Hyperresponsiveness of the Airways Following Exposure of Guinea-pigs to Racemic Mixtures and Distomers of β2-selective Sympathomimetics

doi:10.1006/pulp.1994.1043

Pulmonary Pharmacology

Volume 7, Issue 6, December 1994, Pages 367-376

https://doi.org/10.1006/pulp.1994.1043 Get rights and content

Abstract

Summary: Allergic bronchospasm in sensitized guinea-pigs was totally suppressed by acute subcutaneous infusion of rac-salbutamol (0.69 μg/kg per min) for <1 h. More prolonged infusion of rac-salbutamol induced a progressive susceptibility to inhaled antigen so that, by 48 h, animals collapsed and died following inhalation of antigen. In anaesthetized animals, acute infusion of rac-salbutamol (1.67 μg/kg per min) suppressed airway obstruction, an effect that can be attributed to β₂-adrenoceptor activation by the eutomer (R-salbutamol). Acute intravenous infusion of the distomer (S-salbutamol) (1.67 μg/kg per min) induced hyperresponsiveness to histamine without having any effect upon airway calibre. It is suggested therefore that subcutaneous infusion of rac-salbutamol initially abrogates the bronchoconstrictor response to antigen because the bronchodilator action of the eutomer predominates over hyperreactivity attributable to the distomer. Conversion from protection to susceptibility was not determined by reduced β₂-adrenoceptor activation since animals could be protected from a lethal response to antigen by inhalation of rac-isoprenaline or by subcutaneous injection of rac-salbutamol. The seeming progressive loss of efficacy of R-salbutamol may result from disproportionate accumulation of S-salbutamol if, as in man, there is stereospecific metabolism of R-salbutamol. The capacity of S-salbutamol to evoke hyperresponsiveness is shared by S-isoprenaline and S-terbutaline and, as has been shown previously for rac-isoprenaline, the capacity of S-salbutamol to elicit hyperresponsiveness was not evidenced following section of the vagus nerves. No mechanism has yet been established which might account for this property of S-salbutamol or for other S-enantiomers of sympathomimetics.

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Cited by (79)

Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action
2018, Journal of Pharmaceutical and Biomedical Analysis
Salmeterol (a long acting beta2-agonist) is a chiral molecule. (RR)-salmeterol is responsible for pharmacological effect, but basic knowledge of enantioselective pulmonary pharmacodynamics and pharmacokinetics of salmeterol remains unknown. There are safety concerns with (S)-enantiomers of beta2-agonists, with suggestions that these enantiomers may increase bronchial hyperresponsivneness in asthma patients.
Horses (n = 12) received racemic (rac-) salmeterol 250 μg via inhalation. Enantioselective UPLC–MS/MS was used to determine (R)- and (S)-salmeterol concentrations in pulmonary epithelial lining fluid (PELF) sampled 2, 5, 10 and 15 min after administration, in central lung (endoscopic bronchial biopsy) and peripheral lung (percutaneous pulmonary biopsy) tissues (at 20 and 25 min respectively), and in plasma samples.
Physiologically relevant tissue concentrations were found for both enantiomers, with median levels greater in central than peripheral lung (equivalent to 32 and 5 mM (R)-salmeterol for central and peripheral lung respectively). Levels in PELF decreased around 50% over 15 min and enantioselective distribution was observed in the central lung with levels of (R)-salmeterol around 30% higher than (S)-salmeterol.
Salmeterol distribution is enantioselective in the central lung. This suggests duration of action is more likely associated with specific B2ADR localisation effects rather than non-specific physiochemical factors which would not be enantioselective.
R- and S-terbutaline activate large conductance and Ca<sup>2 +</sup> dependent K<sup>+</sup> (BK<inf>Ca</inf>) channel through interacting with β<inf>2</inf> and M receptor respectively
2016, Biochimica et Biophysica Acta - Biomembranes
Citation Excerpt :
The paradoxic effect of distomers may be responsible for airway hyperreactivity (AHR) and contribute to morbidity and mortality in asthma patients [16]. For example, S-albuterol has been demonstrated to be linked to airway hyperresponsiveness by experimental animal and clinical studies [16,26]. Besides, studies in cells have indicated the proinflammatory effects of S-albuterol, that could negatively affect long-term asthma control [27–29].
This study investigated the effect of the β₂ receptor agonist terbutaline on the single channel activity of BK_Ca channel. The effects of racemate and two isomers of terbutaline were all assessed. β₂ adrenoceptors were stably overexpressed on HEK293 cells by lentiviral transduction method and chicken BK_Ca channels were transiently expressed on normal HEK293 cell line or HEK293 cells overexpressing β₂ receptors. Data showed that terbutaline significantly increased the single channel open probability of BK_Ca channel within 10 min. The channel activating effects of terbutaline are stereoselective and mainly stay with the R-enantiomers. The opening probability of BK_Ca channel at 10 min after drug application normalized to that just before drug application (Po10/Po0s) for R- and S-terbutaline were 7.85 ± 3.20 and 1.06 ± 0.45 respectively at 1 μM concentration, corresponding to 28.37 ± 9.96 and 2.68 ± 1.09 at the higher concentration of 10 μM. ICI 118551 blocked the effect of R- but not S-terbutaline (10 μM), whereas atropine blocked the channel activating effects of S-terbutaline of higher concentration. In addition, the muscarinic receptor agonist carbachol increased the BK_Ca channel activity in an atropine-sensitive manner as an positive control experiment, which indicate the involvement of M receptor in the channel activating effect of S-terbutaline.
Sports doping: Emerging designer and therapeutic β<inf>2</inf>-agonists
2013, Clinica Chimica Acta
Beta₂-adrenergic agonists, or β₂-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β₂-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006–2012) literature concerning the development of novel β₂-agonists molecules either by modifying the molecule of known β₂-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β₂-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.
Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi
2011, Pulmonary Pharmacology and Therapeutics
Equine obstructive pulmonary disease, also known as heaves or recurrent airway obstruction (RAO) is a common equine pulmonary disease with some similarities to human asthma and COPD, which represents a major cause of morbidity and loss of lung performance. Salbutamol has been widely used for the treatment of human airway diseases and has usually been prepared as the racemic form of the drug. However, recently the R-enantiomer of salbutamol has been introduced into clinical practice in the treatment of asthma in humans and this has been suggested to be an improvement on the racemic form of the drug; therefore thus the S-enantiomer has been demonstrated to have adverse effects in the lung and thus using the R-enantiomer may improve the therapeutic ratio. However, little is known about the properties of the R- and S-enantiomers of salbutamol in equine airways and the present study has evaluated the relaxant effects of racemic β₂-agonists in comparison with the R- and S-enantiomers in isolated equine isolated bronchi, as well as the bronchoprotective effects of these drugs on cholinergic and histaminergic pathway.
We have studied the effects of the R- and S-enantiomers of salbutamol on bronchi isolated from RAO-affected or unaffected horses. The first study assayed the relaxant effects of R- and S-salbutamol on isolated bronchial rings contracted with carbachol or histamine at a sub-maximal concentration (EC70). A second study evaluated the effects of R- and S-salbutamol on semi-logarithmic cumulative concentration-response curves induced by carbachol or histamine. Specific software was used to calculate statistical significance and the appropriate sigmoidal curve-fitting model.
Neither enantiomers of salbutamol caused a relaxant effect on the sub-maximal plateau contractile effects of carbachol; in fact, both R- and S-salbutamol induced a slight, but significant contraction (P ≤ 0.05) compared to the controls. In contrast, R-salbutamol induced a significant relaxation of bronchi pre-contracted with histamine (RAO-unaffected: 92.06% ± 2.00; RAO-affected 100.20 ± 3.99; P ≤ 0.01). S-salbutamol induced a weak relaxation (RAO-unaffected: 15.81% ± 5.65; RAO-affected 12.36 ± 5.15) when compared to that induced by papaverine. The incubation with either R- or S-salbutamol shifted rightward (P ≤ 0.001) the carbachol contraction curve in RAO-unaffected bronchi, but not in RAO-affected bronchi, compared to control tissues. R-salbutamol induced a reduction in E_max values (C: 9.07gr ± 0.68; R-salb.: 6.36gr ± 0.21; P ≤ 0.01) in normal bronchi. On the contrary it reduced the histamine potency in RAO-affected bronchi (EC50 7.10 μM ± 0.35, P < 0.001). The incubation with S-salbutamol shifted leftward the histamine concentration curve in both normal bronchi (C: 7.00 μM ± 0.29; S-salb.: 2.25 μM ± 0.19; P ≤ 0.001) and bronchi from RAO-affected horses (C: 2.80 μM ± 0.26; S-salb.: 1.50 μM ± 0.80; P ≤ 0.05).
Our studies have demonstrated that S-salbutamol elicited a modest increase in contraction of equine airway smooth muscle induced by carbachol and induced a significant hyperresponsiveness to histamine. These results confirm the ability of the S-enantiomer of salbutamol to potentiate the contractile effect of certain spasmogens on airway smooth muscle. Such an adverse effect would be determined in the airways of horses with RAO and suggest that if salbutamol is to be used in the treatment of symptoms of RAO in horses, the R-enantiomer, rather than the racemic mixture should be considered.
Counterregulation of β<inf>2</inf>-adrenoceptor function in human mast cells by stem cell factor
2010, Journal of Allergy and Clinical Immunology
Citation Excerpt :
The R-enantiomer is the agonist at the β2-AR leading to the accumulation of cAMP, and this binds with 100-fold greater affinity than the S-enantiomer.39 The S-enantiomer of albuterol is thought to mediate nonreceptor-dependent effects and has been shown to induce both Ca2+ mobilization and contraction in airway smooth muscle cells and to be proinflammatory in animal models.9-11 It is possible therefore that in HLMCs, the inhibition of antisecretory R-albuterol signaling through β2-AR counterregulation by SCF leaves the harmful effects of the S-enantiomer unchecked, leading to enhanced secretion in the presence of free IgE.
Mast cells contribute to the pathophysiology of asthma with the sustained release of both preformed and newly generated mediators in response to allergens and other diverse stimuli. Stem cell factor (SCF) is the key human mast cell growth factor, but also primes mast cells for mediator release. SCF expression is markedly increased in asthmatic airways. Short-acting β₂-adrenoceptor drugs such as albuterol inhibit human lung mast cell (HLMC) degranulation in vitro in the absence of SCF, but their effect in the presence of SCF is not known.
The aim of this study was to elucidate the effects of albuterol on HLMC function in the presence of SCF.
Mediator release and K_Ca3.1 ion channel activity were analyzed in purified HLMC. Intracellular signalling and β₂-adrenoceptor phosphorylation and internalization were analyzed in the HMC-1 human mast cell line.
β₂-Adrenoceptor agonist-dependent inhibition of K_Ca3.1 ion channels and HLMC mediator release was markedly attenuated in the presence of SCF. Remarkably, albuterol actually potentiated IgE-induced histamine release in a dose-dependent manner when both SCF and IgE were present. These effects were related to the SCF-dependent phosphorylation of Tyr350 on the β₂-adrenoceptor with immediate uncoupling of the receptor followed by receptor internalization.
The potentially beneficial effects of β₂-adrenoceptor agonists in asthmatic airways may be blunted as a result of the high concentrations of SCF present.
Long-term safety study of levalbuterol administered via metered-dose inhaler in patients with asthma
2007, Annals of Allergy, Asthma and Immunology
Previous studies have raised concerns regarding the safety of regular use of β₂-agonists for treating asthma. Few studies have explored the safety of at least 1 year of use of racemic albuterol, and none have examined long-term dosing of levalbuterol.
To examine the long-term safety of levalbuterol hydrofluoroalkane (HFA) vs racemic albuterol HFA administered via metered-dose inhaler (MDI) in patients with stable asthma.
Patients with mild to moderate asthma (mean forced expiratory volume in 1 second [FEV₁], 68.3% of predicted) 12 years or older participated in a multicenter, parallel-group, open-label study. Patients were randomized to levalbuterol HFA MDI (90 μg; 2 actuations of 45 μg; n = 496) or racemic albuterol HFA MDI (180 μg; 2 actuations of 90 μg; n = 250) for 52 weeks of 4 times daily dosing. The primary end point was the incidence of postrandomization adverse events. Asthma exacerbations and pulmonary parameters were also assessed.
The overall incidence of adverse events was similar for levalbuterol (72.0%) and racemic albuterol (76.8%). Rates of β-mediated adverse events, serious adverse events, and discontinuations because of adverse events were low (<15%) and were comparable between groups. Rates of asthma adverse events for levalbuterol and racemic albuterol were 18.3% and 19.6%, respectively. Mean percentage of predicted FEV₁ improved after dosing and was stable for both groups.
In this trial, up to 52 weeks of regular use of levalbuterol HFA MDI or racemic albuterol HFA MDI was well tolerated, and no deterioration of lung function was detected during the study period.

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Regular ArticleHyperresponsiveness of the Airways Following Exposure of Guinea-pigs to Racemic Mixtures and Distomers of β2-selective Sympathomimetics

Abstract

Regular Article
Hyperresponsiveness of the Airways Following Exposure of Guinea-pigs to Racemic Mixtures and Distomers of β₂-selective Sympathomimetics