Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi
Introduction
There is an increasing amount of evidence demonstrating an association of inhaled β2-agonists with a rise in asthma-related deaths and life-threatening experiences, as well as an ability of β2-agonists to induce bronchial hyperresponsiveness when used clinically, particularly when administered as monotherapy [1]. The mechanisms contributing to the adverse effects in the airways are not known, but it has been suggested that some of these undesirable effects may be due to the S-enantiomer as most commonly available β2-agonists are produced as racemic mixtures of R- and S-enantiomers in equal ratios [2]. The S-enantiomer of salbutamol has been considered to be largely inert or at best to have weak β2-agonist activities. However, recent studies have documented that S-salbutamol can potentiate the effects of spasmogens in airway smooth muscle from both guinea pigs and humans, with a number of clinical studies also reporting worsening of airways hyperresponsiveness in animals [3] and in subjects with asthma [4]. It has also been documented that the metabolic clearance of S-salbutamol occurs much less rapidly than R-salbutamol [5], and thus the paradoxical responses may persist after the beneficial effects of (R)-salbutamol have waned [2], particularly after chronic use of the drug. S-salbutamol has also been reported to have pro-inflammatory effects that could negatively affect the airways [6].
Chemically, all β-agonists are racemates, or drugs composed of two non-superimposable mirror image molecules in a 50/50 ratio [7]. These molecules are classified as R- or S- according to their molecular configuration, and as ‘lev’ or ‘dex’ based on the rotation of polarized light as it passes through the molecule.
Equine obstructive pulmonary disease, also known as heaves or recurrent airway obstruction (RAO) is a common equine pulmonary disease with certain similarities to human asthma and COPD and represents a major cause of morbidity and loss of lung performance in this species [8], [9].
Whilst β2-agonists are used in the treatment of RAO, little is known about the properties of the enantiomers of salbutamol in the horse. The present study has therefore evaluated effects of racemic β2-agonists in isolated equine bronchi in comparison with the pure R- and S-enantiomers.
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Tissue preparations
Equine lungs, derived from healthy horses following humane killing in an abattoir, were obtained from six RAO-unaffected horses (3 male and 3 female; aged 2.3 ± 0.1 years; weighted kg 375 ± 54.3) and four RAO-affected horses (2 male and 1 female; aged 2.5 ± 0.2 years; weighted kg 388 ± 46.5). Lungs were rapidly transported to our laboratory in a Krebs–Henseleit solution (KH) (composition, mM: NaCl 117.5. KCl 5.60. MgSO4 1.18. CaCl2 2.50. NaH2P04 1.28. NaHCO3 25.00 and glucose 5.5, pregassed
Protocol 1: relaxant effect of salbutamol enantiomers on sub-maximal contractions induced by carbachol or histamine
The baseline tension of bronchial tissues did not change throughout the experiments carried out with S-Salbutamol or the racemic mixture.
In the control bronchi, papaverine completely relaxed equine bronchial rings contracted with a sub-maximal concentration of carbachol (CCh: +4.37gr ± 0.42; P: −4.64gr ± 0.45) or histamine (His: +6.59gr ± 0.98; P: −7.93gr ± 0.85). In contrast, salbutamol enantiomers did not show direct relaxant effects on the sub-maximal plateau contractile response induced by
Discussion
Inhaled β2-agonists remain the first line treatment of acute symptoms of airway obstructive diseases in horses. Most commonly available β2-agonist preparations are racemic, i.e. they are composed of an equimolar mixture of R- and S-stereoisomers. Traditionally the S-enantiomers were considered inert or at best weak β2-agonists [10], but it is now recognized that the S-enantiomer can have adverse effect in the airways [2]. Thus, it has been documented in in vitro and in vivo experimental studies
References (30)
- et al.
Contrasting properties of albuterol stereoisomers
J Allergy Clin Immunol
(1999) - et al.
(S)-Albuterol activates pro-constrictory and pro-inflammatory pathways in human bronchial smooth muscle cells
J Allergy Clin Immunol
(2004) - et al.
The pathogenesis of chronic obstructive pulmonary disease of horses
Br Vet J
(1996) - et al.
Innervation of equine airways
Pulm Pharmacol Ther
(2002) - et al.
Excitatory prejunctional β2-adrenoceptor distribution within equine airway cholinergic nerves
Respir Physiol
(1996) - et al.
Role of phosphoinositide metabolism in functional antagonism of airway smooth muscle contraction by β-adrenoceptor agonists
Eur J Pharmacol
(1989) - et al.
Protein kinase C potentiates homologous desensitization of the β2-adrenoceptor in bovine tracheal smooth muscle
Eur J Pharmacol
(2006) - et al.
Agonist-independent alteration in β-adrenoceptor–G-protein–adenylate cyclase system in an equine model of recurrent airway obstruction
Pulm Pharmacol Ther
(2006) - et al.
Exacerbation of airway hyperreactivity by (+/−)salbutamol in sensitized guinea pig
Jpn J Pharmacol
(1993) - et al.
Hyperresponsiveness of the airways following exposure of guinea-pigs to racemic mixtures and distomers of β2-selective sympathomimetics
Pulm Pharmacol
(1994)
Modulation of T-cell function by (R)- and (S)-isomers of albuterol: anti-inflammatory influences of (R)-isomers are negated in the presence of the (S)-isomer
J Allergy Clin Immunol
Safety of long-acting β2-agonists in the treatment of asthma
Ther Adv Respir Dis
Evidence based review on levosalbutamol
Indian J Pediatr
Differential responses of asthmatic airways to enantiomers of albuterol. Implications for clinical treatment of asthma
Clin Rev Allergy Immunol
The use of β-agonists and the risk of death and near death from asthma
N Engl J Med
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