ArticleAmerican journal of physiology. Lung cellular and molecular physiology2014
Chloride channel blockade relaxes airway smooth muscle and potentiates relaxation by β-agonists.
Article in American journal of physiology. Lung cellular and molecular physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- TMEM16A Antagonism: Therapeutic Potential with Desensitization of β-Agonist Responsiveness in Asthma.American journal of respiratory cell and molecular biology · 2025Article
- Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle.International journal of molecular sciences · 2023Review
- Molecular mechanisms of activation and regulation of ANO1-Encoded CaChannels (Austin, Tex.) · 2021Review
- Agonism of the TMEM16A calcium-activated chloride channel modulates airway smooth muscle tone.American journal of physiology. Lung cellular and molecular physiology · 2020Article
- Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways.Frontiers in pharmacology · 2019Article
- Review
- Ion channels of the lung and their role in disease pathogenesis.American journal of physiology. Lung cellular and molecular physiology · 2017Review
- Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of β2-Adrenergic Receptor.American journal of respiratory cell and molecular biology · 2016Article
- Antagonists of the TMEM16A calcium-activated chloride channel modulate airway smooth muscle tone and intracellular calcium.Anesthesiology · 2015Article
- NKCC1 and NKCC2: The pathogenetic role of cation-chloride cotransporters in hypertension.Genes & diseases · 2015Article
- Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling.American journal of physiology. Lung cellular and molecular physiology · 2015Article
- Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury.American journal of physiology. Lung cellular and molecular physiology · 2015Article
- Physiology. Calcilytics for asthma relief.Science (New York, N.Y.) · 2015Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Severe bronchospasm refractory to β-agonists continues to cause significant morbidity and mortality in asthmatic patients. We questioned whether chloride channels/transporters are novel targets for the relaxation of airway smooth muscle (ASM). We have screened a library of compounds, derivatives of anthranilic and indanyloxyacetic acid, that were originally developed to antagonize chloride channels in the kidney. We hypothesized that members of this library would be novel calcium-activated chloride channel blockers for the airway. The initial screen of this compound library identified 4 of 20 compounds that relaxed a tetraethylammonium chloride-induced contraction in guinea pig tracheal rings. The two most effective compounds, compounds 1 and 13, were further studied for their potential to either prevent the initiation of or relax the maintenance phase of an acetylcholine (ACh)-induced contraction or to potentiate β-agonist-mediated relaxation. Both relaxed an established ACh-induced contraction in human and guinea pig ex vivo ASM. In contrast, the prevention of an ACh-induced contraction required copretreatment with the sodium-potassium-chloride cotransporter blocker bumetanide. The combination of compound 13 and bumetanide also potentiated relaxation by the β-agonist isoproterenol in guinea pig tracheal rings. Compounds 1 and 13 hyperpolarized the plasma cell membrane of human ASM cells and blocked spontaneous transient inward currents, a measure of chloride currents in these cells. These functional and electrophysiological data suggest that modulating ASM chloride flux is a novel therapeutic target in asthma and other bronchoconstrictive diseases.
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