 horses were classified as NR. There was no statistical difference between R and NR for demographic data or initial intraoperative variables except for body weight [R: 531 (170-715) kg, NR: 540 (420-914) kg]. While salbutamol did not alter C dyn in either group, it significantly decreased P(a-E´)CO 2 , est.V D /V T and F-shunt in R only. ΔP(a-E´)CO 2 , Δest.V D /V T and ΔF-shunt were significantly greater in R (-17.8%, -19.0% and -24.1%, respectively) than in NR (11.5%, 6.6% and -0.3%, respectively)., Conclusions and Clinical Relevance: In hypoxaemic anaesthetized horses responding to inhaled salbutamol by a ≥1.2 increase in PaO 2 no change in C dyn was detected, but indicators of V˙/ Q˙ mismatch improved., (Copyright © 2024 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

The objective of this study is to explore the transport, size growth, and deposition of Salbutamol Sulphate (SS) using Computational Fluid Dynamics (CFD). A CT-based realistic model of human airways from the oral cavity to the 5th generation of the lung was utilized as the computational domain. Four Test Cases (TC) with varying temperature and relative humidity (RH) under two inspiratory waveforms were considered to completely evaluate the impact of inhalation conditions on particle growth. Salbutamol Sulphate (SS) is a β2-adrenergic agonist and has been extensively used for asthma treatment. A monodispersed distribution of SS particles with an initial diameter of 167 nm was considered at the mouth inlet based on pharmaceutical data. Results indicated that inhalation of saturated/supersaturated air (RH>100%) leads to significant hygroscopic growth of SS particles with a factor of 10. In addition, the deposition efficiency of SS particles under the Quick and Deep (QD) inhalation profile was enhanced as the flow temperature and humidity increased. However, the implementation of Slow and Deep (SD) inspiratory waveform revealed that the same particle size growth is achieved in the respiratory system with lower deposition efficiency in the mouth-throat (less than 3%) and tracheobronchial airway (less than 2.18%). For the escaped particles form the right lung, in the SD waveform under TC 3, the maximum particle size distribution was for 600 nm particles with 25% probability. In the left lung, 30% of the particles were increased up to 950 nm in size. For the QD waveform in TC 3 and TC4, the most frequent particles were 800 nm with 36% probability. This holds practical significance in the context of deep lung delivery for asthmatic patients with enhanced deposition efficiency and large particle size. The findings of the present study can contribute to the development of targeted drug delivery strategies for the treatment of pulmonary diseases using hygroscopic dry powder formulations., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Salbutamol and hyoscine butylbromide (HBB) are commonly used bronchodilators in horses with severe asthma (SA)., Objective: To compare the bronchodilation potency, duration, and adverse effects of salbutamol and HBB in SA., Animals: Six horses in exacerbation of SA., Methods: The effects of inhaled salbutamol (1000 μg) and HBB (150 mg, IV) were compared in a randomized, blinded, crossover experiment. Lung function, intestinal borborygmi and heart rate were assessed before and sequentially until 180 minutes after drug administration, and analyzed with 2-way repeated-measures ANOVA and Dunnett's multiple comparison tests., Results: Both treatments caused a similar improvement in lung function. Pulmonary resistance and reactance returned to baseline values within 30 minutes after HBB administration, whereas salbutamol improved reactance until 180 minutes (mean improvement at 180 minutes of 0.040 Kpa/L/s, 95% CI = 0.004 to 0.076; P = .02 for salbutamol and of 0.009 Kpa/L/s, 95% CI = -0.028 to 0.045; P = .98 for HBB for the resistance at 3 Hz and of 0.040 Kpa/L/s, 95% CI = 0.007 to 0.074; P = .01 for salbutamol and of 0.009 Kpa/L/s, 95% CI = -0.024 to 0.042; P = .97 for HBB for the reactance at 7 Hz). From 5 to 30 minutes after HBB administration, the heart rate accelerated (mean increase of 3.3 beats per minute, 95% CI = -6.6 to 13.1; P = .92 for salbutamol, and of 13.0 beats per minute, 95% CI = 3.6 to 22.4; P = .002 for HBB at 30 minutes) and the gut sounds decreased (mean reduction of 1.3, 95% CI = -0.1 to 2.8; P = .09 for salbutamol and of 2.8 for the gastrointestinal auscultation score, 95% CI = 1.4 to 4.3; P < .0001 for HBB at 30 minutes)., Conclusions and Clinical Importance: Both drugs have a similar bronchodilator potency but with a longer duration for salbutamol. Gastrointestinal and cardiovascular effects were noted only with HBB, suggesting the preferential use of salbutamol to relieve bronchoconstriction in horses with asthma., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Endometriosis is an immune chronic inflammatory disease, and there are currently no more effective drugs for treating endometriosis due to its unknown etiology. Salbutamol is a β2-adrenergic receptor (β2AR) agonist commonly used to treat asthma by selectively activating β2 receptors on airway smooth muscle and leukocytes, exerting bronchial dilation and synergistic anti-inflammatory effects. In recent years, β2AR agonists have been used in endometriosis studies, and we speculate that salbutamol may have a therapeutic effect on endometriosis. The purpose of this research was to explore the therapeutic effect of salbutamol on endometriosis mice. The mouse endometriosis model was established and treated with different doses of salbutamol. Endometrial lesions were harvested for pathological diagnosis, immunohistochemistry (IHC), Masson staining, and toluidine blue analysis. We found that the number and size of endometriotic lesions were all significantly decreased after 3 weeks of treatment with different doses of salbutamol on endometriosis model mice (P < 0.05). After Salbutamol treatment, the amount of mast cells (toluidine blue) and macrophages (F4/80) in the lesions as well as the expressions of interleukin (IL)-1β, tumor necrosis factor (TNF)-ɑ, platelet-derived growth factor subunit B (PDGFB), CD31, transforming growth factor (TGF)-β, Masson staining, BCL2, TUBB3, substance P (SP), and nerve growth factor (NGF) were significantly reduced (P < 0.05). These results suggested that salbutamol could effectively treat endometriosis in mice by reducing immune inflammatory cells and factors, angiogenesis, and fibrosis, increasing apoptosis of endometriotic lesions, and decreasing neurogenesis., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Background: In tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping., Methods: We performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO 2 ) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed., Results: Overall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV 1 ] = 103 ± 16% predicted; FEV 1 to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO 2 (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P < 0.05), but no change in symptoms or physical activity., Conclusions: Albuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression., Objective: The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients., Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160μg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μg on Day 1, 40μg on Day 2, 80μg on Days 3-7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests., Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2-AR effects were observed with clenbuterol., Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS.

Purpose: Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with chemotherapy, resulting in significant side-effects. We aimed to investigate if the dose of chemotherapeutic drugs could be diminished by co-administering it with the β2-agonist salbutamol., Methods: Cell proliferation was measured by thymidine incorporation; gene expression, by real-time PCR and protein phosphorylation by WB. Apoptosis was assessed by acridine orange / ethidium bromide and TUNEL tests. Public patient databases were consulted. Cells were inoculated to nude mice and their growth assessed., Results: The β 2 -agonist salbutamol synergizes in MDA-MB-231 cells in vitro with paclitaxel and doxorubicin on cell proliferation through ADRB2 receptors, while the β-blocker propranolol does not. The expression of this receptor was assessed in patient databases and other cell lines. Triple negative samples had the lowest expression. Salbutamol and paclitaxel decreased MDA-MB-231 cell proliferation while their combination further inhibited it. The pathways involved were analyzed. When these cells were inoculated to nude mice, paclitaxel and salbutamol inhibited tumor growth. The combined effect was significantly greater. Paclitaxel increased the expression of MDR1 while salbutamol partially reversed this increase., Conclusion: While the effect of salbutamol was mainly on cell proliferation, suboptimal concentrations of paclitaxel provoked a very important enhancement of apoptosis. The latter enhanced transporter proteins as MDR1, whose expression were diminished by salbutamol. The expression of ADRB2 should be assessed in the biopsy or tumor to eventually select patients that could benefit from salbutamol repurposing., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To compare the atomization efficacy of a novel micro-dose mesh nebulizer (CVS-100) versus the traditional mesh nebulizer (M102) in nebulizing a combination of ipratropium bromide and salbutamol for treatment of stable moderate-to-severe chronic obstructive pulmonary disease (COPD)., Methods: A randomized, parallel, non-inferiority study was conducted. A total of 64 stable COPD patients were randomly assigned to either the experimental group or the control group in a 1:1 ratio. Each the experimental group received nebulized Combivent (Compound Ipratropium Bromide Solution) with CVS-100, while the control group received Combivent with M102. Lung ventilation function was measured before and 30 min after nebulization, and the difference in percentage of forced expiratory volume in the first second (FEV1) of predicted value (FEV1%pred), the forced expiratory flow at 50% (FEF50%), the forced expiratory flow at 75% (FEF75%), the mid-expiratory flow (FEF25-75%), and maximal voluntary ventilation (MVV) was evaluated. The non-inferiority margin for the lower 95% confidence limit was set at 3.5%., Results: The lower limit of the 95% confidence interval for the difference in FEV1%pred between the two groups was -1.83357, which was greater than -3.5. No significant differences were found in FEF50%, FEF75%, FEF25∼75%, MVV before and after nebulization between the two groups., Conclusion: The novel micro-dose mesh nebulizer (CVS-100) was found to be non-inferior to the traditional mesh nebulizer (M102) in terms of the change in FEV1%pred from baseline after nebulization. Similar results were observed for all other measures of efficacy., Competing Interests: Declaration of competing interest All the authors declared there are no competing financial interests in relation to the work described., (Copyright © 2023. Published by Elsevier Ltd.)

We use enhanced-sampling simulations with an effective collective variable to study the activation of the β 2 -adrenergic receptor in the presence of ligands with different efficacy. The free-energy profiles are computed for the ligand-free ( apo ) receptor and binary ( apo -receptor + G-protein α-subunit and receptor + ligand) and ternary complexes. The results are not only compatible with available experiments but also allow unprecedented structural insight into the nature of GPCR conformations along the activation pathway and their role in the activation mechanism. In particular, the simulations reveal an unexpected mode of action of partial agonists such as salmeterol and salbutamol that arises already in the binary complex without the G-protein. Specific differences in the polar interactions with residues in TM5, which are required to stabilize an optimal TM6 conformation that facilitates G-protein binding and receptor activation, play a major role in differentiating them from full agonists.

Background: Albuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and bronchodilator drug response (BDR), no study has assessed whether albuterol could induce changes in the airway epithelial methylome. We aimed to characterize albuterol-induced DNAm changes in airway epithelial cells, and assess potential functional consequences and the influence of genetic variation and asthma-related clinical variables., Results: We followed a discovery and validation study design to characterize albuterol-induced DNAm changes in paired airway epithelial cultures stimulated in vitro with albuterol. In the discovery phase, an epigenome-wide association study using paired nasal epithelial cultures from Puerto Rican children (n = 97) identified 22 CpGs genome-wide associated with repeated-use albuterol treatment (p < 9 × 10 -8 ). Albuterol predominantly induced a hypomethylation effect on CpGs captured by the EPIC array across the genome (probability of hypomethylation: 76%, p value = 3.3 × 10 -5 ). DNAm changes on the CpGs cg23032799 (CREB3L1), cg00483640 (MYLK4-LINC01600), and cg05673431 (KSR1) were validated in nasal epithelia from 10 independent donors (false discovery rate [FDR] < 0.05). The effect on the CpG cg23032799 (CREB3L1) was cross-tissue validated in bronchial epithelial cells at nominal level (p = 0.030). DNAm changes in these three CpGs were shown to be influenced by three independent genetic variants (FDR < 0.05). In silico analyses showed these polymorphisms regulated gene expression of nearby genes in lungs and/or fibroblasts including KSR1 and LINC01600 (6.30 × 10 -14  ≤ p ≤ 6.60 × 10 -5 ). Additionally, hypomethylation at the CpGs cg10290200 (FLNC) and cg05673431 (KSR1) was associated with increased gene expression of the genes where they are located (FDR < 0.05). Furthermore, while the epigenetic effect of albuterol was independent of the asthma status, severity, and use of medication, BDR was nominally associated with the effect on the CpG cg23032799 (CREB3L1) (p = 0.004). Gene-set enrichment analyses revealed that epigenomic modifications of albuterol could participate in asthma-relevant processes (e.g., IL-2, TNF-α, and NF-κB signaling pathways). Finally, nine differentially methylated regions were associated with albuterol treatment, including CREB3L1, MYLK4, and KSR1 (adjusted p value < 0.05)., Conclusions: This study revealed evidence of epigenetic modifications induced by albuterol in the mucociliary airway epithelium. The epigenomic response induced by albuterol might have potential clinical implications by affecting biological pathways relevant to asthma., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Bronchial thermoplasty is an effective intervention to improve respiratory symptoms and to reduce the rate of exacerbations in uncontrolled severe asthma. A reduction in airway smooth muscle is arguably the most widely discussed mechanisms accounting for these clinical benefits. Yet, this smooth muscle reduction should also translate into an impaired response to bronchodilator drugs. This study was designed to address this question., Methods: Eight patients with clinical indication for thermoplasty were studied. They were uncontrolled severe asthmatics despite optimal environmental control, treatment of comorbidities, and the use of high-dose inhaled corticosteroids and long-acting β 2 -agonists. Lung function measured by spirometry and respiratory mechanics measured by oscillometry were examined pre- and post-bronchodilator (salbutamol, 400 μg), both before and at least 1 year after thermoplasty., Results: Consistent with previous studies, thermoplasty yielded no benefits in terms of baseline lung function and respiratory mechanics, despite improving symptoms based on two asthma questionnaires (ACQ-5 and ACT-5). The response to salbutamol was also not affected by thermoplasty based on spirometric readouts, including forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), and FEV 1 /FVC ratio. However, a significant interaction was observed between thermoplasty and salbutamol for two oscillometric readouts, namely reactance at 5 Hz (X rs5 ) and reactance area (Ax), showing an attenuated response to salbutamol after thermoplasty., Conclusions: Thermoplasty attenuates the response to a bronchodilator. We argue that this result is a physiological proof of therapeutic efficacy, consistent with the well-described effect of thermoplasty in reducing the amount of airway smooth muscle., Competing Interests: Declaration of competing interest YB's laboratory received funds from Boston Scientific Inc (25800$) to conduct this project. AC is funded partially by GlaxoSmithKline, and has received consulting fees and honoraria for lectures from AstraZeneca, Sanofi, GlaxoSmithKline, Regeneron and Valeo pharma. CH, SB, MB, KG, JC and ML declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Inhalation of hypertonic saline (HS) is standard of care in patients with cystic fibrosis (CF). However, it is unclear if adding salbutamol has-besides bronchodilation-further benefits, for example, on the mucociliary clearance. We assessed this in vitro by measuring the ciliary beating frequency (CBF) and the mucociliary transport rate (MCT) in nasal epithelial cells (NECs) of healthy volunteers and patients with CF. Aims: To investigate the effect of HS, salbutamol, and its combination on (muco)ciliary activity of NECs in vitro , and to assess potential differences between healthy controls and patients with CF. Methods: NECs obtained from 10 healthy volunteers and 5 patients with CF were differentiated at the air-liquid interface and aerosolized with 0.9% isotonic saline ([IS] control), 6% HS, 0.06% salbutamol, or combined HS and salbutamol. CBF and MCT were monitored over 48-72 hours. Results: In NECs of healthy controls, the absolute CBF increase was comparable for all substances, but CBF dynamics were different: HS increased CBF slowly and its effect lasted for an extended period, salbutamol and IS increased CBF rapidly and the effect subsided similarly fast, and HS and salbutamol resulted in a rapid and long-lasting CBF increase. Results for CF cells were comparable, but less pronounced. Similar to CBF, MCT increased after the application of all the tested substances. Conclusion: CBF and MCT of NECs of healthy participants and CBF of patients with CF increased upon treatment with aerosolized IS, HS, salbutamol, or HS and salbutamol, showing a relevant effect for all tested substances. The difference in the CBF dynamics can be explained by the fact that the properties of the mucus are changed differently by different saline concentrations.

Asthma is a heterogeneous chronic airway disease with an unmet need for improved therapeutics in uncontrolled severe disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor upregulated in asthma. The CaSR agonist, spermine, is also increased in asthmatic airways and contributes to bronchoconstriction. CaSR negative allosteric modulators (NAMs) oppose chronic airway inflammation, remodeling, and hyperresponsiveness in murine and guinea pig asthma models, but whether CaSR NAMs are effective acute bronchodilators compared with standard of care has not yet been established. Furthermore, the ability of different classes of NAMs to inhibit spermine-induced CaSR signaling or methacholine (MCh)-induced airway contraction has not been quantified. Here, we show CaSR NAMs differentially inhibit spermine-induced intracellular calcium mobilization and inositol monophosphate accumulation in HEK293 cells stably expressing the CaSR. NAMs reverse MCh-mediated airway contraction in mouse precision-cut lung slices with similar maximal relaxation compared with the standard treatment, salbutamol. Of note, the bronchodilator effects of CaSR NAMs are maintained under conditions of β 2 -adrenergic receptor desensitization when salbutamol efficacy is abolished. Furthermore, overnight treatment with some, but not all, CaSR NAMs prevents MCh-mediated bronchoconstriction. These findings further support the CaSR as a putative drug target and NAMs as alternative or adjunct bronchodilators in asthma.

Altered sensitivity to the chronotropic and inotropic effects of catecholamines and reduction in β 1 /β 2 -adrenoceptor (β 1 /β 2 -AR) ratio were reported in failing and in senescent human heart, as well as in isolated atria and ventricle of rats submitted to stress. This was due to downregulation of β 1 -AR with or without up-regulation of β 2 -AR., Aims: To investigate the stress-induced behavior of β 1 -AR in the heart of mice expressing a non-functional β 2 -AR subtype. The guiding hypothesis is that the absence of β 2 -AR signaling will not affect the behavior of β 1 -AR during stress and that those are independent processes., Materials and Methods: The chronotropic and inotropic responses to β-AR agonists in isolated atria of stressed mice expressing a non-functional β 2 -AR were analyzed. The mRNA and protein expressions of β 1 - and β 2 -AR were also determined., Key Findings: No deaths were observed in mice under stress protocol. Atria of stressed mice displayed reduced sensitivity to isoprenaline compared to the controls, an effect that was abolished by the β 2 - and β 1 -AR antagonists 50 nM ICI118,551 and 300 nM CGP20712A, respectively. Sensitivity and maximum response to the β-agonists dobutamine and salbutamol were not altered by stress or ICI118,551. The responses to dobutamine and salbutamol were prevented by CGP20712A. The expression of β 1 -AR was reduced at protein levels., Significance: Collectively, our data provide evidence that the cardiac β 2 -AR is not essential for survival in a stressful situation and that the stress-induced reduction of β 1 -AR expression was independent of the β 2 -AR presence., Competing Interests: Declaration of competing interest There are no conflicting interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: The pulse wave response to salbutamol (PWRS) - change in augmentation index (AIx) - provides a means to assess endothelial vasodilator function in vivo . Endothelial dysfunction plays a relevant role in the pathogenesis of hypertension and cardiovascular disease and appears to underlie many of the complications of coronavirus disease 2019 (COVID-19). However, to what degree this persists after recovery is unknown., Methods: Individuals previously hospitalized with COVID-19, those recovered from mild symptoms and seronegative controls with well known risk factors for endothelial dysfunction were studied. To assess the involvement of nitric oxide-cyclic guanosine monophosphate pathway (NO-cGMP) on PWRS, sildenafil was also administrated in a subsample., Results: One hundred and one participants (60 men) aged 47.8 ± 14.1 (mean ± SD) years of whom 33 were previously hospitalized with COVID-19 were recruited. Salbutamol had minimal effect on haemodynamics including blood pressure and heart rate. It reduced AIx in controls ( n  = 34) and those recovered from mild symptoms of COVID-19 ( n  = 34) but produced an increase in AIx in those previously hospitalized: mean change [95% confidence interval] -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % for controls, those recovered from mild symptoms and those previously hospitalized, respectively ( P  = 0.001). In a sub-sample ( n  = 22), sildenafil enhanced PWRS (change in AIx 0.05 [-2.15,2.24] vs. -3.96 [-7.01. -2.18], P  = 0.006) with no significant difference between hospitalized ( n  = 12) and nonhospitalized participants ( n  = 10)., Conclusions: In patients previously hospitalized with COVID-19, there is long-lasting impairment of endothelial function as measured by the salbutamol-induced stimulation of the NO-cGMP pathway that may contribute to cardiovascular complications., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of diseases. Several recently identified genes highlight the overlap between peripheral neuropathies and congenital myasthenic syndromes (CMS). The beta-2 adrenergic receptor agonist salbutamol has been shown to provide symptomatic benefit in CMS, while improving structural defects at the NMJ. Based on these findings, we identified cases of motor neuropathy with NMJ dysfunction and assessed the effect of salbutamol on motor function., Methods: Cases of motor neuropathy with significant NMJ dysfunction, were identified using repetitive nerve stimulation and single fibre electromyography. Oral salbutamol was administered for 12 months. Repeat neurophysiological and clinical assessments were undertaken at baseline, 6 months and 12 months., Results: Significant defects of neuromuscular transmission were identified in 15 patients harbouring a range of genetic defects, including mutations in GARS1, DNM2, SYT2 and DYNC1H. No clear benefit on motor function was seen following the administration of 12 months of oral salbutamol; however, there was a significant improvement in patient reported fatigue. In addition, no clear effect on neurophysiological parameters was seen in patients treated with salbutamol. Side-effects due to off-target beta-adrenergic effects were significant in the patient cohort., Conclusion: These results highlight the involvement of the NMJ in several subtypes of motor neuropathies, including subtypes of neuropathy due to deficits in mitochondrial fusion-fission, synaptic vesicle transport, calcium channels and tRNA synthetases. Whether the NMJ dysfunction is simply due to muscle reinnervation or a pathology unrelated to denervation is unknown. The involvement of the NMJ may represent a novel therapeutic target in these conditions. However, treatment regimens will need to be more targeted for patients with primary inherited defects of neuromuscular transmission., (© 2023. The Author(s).)

Purpose: To study the effect of inhaling a beta-agonist (salbutamol) compared to placebo on skiing and cycling performance in well-trained elite athletes., Methods: Three different exercise protocols were used, all with a cross-over double blind placebo-controlled design. Participants inhaled 800 µg salbutamol or a placebo prior to the test, which was repeated on a following day with the participants inhaling the other substance. Fifteen junior elite skiers performed four free-style high intensity sprints (1100 m/work time 3.5-4.5 min). Twelve elite cyclists carried out a short cycling protocol, starting with two 5 min submaximal workloads followed by a maximal intermittent performance test to exhaustion. Another 12 elite cyclists performed the maximal intermittent performance test to exhaustion after a 150 min long submaximal cycling protocol., Results: Group mean time for the ski sprints increased, with no difference between treatment groups. In the short cycling protocol time to exhaustion was 9.1% (95% CI 52-161) lower after inhaling salbutamol compared to placebo and in the long cycling protocol time to exhaustion was 9.1% (95% CI - 121-267) lower after inhaling salbutamol compared to placebo. Blood lactate, heart rate and ventilation increased during submaximal exercise with salbutamol compared to placebo in the short cycling protocol ( p  < .05)., Conclusion: This study could not confirm any positive performance effects from inhaling 800 µg salbutamol compared to placebo in skiing and high-intensity intermittent cycling performance. Instead, time to exhaustion in the maximal intermittent performance test was lower in both cycling protocols. Highlights There was no difference in performance time between salbutamol and placebo treatment in real-life applicable repeated ski sprints.Time to exhaustion in the maximal intermittent performance test was 9.1% lower after inhaling salbutamol compared to placebo, both when performed after 10 and 150 min of submaximal cycling.

We analyzed the fractal dimension (Df) of lung gas and blood distribution imaged with synchrotron radiation K-edge subtraction (KES), in six anesthetized adult New Zealand White rabbits. KES imaging was performed in upright position during stable Xe gas (64% in O 2 ) inhalation and iodine infusion (Iomeron, 350 mg/mL), respectively, at baseline and after induced bronchoconstriction by aerosolized methacholine (125 mg/mL, 90 s) and bronchodilator (salbutamol, 10 mg/mL, 90 s) inhalation, at two axial image levels. Lung Xe and iodine images were segmented, and maps of regional lung gas and blood fractions were computed. The Df of lung gas (Df Xe ) and blood (Df Iodine ) distribution was computed based on a log-log plot of variation coefficient as a function of region volume. Df Xe decreased significantly during bronchoconstriction ( P < 0.0001), and remained low after salbutamol. Df Iodine depended on the axial image level ( P < 0.0001), but did not change with bronchoconstriction. Df Xe was significantly associated with arterial [Formula: see text] ( R = 0.67, P = 0.002), and negatively associated with [Formula: see text] ( R = -0.62, P = 0.006), respiratory resistance ( R = -0.58, P = 0.011), and elastance ( R = -0.55, P = 0.023). These data demonstrate the reduced Df of gas distribution during acute bronchoconstriction, and the association of this parameter with physiologically meaningful variables. This finding suggests a decreased complexity and space-filling properties of lung ventilation during bronchoconstriction, and could serve as a functional imaging biomarker in obstructive airway diseases. NEW & NOTEWORTHY Here, we used an energy-subtractive imaging technique to assess the fractal dimension (Df) of lung gas and blood distribution and the effect of acute bronchoconstriction. We found that Df of gas significantly decreases in bronchoconstriction. Conversely, Df of blood exhibits gravity-dependent changes only, and is not affected by acute bronchoconstriction. Our data show that the fractal dimension of lung gas detects the emergence of clustered rather than scattered loss of ventilatory units during bronchoconstriction.

While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and responsible for noradrenergic activation. Therefore, we performed a randomized double-blinded crossover trial in young lean men to compare the effects of single intravenous bolus of the ADRB2 agonist salbutamol without and with the ADRB1/2 antagonist propranolol on glucose uptake by BAT, assessed by dynamic 2-[ 18 F]fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan (i.e., primary outcome). Salbutamol, compared with salbutamol with propranolol, increases glucose uptake by BAT, without affecting the glucose uptake by skeletal muscle and white adipose tissue. The salbutamol-induced glucose uptake by BAT positively associates with the increase in energy expenditure. Notably, participants with high salbutamol-induced glucose uptake by BAT have lower body fat mass, waist-hip ratio, and serum LDL-cholesterol concentration. In conclusion, specific ADRB2 agonism activates human BAT, which warrants investigation of ADRB2 activation in long-term studies (EudraCT: 2020-004059-34)., Competing Interests: Declaration of interests The authors declare no competing interests associated with this manuscript., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Bronchial asthma is one of the much known long-term respiratory conditions. Incidence is increasing, in developing countries like Bangladesh. Cross-sectional type of observational study was carried out over one year (July 2017 to June 2018) in the department of Pharmacology with collaboration of the department of Respiratory Medicine and Medicine, Mymensingh Medical College and Hospital, Mymensingh, Bangladesh. A total of 160 patients were selected non-randomly for the study. Inhalation route (52.35%) was the most preferred one over oral route (47.65%). In total 245 drugs, 131 FDC drugs (Salmeterol + Fluticasone) were prescribed with inhalation therapy which is 53.46%, another 9 FDC drugs that is (Ipratropium bromide + Salbutamol) were prescribed with inhalation therapy which is 3.67%, 101 drugs (Salbutamol) were prescribed with inhalation therapy that is 41.23%, 4 drugs (Beclomethasone) were prescribed with inhalation therapy that is 1.64%. Majority of patient were taking inhalation form of anti-asthmatic drugs.

Physiologically, β-adrenoceptors are major regulators of lipid metabolism, which may be reflected in alterations in lipid droplet dynamics. β-adrenoceptors have also been shown to participate in breast cancer carcinogenesis. Since lipid droplets may be seen as a hallmark of cancer, the present study aimed to investigate the role of β-adrenoceptors in the regulation of lipid droplet dynamics in MCF-7 breast cancer cells. Cells were treated for up to 72 h with adrenaline (an endogenous adrenoceptor agonist), isoprenaline (a non-selective β-adrenoceptor agonist) and salbutamol (a selective β 2 -selective agonist), and their effects on lipid droplets were evaluated using Nile Red staining. Adrenaline or isoprenaline, but not salbutamol, caused a lipid-accumulating phenotype in the MCF-7 cells. These effects were significantly reduced by selective β 1 - and β 3 -antagonists (10 nM atenolol and 100 nM L-748,337, respectively), indicating a dependence on both β 1 - and β 3 -adrenoceptors. These effects were dependent on the cAMP signalling pathway, involving both protein kinase A (PKA) and cAMP-dependent guanine-nucleotide-exchange (EPAC) proteins: treatment with cAMP-elevating agents (forskolin or 8-Br-cAMP) induced lipid droplet accumulation, whereas either 1 µM H-89 or 1 µM ESI-09 (PKA or EPAC inhibitors, respectively) abrogated this effect. Taken together, the present results demonstrate the existence of a β-adrenoceptor-mediated regulation of lipid droplet dynamics in breast cancer cells, likely involving β 1 - and β 3 -adrenoceptors, revealing a new mechanism by which adrenergic stimulation may influence cancer cell metabolism.

Background: The recommended delivery mode for bronchodilators in bronchodilator responsiveness (BDR) testing remains controversial., Objective: To compare the efficacy of salbutamol administration using a nebulizer versus a metered-dose inhaler (MDI) with spacer in BDR testing., Design: A retrospective study., Methods: This study examined the data of patients with chronic obstructive pulmonary disease who completed BDR testing between 1 December 2021 and 30 June 2022, at Xiangya Hospital, Central South University. After administering 400 μg of salbutamol through an MDI with spacer or 2.5 mg using a nebulizer, the changes in forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC) were analyzed in patients with moderate-to-very severe spirometric abnormalities [pre-bronchodilator FEV 1 percentage predicted values (FEV 1 %pred) ⩽59%]. Significant responsiveness was assessed as >12% and >200 mL improvement in FEV 1 and/or FVC or >10% increase in FEV 1 %pred or FVC percentage predicted values (FVC%pred) from pre- to post-bronchodilator administration., Results: Of the enrolled 894 patients, 83.2% were male (median age, 63 years). After propensity score matching, 240 pairs of patients were selected. The increment in FEV 1 and increased FEV 1 relative to the predicted value (ΔFEV 1 %pred) were significantly higher in patients <65 years and those with severe spirometric abnormalities in the nebulization group than patients in the MDI group (all p  < 0.05). Compared with MDI with spacer, patients who used nebulization had a 30 mL greater increase in ΔFEV 1 (95% CI: 0.01-0.05, p  = 0.004) and a 1.09% greater increase in ΔFEV 1 %pred (95% CI: 0.303-1.896, p  = 0.007) from baseline. According to the > 12% and >200 mL increase criterion, the significant BDR rate with nebulization was 1.67 times higher than that with an MDI with spacer (OR = 1.67, 95% CI: 1.13-2.47, p  = 0.009)., Conclusion: Salbutamol delivered using a nebulizer may be preferable to an MDI with spacer in certain circumstances. Nebulization has the potential to increase responsiveness to salbutamol in BDR testing.

The transient receptor potential vanilloid 4 (TRPV4) ion channel is present in different tissues including those of the airways. This channel is activated in response to stimuli such as changes in temperature, hypoosmotic conditions, mechanical stress, and chemicals from plants, lipids, and others. TRPV4's overactivity and/or dysfunction has been associated with several diseases, such as skeletal dysplasias, neuromuscular disorders, and lung pathologies such as asthma and cardiogenic lung edema and COVID-19-related respiratory malfunction. TRPV4 antagonists and blockers have been described; nonetheless, the mechanisms involved in achieving inhibition of the channel remain scarce, and the search for safe use of these molecules in humans continues. Here, we show that the widely used bronchodilator salbutamol and other ligands of β-adrenergic receptors inhibit TRPV4's activation. We also demonstrate that inhibition of TRPV4 by salbutamol is achieved through interaction with two residues located in the outer region of the pore and that salbutamol leads to channel closing, consistent with an allosteric mechanism. Our study provides molecular insights into the mechanisms that regulate the activity of this physiopathologically important ion channel., (© 2022 Benítez-Angeles et al.)

Background: In children, obesity typically reduces functional residual capacity (FRC), which reduces airway caliber and increases airway resistance. Whether these obesity-related changes in respiratory function can alter bronchodilator responsiveness is unknown., Objective: To investigate bronchodilator responsiveness in nonasthmatic children with and without obesity., Methods: Seventy nonasthmatic children, 8-12 years old, without (n = 19) and with (n = 51) obesity, completed spirometry, impulse oscillometry, and airway resistance measurements through plethysmography pre/post 360 µg of inhaled albuterol. FRC was assessed pre albuterol. A two-way analysis of variance determined the effects of obesity (group) and inhaled albuterol (pre-post) on outcome measures., Results: FRC (%total lung capacity) was 16% lower in children with obesity compared with those without obesity. There was no significant group by pre-post albuterol interaction on any outcome variables. Albuterol inhalation reduced total, central and peripheral airway resistance and increased airway reactance (i.e., less negative) to a similar degree in children with and without obesity. In children with obesity, airway resistance was increased whether measured by impulse oscillometry or plethysmography. However, once airway resistance was adjusted for lung volumes (i.e., specific airway resistance or sR aw ), there were no differences between children with and without obesity. In addition, significant but moderate associations were detected between chest mass and FRC (r = -0.566; p < 0.001), FRC and total airway resistance (i.e., R aw ; r = -0.445; p < 0.001)., Conclusions: In nonasthmatic early pubescent children, obesity increases total, central, and peripheral respiratory system resistance. However, the added respiratory system resistance and low lung volume breathing with obesity are not sufficient to reduce bronchodilator responsiveness., (© 2022 Wiley Periodicals LLC.)

The outcomes of ulcerative colitis (UC) treatment remain unsatisfactory. Salbutamol is a β2-adrenergic receptor (β2AR) agonist that is frequently used to treat human airway diseases, and it is a chiral drug with (RS)-isomers. However, the effects of (RS)-enantiomers of this drug on acute ulcerative colitis remain unknown. The present work determined and compared the effects of different chiral β2AR agonists in acute colitis. Acute colitis was established in mice with 3% dextran sulfate sodium and the mice were orally administered different salbutamol isomers. Body weight loss, colon length, disease activity index (DAI), and colon histopathology were assessed. Inflammatory cytokine levels were detected by ELISA. Colonic biopsies were collected from colitis patients. 16S rDNA amplicon sequencing was carried out to assess the composition and relative abundance of the gut microbiome. The expression of M1 and M2 macrophage markers in the colon were assessed by immunofluorescence staining and Western blotting. The results revealed that (R)-salbutamol prevented body weight loss and colonic shortening, decreased the DAI and histopathological scores, and reduced splenomegaly and inflammatory cytokine levels significantly better than (RS)-salbutamol and (S)-salbutamol. (R)-salbutamol downregulated levels of inflammatory protein in LPS-induced human colon tissue specimens. Furthermore, (R)-salbutamol ameliorated gut dysbiosis and macrophage polarization in mice with colitis. The β2AR antagonist ICI-118551 reversed the effect of (R)-salbutamol in ameliorating acute colitis. Taken together, (R)-salbutamol ameliorated the mice with acute colitis, which can serve as a new candidate or lead compound for UC treatment., (Copyright © 2022. Published by Elsevier B.V.)

We studied contractile responses of isolated airway smooth muscle segments from rats with metabolic syndrome. Metabolic syndrome was induced in rats by high-fat and high-carbohydrate diet. It was shown that metabolic syndrome was associated with an increase of bronchoconstrictor action of cholinergic receptor activator carbacholine (0.1-100 μM) and a decrease of the dilatory effect of β 2 -adrenoreceptor activator salbutamol (0.1-100 μM). The observed effects of agonists are epithelium-dependent. Disorders in contractile activity in the airway smooth muscles were accompanied by bronchial epithelium destruction, immune inflammation in the bronchial wall, muscular and peribronchial adipose tissue hypertrophy., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Standard spirograms are widely used in the respiratory disease management community to help diagnosis asthma and provide longitudinal information. Surprisingly, basic information obtained on the spirogram, beyond the FEV 1 and change in FEV 1 after bronchodilator is underutilized. We reviewed information on pulmonary function and bronchodilator response in children since 2016. We present here a discussion of other element of the standard spirogram that can be used for pediatric asthma management. Methods: Medline search of pulmonary function, children, adolescents, bronchodilator reversibility, small airway disease, small airway function, asthma, airflow limitation, bronchodilator response. Studies since 2016 that provide information on normal or asthmatic children bronchodilator response, and/or small airway or pulmonary function values after albuterol., Results: Limited data has been published on FEV 1 bronchodilator response in children since 2016. Other parameters of the pulmonary function test in children have had recent documentation., Conclusions: New data on FEV 1 bronchodilator response in normal children is limited since 2016. However, other details of pulmonary function interpretation in asthmatic children has had considerable attention, and are reviewed here.

Purpose: In patients with chronic obstructive pulmonary disease (COPD), bronchial responsiveness after acute administration of short acting bronchodilators is conventionally assessed by measuring the improvement of forced expiratory volume in the first second (FEV 1 ) during a maximal forced expiratory maneuver. This study aimed to measure the variation of intrathoracic airway wall compliance (AWC) after acute administration of short acting beta-2 agonist in COPD patients since this might influence the final modification of airway caliber during maximal expiratory effort and the resulting bronchodilation as inferred by FEV 1 changes., Methods: In a group of 10 patients suffering from COPD, intrathoracic AWC was measured at middle (50% of Forced Vital Capacity (FVC) and low (75% of FVC) lung volumes using the interrupter method during forced expiratory maneuver in basal conditions and after acute inhalation of albuterol (salbutamol) (400 mcg by MDI). Ten healthy subjects were examined similarly as a control group., Results: Lower values of baseline intrathoracic AWC at both lung volumes were found in COPD patients (1.72 ± 0.20 ml/cmH 2 O and 1.08 ± 0.20 ml/cmH 2 O, respectively) as compared to controls (2.28 ± 0.27 ml/cmH 2 O and 1.44 ± 0.22 ml/cmH 2 O, respectively) (p < 0.001). In COPD patients, AWC increased significantly at both lung volumes after salbutamol, amounting to 1.81 ± 0.38 ml/cmH 2 O and 1.31 ± 0.39 ml/cmH 2 O, respectively (p < 0.01), but the relative change was not different from that observed in controls., Conclusion: In COPD patients, AWC is reduced compared to controls, but after bronchodilator, the intrathoracic airways become more compliant. The consequent increased collapsibility under high positive pleural pressure could limit the airway caliber improvement seen after bronchodilator, as assessed by the FEV 1 changes during the forced expiratory maneuver, underestimating the effective bronchodilation achieved in these patients., (© 2022. The Author(s).)

Objective: Several tissues produce and release interleukin-6 (IL-6) in response to beta 2 -adrenergic stimulation with selective agonists (beta 2 -agonists). Moreover, exercise stimulates muscle IL-6 production, but whether beta 2 -agonists regulate skeletal muscle production and release of IL-6 in humans in association with exercise remains to be clarified. Thus, we investigated leg IL-6 release in response to beta 2 -agonist salbutamol in lean young men at rest and in recovery from resistance exercise., Design: The study employed a randomized controlled crossover design, where 12 men ingested either salbutamol (16 mg) or placebo for 4 days, followed by the last dose (24 mg) administered 1½ h before exercise. Arterial and femoral venous plasma IL-6 as well as femoral artery blood flow was measured before and ½-5 h in recovery from quadriceps muscle resistance exercise. Furthermore, vastus lateralis muscle biopsies were collected ½ and 5 h after exercise for determination of mRNA levels of IL-6 and Tumor Necrosis Factor (TNF)-α., Results: Average leg IL-6 release was 1.7-fold higher (p = 0.01) for salbutamol than placebo, being 138 ± 76 and 79 ± 66 pg min -1 (mean ± SD) for salbutamol and placebo, respectively, but IL-6 release was not significantly different between treatments within specific sampling points at rest and after exercise. Muscle IL-6 mRNA was 1.5- and 1.7-fold higher (p = 0.001) for salbutamol than placebo ½ and 5 h after exercise, respectively, whereas no significant treatment differences were observed for TNF-α mRNA., Conclusions: Beta 2 -adrenergic stimulation with high doses of the selective beta 2 -agonist salbutamol, preceeded by 4 consecutive daily doses, induces transcription of IL-6 in skeletal muscle in response to resistance exercise, and increases muscle IL-6 release in lean individuals., (© 2022 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Impairment of oxygen uptake can occur during general anesthesia in horses resulting in hypoxemia. Multiple treatments have been investigated for correction of hypoxemia with varying levels of success. In clinical trials, albuterol, a short-acting β 2 adrenergic agonist, improved arterial oxygen partial pressure (PaO 2 ) in anesthetized horses unresponsive to adjustments in mechanical ventilation and administration of positive inotropic drugs. However, controlled studies comparing the magnitude of change and duration of effect of albuterol on PaO 2 in healthy, nonhypoxemic anesthetized horses are lacking. In a prospective study, 14 horses were anesthetized and received a FiO 2 of 0.5 (n = 7) or > 0.95 (n = 7). Horses were maintained on isoflurane and mechanically ventilated. After 15 minutes, baseline PaO 2 was determined. Within each FiO 2 group, five horses were administered inhaled albuterol (2 µg/kg) and two horses received no treatment. At 10, 20, 30, and 40 minutes after baseline, PaO 2 was measured. Data for horses that received albuterol were analyzed with repeated measures analysis of variance with significance at P < .05. Horses that received albuterol had an increase in PaO 2 for at least 40 minutes after baseline. Albuterol administered via inhalation, was associated with an increased PaO 2 of at least 40 minutes compared to baseline in healthy, nonhypoxemic horses undergoing anesthesia at similar depth, using a FiO 2 of 0.5 and > 0.95. Side effects were mild and consisted of increased heart rate and sweating. Albuterol administered at 2 μg/kg via inhalation may be useful for increasing PaO 2 in anesthetized horses., (Copyright © 2022. Published by Elsevier Inc.)

Racemic salbutamol ((RS)-sal), which consist of the same amount of (R)-sal and (S)-sal, has been used for asthma and COPD due to its bronchodilation effect. However, the effect of (R)-sal on repeated dextran sulfate sodium (DSS)-induced chronic colitis has not yet been investigated. In this study evaluated the potential effect of (R)-, (S)-, and (RS)-sal in mice with repeated DSS-induced chronic colitis and investigated the underlying mechanisms. Here, we verified that chronic colitis was significantly attenuated by (R)-sal, which was evidenced by notably mitigated body weight loss, disease activity index (DAI), splenomegaly, colonic lengths shortening, and histopathological scores. (R)-sal treatment noticeably diminished the levels of inflammatory cytokines (such as TNF- α , IL-6, IL-1 β , and IFN- γ ). Notably, the efficacy of (R)-sal was better than that of (RS)-sal. Further research revealed that (R)-sal mitigated colonic CD4 leukocyte infiltration, decreased NF- κ B signaling pathway activation, improved the Nrf-2/HO-1 signaling pathway, and increased the expression of ZO-1 and occludin. In addition, (R)-sal suppressed the levels of TGF- β 1, α -SMA, and collagen in mice with chronic colitis. Furthermore, the 16S rDNA sequences analyzed of the intestinal microbiome revealed that (R)-sal could mitigate the intestinal microbiome structure and made it more similar to the control group, which mainly by relieving the relative abundance of pathogens (such as Bacteroides) and increasing the relative abundance of probiotics (such as Akkermansia). Therefore, (R)-sal ameliorates repeated DSS-induced chronic colitis in mice by improving inflammation, suppressing oxidative stress, mitigating intestinal barrier function, relieving intestinal fibrosis, and regulating the intestinal microbiome community. These results indicate that (R)-sal maybe a novel treatment alternative for chronic colitis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Liangjun Deng et al.)

Objective: To determine the effect of anti-asthmatic inhalers salbutamol and budesonide on the surface microhardness of bovine tooth enamel., Materials and Methods: The study was experimental, prospective, longitudinal, and comparative. The sample consisted of permanent mandibular incisors, which were prepared in ( n = 90) blocks of dental enamel of size 3 × 3 mm and 2 mm thick, separated into 6 groups of 15 specimens each in sterile bottles properly labeled and contained in artificial saliva at 37°C. Three measurements (baseline, 5 days, and 10 days) were performed after immersion to determine the microhardness using a Vickers microdurometer programmed to apply a load of 100 gm for 15 seconds., Results: It was observed that the enamel surface microhardness decreased after 5 and 10 days, after being in contact with the anti-asthmatic inhalers based on salbutamol and budesonide. In addition, it was evidenced that there is a greater decrease in the superficial microhardness of the enamel when comparing the values at the beginning and after 10 days; likewise, the reduction in the microhardness of enamel exposed to budesonide was greater (120.8 kg/mm 2 ) compared to salbutamol (112.3 kg/mm 2 ) ( p <0.001)., Conclusion: The two anti-asthmatic inhalers studied decreased superficial enamel microhardness, with the budesonide-based inhaler having a greater erosive effect., Clinical Significance: This research allowed us to know the values of the microhardness of the superficial enamel after being exposed to different anti-asthmatic inhalers that are indicated in daily clinical practice. Therefore, it is important to evaluate this microhardness since the use of different inhalers is very prevalent.

Moderate elevations of extracellular K + concentration ([K + ] o ) occur during exercise and have been shown to potentiate force during contractions elicited with subtetanic frequencies. Here, we investigated whether lactic acid (reduced chloride conductance), β 2 -adrenoceptor activation, and increased temperature would influence the potentiating effect of potassium in slow- and fast-twitch muscles. Isometric contractions were elicited by electrical stimulation at various frequencies in isolated rat soleus and extensor digitorum longus (EDL) muscles incubated at normal (4 mM) or elevated K + , in combination with salbutamol (5 μM), lactic acid (18.1 mM), 9-anthracene-carboxylic acid (9-AC; 25 μM), or increased temperature (30-35°C). Elevating [K + ] o from 4 mM to 7 mM (soleus) and 10 mM (EDL) potentiated isometric twitch and subtetanic force while slightly reducing tetanic force. In EDL, salbutamol further augmented twitch force (+27 ± 3%, P < 0.001) and subtetanic force (+22 ± 4%, P < 0.001). In contrast, salbutamol reduced subtetanic force (-28 ± 6%, P < 0.001) in soleus muscles. Lactic acid and 9-AC had no significant effects on isometric force of muscles already exposed to moderate elevations of [K + ] o . The potentiating effect of elevated [K + ] o was still well maintained at 35°C. Addition of salbutamol exerts a further force-potentiating effect in fast-twitch but not in slow-twitch muscles already potentiated by moderately elevated [K + ] o , whereas lactic acid, 9-AC, or increased temperature does not exert any further augmentation. However, the potentiating effect of elevated [K + ] o was still maintained in the presence of these, thus emphasizing the positive influence of moderately elevated [K + ] o for contractile performance during exercise.

Purpose: Relvar® (fluticasone furoate [FF]/vilanterol [VI]) is a once-daily inhaler with bronchodilator effect lasting 24 h. Our aim was to investigate the short- and long-term effects of FF/VI on exercise-induced asthma (EIA) in adolescents., Methods: Ninety-three adolescent asthmatics aged 12-18 years were referred for evaluation of EIA. Following a positive exercise challenge test (ECT), 22/44 were allocated to a single administration of salbutamol (400 μg) and 22/44 to FF/VI (92/22 μg) in a double-blind method. Thirty-five subjects were reassessed by repeat ECT 30-60 days of FF/VI., Results: Median FEV 1 change post-ECT at baseline was -22.8% predicted (interquartile range [IQR] -26.1 and -18.0) for salbutamol and -21.0 (IQR -30.7 and -16.8) for FF/VI. Following bronchodilator, FEV 1 improved similarly in both groups. Repeat ECT following 30-60 days of FF/VI resulted in negative ECT in 33/35 subjects; the median decrease in FEV 1 of these 35 subjects was 22.6% predicted (IQR 29-18) before, and 4.6% predicted (IQR 8.7-2.5) after 30-60 days of FF/VI treatment (p < 0.0001)., Conclusions: FF/VI is effective in reversing EIA after 15 min in adolescents and in protecting EIA after 30-60 days in adolescents. Larger studies are needed to assess the effect of FF/VI on EIA., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

We have compared the prophylactic efficacies of quercetin and salbutamol in preventing pulmonary surfactants oxidation under hypoxia. Male SD rats supplemented orally with quercetin (50 mg/Kg BW) and salbutamol (2 mg/Kg BW) were exposed to hypobaric hypoxia (7,620 m for 6 h). Hypoxia-mediated elevation in oxidative stress, inflammation, and extravasations of LDH & albumin content in BALF of rats were assessed. Western blotting and mRNA studies determined the differential expressions of Nrf-2, HO-1, and associated surfactant proteins (SP-A, SP-B, SP-C, & SP-D) in rat lungs. Later, the lung configuration under hypoxia was assessed histopathologically. Quercetin and salbutamol pretreatment considerably restored the expressions of Nrf-2, HO-1, and surfactant proteins to normal by attenuating the increase in oxidative stress, inflammation, and extravasations of plasma proteins in the animals under hypoxia. The histopathology has also evidenced the protective effect of quercetin in retaining normal lung architecture under hypoxia over salbutamol. The present study indicates the effectiveness of quercetin prophylaxis in preventing pulmonary surfactants oxidation under hypoxia over salbutamol., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease, initiated by delayed retinal vascular growth after premature birth. In the majority of cases, ROP resolves spontaneously; however, a history of ROP may increase the risk of long-term visual problems. In this study, we evaluated the endothelial function of retinal blood vessels in adult rats with a history of ROP. ROP was induced in rats by subcutaneous injection of a vascular endothelial growth factor receptor tyrosine kinase inhibitor (KRN633) on postnatal day (P) 7 and P8. On P56, vasodilator responses to acetylcholine, GSK1016790A (an activator of transient receptor potential vanilloid 4 channels), NOR3 (a nitric oxide [NO] donor), and salbutamol (a β 2 -adrenoceptor agonist) were assessed. Compared to age-matched controls, retinal vasodilator responses to acetylcholine and GSK1016790A were attenuated in P56 rats with a history of ROP. No attenuation of acetylcholine-induced retinal vasodilator response was observed under inhibition of NO synthase. Retinal vasodilator responses to NOR3 and salbutamol were unaffected. These results suggest that the production of and/or release of NO is impaired in retinal blood vessels in adult rats with a history of ROP. A history of ROP might increase the risk of impaired retinal circulation in adulthood., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interest in this study., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Currently, there are no regulatory guidelines indicating spacer devices/valved holding chamber (VHC) should be used routinely during pulmonary function tests, and few studies evaluated if spacer devices reduce beta-agonist bronchodilators' side effects. Methods: A prospective study compared salbutamol's cardiovascular effects and bronchodilation response during spirometry tests with and without a spacer device/VHC. Heart rate (HR), the corrected QT interval (QTc), and systolic and diastolic blood pressure were measured 10 minutes after the first spirometry test, before the drug administration, and 20 minutes after inhalation in both groups. Spirometric parameters (forced expiratory volume in the first second [FEV1], forced vital capacity [FVC], and FEV1/FVC) were also measured for both groups. Results: HR and QTc increase were significantly higher in the pressurized meter dose inhalers alone group versus the VHC group [mean SD] [73.1 ± 10 bpm to 74.3 + 10 bpm, p  = 0.021] and [median (25%-75% interquartile range)] [389 ms (381-404) to 398 ms (387-407), p  = 0.045] vs. [mean SD] [75.4 ± 9 to 73.8 + 8 bpm, p  = 0.4] and [median (25%-75% interquartile range)] [388 ms (347-408) to 385 ms (366-408), p  = 0.35], respectively. FEV1 variation before and after salbutamol were similar between both groups. Discussion: Although VHC significantly reduces HR and QTc variation when using beta-agonist bronchodilators in healthy patients, no clinical repercussions of this variation were found in this study, since no event of tachycardia or pathological QTc was recorded. Conclusion: VHC has a diminished clinical impact for healthy patients when considering cardiovascular effects and spirometric parameters. Beta-agonist bronchodilators may be administrated despite the use of spacer devices in patients without known cardiovascular diseases. Its significance for other populations still needs to be determined.

The thiazide-sensitive sodium-chloride-cotransporter (NCC) in the kidney distal convoluted tubule (DCT) plays an essential role in sodium and potassium homeostasis. Here, we demonstrate that NCC activity is increased by the β2-adrenoceptor agonist salbutamol, a drug prevalently used to treat asthma. Relative to β1-adrenergic receptors, the β2-adrenergic receptors were greatly enriched in mouse DCT cells. In mice, administration of salbutamol increased NCC phosphorylation (indicating increased activity) within 30 minutes but also caused hypokalemia, which also increases NCC phosphorylation. In ex vivo kidney slices and isolated tubules, salbutamol increased NCC phosphorylation in the pharmacologically relevant range of 0.01-10 μM, an effect observed after 15 minutes and maintained at 60 minutes. Inhibition of the inwardly rectifying potassium channel (Kir) 4.1 or the downstream with-no-lysine kinases (WNKs) and STE20/SPS1-related proline alanine-rich kinase (SPAK) pathway greatly attenuated, but did not prevent, salbutamol-induced NCC phosphorylation. Salbutamol increased cAMP in tubules, kidney slices and mpkDCT cells (model of DCT). Phosphoproteomics indicated that protein phosphatase 1 (PP1) was a key upstream regulator of salbutamol effects. A role for PP1 and the PP1 inhibitor 1 (I1) was confirmed in tubules using inhibitors of PP1 or kidney slices from I1 knockout mice. On normal and high salt diets, salbutamol infusion increased systolic blood pressure, but this increase was normalized by thiazide suggesting a role for NCC. Thus, β2-adrenergic receptor signaling modulates NCC activity via I1/PP1 and WNK-dependent pathways, and chronic salbutamol administration may be a risk factor for hypertension., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Asthma is the most common chronic disorders of the respiratory tract. This study aimed to evaluate the effect of low-molecular-weight heparins (LMWHs) in the treatment of acute asthma., Methods: In this randomized clinical trial, patients with acute asthma attacks were enrolled. The patients were divided randomly into two groups. Patients in the intervention group received nebulized LMWH (1 mg/kg) with albuterol (2.5 mg) every 20 min for 10 min. The patients in the control group received nebulized albuterol with the same dose. Then peak expiratory flow rates (PEFR) and forced expiratory volume in 1 s (FEV1), and hemodynamic parameters in both groups were assessed for every 20 min., Results: In total 70 patients enrolled in this study. We found that the mean PEFR at 40 min was higher in the LMWH group than the control group (202.51 L/min and 180.2 L/min) (p = 0.001). Moreover, this difference remains significant in the 60th minute (p < 0.001). Further, FEV1 was significantly higher in the LMWH group after 60 min (1.82 L/min vs 1.48 L/min, p < 0.001). Moreover, we found that the hemodynamic parameters were sustainable in the intervention group., Conclusion: The study suggests that LMWH in mild-moderate asthma attacks may be beneficial in the short term and could be prescribed in addition to standard albuterol therapy., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The aim of this study was to investigate and discuss the salbutamol combined with budesonide in treatment of pediatric bronchial asthma (BA) and its effect on eosinophils (EOS)., Methods: Ninety-eight BA children admitted and treated in our hospital from July 2016 to June 2017 were collected and divided into control group (N.=49) and observation group (N.=49) according to random number table. The children in control group were treated with budesonide and those in observation group were treated with salbutamol combined with budesonide. The clinical efficacy, pulmonary functions and levels of T-lymphocyte subsets (including cluster of differentiation 3 (CD3)+, CD4+, CD8+ and CD4+/CD8+) in the immune system between two groups were compared after the treatment; the levels of eosinophil cationic protein (ECP) and eotaxin in the children were compared before the treatment and at 1, 4 and 8 weeks after the treatment; the changes in EOS counts in blood and induced sputum of the children before and after the treatment were compared, and the EOS apoptosis rate was compared at 1, 4 and 8 weeks after the treatment., Results: The effective rate of treatment in observation group was significantly higher than that in control group (P<0.05). After the treatment, the indexes of pulmonary function in observation group were obviously better than those in control group (P<0.05). Compared with those in control group, the levels of CD3+, CD4+ and CD4+/CD8+ of the children in observation group were elevated remarkably, while the CD8+ level was lowered (P<0.05). The levels of ECP and eotaxin in the two groups were decreased after the treatment compared with those before the treatment, and the levels in observation group were superior to those in control group (P<0.05). After the treatment, the EOS counts of both groups of children were lower than those before the treatment, and the decrease in observation group was more notable than that in control group. At 1, 4 and 8 weeks after the treatment, the EOS apoptosis rate in observation group was obviously higher than that in control group (P<0.05)., Conclusions: The treatment of salbutamol combined with budesonide for pediatric BA has significant therapeutic effects; it can restore the pulmonary functions rapidly and improve the immunity of the lung, reduce the levels of eotaxin, ECP and EOS of the child patients and promote EOS apoptosis.

Treatment with β2-agonists may cause elevated lactic acid, the end product of anaerobic metabolism of glucose. It has been proposed that lactic acidosis associated with β2-agonists is caused by changes to direct biochemical impacts on glycolysis, gluconeogenesis, pyruvate metabolism, and free fatty acid production. However, much remains unknown, and there is a paucity of evidence regarding the underlying chemical changes associated with this lactic acidosis. The goal of our study was to investigate the impact of 1 hour of continuous albuterol on the untargeted serum metabolome of healthy subjects. Twenty-four healthy participants received 7.5 mg of continuous albuterol for 1 hour. Baseline, 1-hour, and 2-hour lactic acid levels were drawn. Samples obtained at baseline and 1 hour were sent for untargeted metabolomic profiling. Participants had a baseline lactic acid of 1.45 ± 0.46 mmol/L. On average, lactate levels increased 0.33 ± 0.67 mmol/L after 1 hour (P = .02) and remained elevated at 2 hours (0.32 ± 0.72 mmol/L, P = .02), although there was overlap in lactate levels across times. For metabolomic analysis, fatty acids, organic acids, and sugars were elevated, and amino acids were reduced. Lactic acid and pyruvic acid metabolites, however, did not significantly change (after false discovery rate adjustment). In healthy participants, continuous albuterol alters the serum metabolome, but this change may not be clinically significant. The data support recent hypotheses that β2-receptor activation stimulates lactic acid production, altering aerobic glycolysis, gluconeogenesis, and free fatty acid production., (© 2020, The American College of Clinical Pharmacology.)

Objective. Asthma is a chronic inflammatory airway disorder known to induce small airways dysfunction (SAD). It is important to develop tools to assess the presence and extent of SAD in daily clinical practice. An Impulse Oscillometry System (IOS) might detect SAD, but the validity of the underlying model (serial Resistive airway and Compliant tissue model: RC model) in diseased lungs remains questionable. Methods. Our objective was to evaluate the usefulness of parameters obtained from six electrical circuit models that were fitted to the measurements of impedance obtained with IOS in asthmatic children characterized by an abnormal lung function defined by an increased baseline interrupter resistance (Rint, z-score > +1.645). Results. The six models were tested in 102 asthmatic children (median age: 5.5 years). Two models allowed the description of 92/102 (90%) children: 74 by the extended RIC model (central and peripheral Resistance, Inertance and peripheral airway Compliance) and 18 by the Mead 1969 model (extended RIC plus lung compliance). Thus, peripheral airway compliance and resistance were essential to describe lung function abnormalities of these asthmatic children. Parenchyma impairment (increased lung compliance) which was responsive to salbutamol was present in 18% of asthmatic children. After salbutamol, peripheral airway resistance decreased while peripheral airway compliance increased, arguing for asthma-related SAD. R5-20Hz independently correlated with the two latter parameters but was increased in two thirds of children with increased Rint only. Conclusion. Additional modeling of IOS results can be a reliable tool to assess the presence and extent of SAD in young asthmatic children.

Forced mid-expiratory flow (i.e., isoFEF 25-75 ) may increase with a short-acting β 2 -agonist in nonasthmatic children without bronchodilator responsiveness. This could also increase estimated ventilatory capacity along mid-expiration (V̇Ecap 25-75 ), especially in vulnerable children with obesity who exhibit altered breathing mechanics. We estimated V̇Ecap 25-75 pre- and post-albuterol treatment in 8-12yo children without (n = 28) and with (n = 46) obesity. A two-way ANOVA was performed to determine effects of an inhaled bronchodilator (pre-post) and obesity (group) on isoFEF 25-75 and V̇Ecap 25-75 . There was no group by bronchodilator interaction or main group effect on outcome variables. However, a significant main effect of the bronchodilator was detected in spirometry parameters, including a substantial increase in isoFEF 25-75 (17.1 ± 18.0 %) and only a slight (non-clinical) but significant increase in FEV 1 (2.4 ± 4.3 %). V̇Ecap 25-75 significantly increased with albuterol (+11.7 ± 10.6 L/min; +15.8 ± 13.9 %). These findings imply potentially important increases in ventilatory reserve with a bronchodilator in nonasthmatic children without and with obesity, which could potentially influence respiratory function at rest and during exercise., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Objective: Non-selective beta-blockers impair the bronchodilator response to beta 2 -agonists. Cardio-selective beta 1 -blockers are less likely to cause this effect, yet they remain relatively contraindicated in asthma. We investigated whether the response to salbutamol is impaired during cardio-selective beta 1 -blocker treatment in people with asthma., Methods: A random-order, double-blind, placebo-controlled, non-inferiority, crossover study was conducted comparing up to 5 mg bisoprolol daily for 2 weeks with matching placebo, with an open-label extension of up to 10 mg bisoprolol daily. After each treatment period, mannitol was inhaled to induce bronchoconstriction with a 15% fall in forced expiratory volume in 1 s (FEV 1 ). Immediately after mannitol challenge, salbutamol (100, 100 and 200 μg) was administered via spacer at 5-min intervals with repeated FEV 1 measures. The FEV 1 recovery with salbutamol was measured as an area under recovery curve (AUC). Based on earlier research, a clinically relevant non-inferiority limit of a 30% reduction in the AUC was set., Results: A total of 19 adults with mild asthma and positive inhaled mannitol challenge completed the study. Adjusting for the FEV 1 fall induced by mannitol and treatment sequence, the mean AUC response to salbutamol after bisoprolol was 5% lower than after placebo, with a one-sided 95% confidence interval (CI) of 26% lower. Thirteen participants completed the open-label extension up to 10 mg bisoprolol daily with mean AUC 11% higher after bisoprolol with a 95% CI of 5% lower., Conclusion: The bronchodilator response to rescue salbutamol after mannitol-induced bronchoconstriction is non-inferior during regular treatment with the cardio-selective beta 1 -blocker, bisoprolol, compared to placebo., Clinical Trial Registration: ACTRN12618000306213 at https://www.anzctr.org.au., (© 2020 Asian Pacific Society of Respirology.)

The adipokine, leptin exerts inhibitory effect on both spontaneous and oxytocin-induced contractions in myometrium. However, the mechanisms involved in leptin-induced effect are not clear. In the present study, we studied the altered characteristics of uterine contractions in the presence of leptin and the possible mechanisms of its effect in late pregnant (18.5 day) mouse uterus. We conducted functional, biochemical and molecular biology studies to demonstrate the mechanism of leptin-induced response. Leptin exerted an inhibitory response (E max 40.5 ± 3.99%) on basal uterine contractions. The extent of inhibition was less than that obtained with known uterine relaxants, salbutamol (E max 103 ± 8.66%) and BRL-37344 (E max 84.79 ± 8.12%). Leptin-induced uterine response was inhibited by leptin receptor antagonist SHLA and JAK-STAT pathway inhibitor, AG-490. The relaxant response was also subdued by NO-cGMP-PK-G pathway blockers L-NAME, 1400W, ODQ and KT-5823. Further, leptin enhanced the levels of NO and cGMP in uterine tissues. Also, SHLA, AG-490 and a combination of 1400 W and L-NAME prevented leptin-induced increase in NO. Similar effect was observed on cGMP levels in presence of leptin and SHLA. However, leptin did not influence CaCl 2 -induced response in potassium-depolarized tissues. We also detected leptin receptor protein in late pregnant mouse uterus located in endometrial luminal epithelium and myometrial layers. Real-time PCR studies revealed significantly higher expression of short forms of the receptor (ObRa and ObRc) in comparison to the long form (ObRb). In conclusion, the results of the present study suggest that leptin inhibits mouse uterine contraction by stimulating short forms of the leptin receptors and activating NO pathway in a JAK-STAT-dependent manner., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Anticoagulant-related nephropathy (ARN), that was described in humans first as warfarin-related nephropathy, is characterized by acute kidney injury and red blood cell (RBC) tubular casts in the kidney. 5/6 nephrectomy (5/7NE) rats treated with warfarin or dabigatran show changes in kidney function and morphology that are similar to human disease. The role of glomerular filtration rate (GFR) in the pathogenesis of ARN is not clear. The aim of these studies was to elucidate the role of GFR in the pathogenesis of dabigatran-induced ARN in 5/6NE rats., Methods: 5/6NE rats were treated per os with 150 mg/kg/day dabigatran alone or with drugs that lower (enalapril, 1.5 mg/kg/day) or increase (albuterol, 4.0 mg/kg/day) GFR for 7 days. Changes in coagulation and kidney function were recorded daily. Kidney morphology was evaluated on day 7 after the treatment., Results: Dabigatran resulted in activated partial thromboplastin time increase that was not affected by GFR-modifying drugs. Blood pressure was significantly lower in 5/6NE rats treated with enalapril and dabigatran as compared to dabigatran alone. The GFR was decreased by 35% in enalapril/dabigatran- and increased by 26% in albuterol/dabigatran-treated animals. There were no changes in serum creatinine, hematuria or urinary kidney injury molecule (KIM-1) levels when GFR-modifying drugs were added to dabigatran. All dabigatran-treated animals had RBC casts in the kidney regardless of the GFR modification., Conclusions: GFR does not play a significant role in the dabigatran-induced acute kidney injury in 5/6 nephrectomy model in rats. Based in these data, modification of GFR in patients with ARN is not warranted., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Salmeterol and albuterol are well-known β2-adenoreceptor agonists widely used in the treatment of inflammatory respiratory diseases, such as bronchial asthma and chronic obstructive pulmonary disease. Here we report the preparation of structural isomers of salmeterol and albuterol, which can be obtained from the same starting material as the corresponding β2-agonists, depending on the synthetic approach employed. Using 1D and various 2D NMR measurements, we determined that the structure of prepared isomers holds the β-aryl-β-aminoethanol moiety, in contrast to the α-aryl-β-aminoethanol moiety found in salmeterol and albuterol. We investigated the reaction of β-halohydrin and amines responsible for the formation of β-aryl-β-amino alcohol - both experimentally and using computational methods. The structure of β-halohydrin with the methyl salicylate moiety imposes the course of the reaction. The solvent plays a relevant, yet ambiguous role in the direction of the reaction, while the strength of the base influences the reaction yield and isomer ratio in a more evident way. Using computational methods, we have shown that the most probable reaction intermediate responsible for the formation of the unexpected isomer is the corresponding para-quinone methide, which can be formed due to phenol present in the methyl salicylate moiety. After successful preparation of albuterol and salmeterol isomers, we tested their inhibition potency to human acetylcholinesterase (AChE) and usual and atypical butyrylcholinesterase (BChE). Kinetic studies revealed that both isomers are low-potency reversible inhibitors of human cholinesterases.