Effects of enantiomers of beta 2-agonists on ACh release and smooth muscle contraction in the trachea.
Abstract: The beta 2-agonists currently used as bronchodilators are racemic mixtures of R- and S-enantiomers. In the present study, we examined the effects of enantiomers of the beta 2-agonists albuterol and formoterol on acetylcholine (ACh) release from equine trachealis parasympathetic nerves. ACh release was evoked by electrical field stimulation (20 V, 0.5 ms, 0.5 Hz) and measured by high-performance liquid chromatography coupled with electrochemical detection. We also tested the effects of enantiomers of albuterol and formoterol on equine tracheal smooth muscle (TSM) contraction in response to exogenous ACh. R- and RS-albuterol (10(-8) to 10(-5) M) and RR- and RR/SS-formoterol (10(-8) to 10(-5) M) augmented ACh release in a concentration-dependent manner. Beginning at 10(-6) M, SS-formoterol significantly increased ACh release, and at 10(-5) M, release increased by 71.9 +/- 8.7% over baseline. This effect was only observed, however, when the prejunctional muscarinic autoinhibitory effect of ACh was prevented with atropine. Both the RR- and SS-formoterol-induced increases in ACh release were abolished by the beta 2-antagonist ICI-118551 (3 x 10(-7) M). The effect of S-albuterol on ACh release was variable, and the mean increase induced by 10(-5) M was 30.8 +/- 16.1% in the presence of atropine. In the muscle tension study, R- and RS-albuterol and RR- and RR/SS-formoterol (10(-8) to 10(-5) M) but not the S-enantiomers inhibited TSM contraction. Even though R-enantiomers augment ACh release, they potently inhibit TSM contraction. Because racemic beta 2-agonists are bronchodilators on acute administration, the postjunctional spasmolytic effects of R-enantiomers predominate over the spasmogenic effect evoked via increased ACh release. The S-enantiomers, in contrast, do not inhibit TSM contraction and therefore would not contribute to the observed bronchodilation of the racemate. The S-enantiomers do prejunctionally facilitate ACh release when prejunctional muscarinic autoreceptors are dysfunctional, suggesting a potentially deleterious effect.
Publication Date: 1998-02-12 PubMed ID: 9458798DOI: 10.1152/ajplung.1998.274.1.L32Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research article discusses a study which examines the effects of specific components, R- and S-enantiomers, of beta 2-agonists on acetylcholine (ACh) release and smooth muscle contraction in the trachea, specifically using albuterol and formoterol as test substances. The researchers found that these components had different influences on ACh release and muscle contraction, which may have implications for the use of beta 2-agonists as bronchodilators.
Research Method
In this study, the researchers investigated the impact of enantiomers (R and S) of the beta 2-agonists beAlbuterol and formoterol on acetylcholine (ACh) release and the contraction of tracheal smooth muscle. Key methods included
- Inducing ACh release from equine trachealis parasympathetic nerves using electrical field stimulation and then measuring it using high-performance liquid chromatography coupled with electrochemical detection.
- Examining the effect of the enantiomers on tracheal smooth muscle (TSM) contraction in response to ACh.
Key Findings
The main findings of the study can be summarized as follows:
- Both R and RS-albuterol and RR and RR/SS-formoterol were found to increase ACh release in a concentration-dependent manner. However, the effect of S-albuterol was variable.
- Beginning at certain concentrations, SS-formoterol significantly increased ACh release, but only when the autoinhibitory effect of ACh was prevented with atropine.
- The increases in ACh release induced by both RR and SS-formoterol could be abolished by the beta 2-antagonist ICI-118551.
- While R and RS-albuterol and RR and RR/SS-formoterol inhibited TSM contraction, the S-enantiomers did not.
Implications and Conclusions
The results indicate distinct roles played by different enantiomers of beta 2-agonists. Despite R-enantiomers enhancing ACh release, they also potently inhibit TSM contraction. This means that on acute administration, the spasmolytic effects of R-enantiomers prevail over any spasmogenic effect induced via increased ACh release.
In contrast, S-enantiomers do not inhibit TSM contraction and thus do not contribute to the bronchodilation observed with use of racemate. Interestingly, S-enantiomers can still facilitate ACh release when prejunctional muscarinic autoreceptors are dysfunctional, suggesting a potentially harmful effect.
These findings suggest a possible need to reconsider the components and dosages of beta 2-agonists used as bronchodilators.
Cite This Article
APA
Zhang XY, Zhu FX, Olszewski MA, Robinson NE.
(1998).
Effects of enantiomers of beta 2-agonists on ACh release and smooth muscle contraction in the trachea.
Am J Physiol, 274(1), L32-L38.
https://doi.org/10.1152/ajplung.1998.274.1.L32 Publication
Researcher Affiliations
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing 48824-1314, USA.
MeSH Terms
- Acetylcholine / metabolism
- Acetylcholine / pharmacology
- Adrenergic beta-2 Receptor Agonists
- Adrenergic beta-Agonists / pharmacology
- Albuterol / pharmacology
- Animals
- Bronchodilator Agents / pharmacology
- Electric Stimulation
- Ethanolamines / pharmacology
- Formoterol Fumarate
- Horses
- In Vitro Techniques
- Kinetics
- Muscle Contraction / drug effects
- Muscle Contraction / physiology
- Muscle, Smooth / drug effects
- Muscle, Smooth / physiology
- Stereoisomerism
- Trachea / drug effects
- Trachea / physiology
Citations
This article has been cited 5 times.- Littmann T, Göttle M, Reinartz MT, Kälble S, Wainer IW, Ozawa T, Seifert R. Recruitment of β-arrestin 1 and 2 to the β2-adrenoceptor: analysis of 65 ligands. J Pharmacol Exp Ther 2015 Nov;355(2):183-90.
- Mhanna MJ, Koester JF, Cohn RC. Effects of (r,r)- and (r,r/s,s)-formoterol on airway relaxation and contraction in an experimental rat model. Curr Ther Res Clin Exp 2007 Jul;68(4):249-61.
- Dale PR, Cernecka H, Schmidt M, Dowling MR, Charlton SJ, Pieper MP, Michel MC. The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease. Curr Opin Pharmacol 2014 Jun;16(100):31-42.
- Ameredes BT, Calhoun WJ. Levalbuterol versus albuterol. Curr Allergy Asthma Rep 2009 Sep;9(5):401-9.
- Delmotte P, Sanderson MJ. Effects of albuterol isomers on the contraction and Ca2+ signaling of small airways in mouse lung slices. Am J Respir Cell Mol Biol 2008 May;38(5):524-31.
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