Antagonists of the TMEM16A Calcium-activated Chloride Channel Modulate Airway Smooth Muscle Tone and Intracellular Calcium. (September 2015)

• Record Type: Journal Article
• Authors: Danielsson, Jennifer; Perez-Zoghbi, Jose; Bernstein, Kyra; Barajas, Matthew B.; Zhang, Yi; Kumar, Satish; Sharma, Pawan K.; Gallos, George; Emala, Charles W.
• Is Part Of: Anesthesiology. Volume 123:Number 3(2015)
• Publication Date: 2015-09
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000000769
• Languages: English
• ISSNs: 0003-3022

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background:</title> <p>Perioperative bronchospasm refractory to β agonists continues to challenge anesthesiologists and intensivists. The TMEM16A calcium-activated chloride channel modulates airway smooth muscle (ASM) contraction. The authors hypothesized that TMEM16A antagonists would relax ASM contraction by modulating membrane potential and calcium flux.</p> </sec> <sec> <title>Methods:</title> <p>Human ASM, guinea pig tracheal rings, or mouse peripheral airways were contracted with acetylcholine or leukotriene D<sub>4</sub> and then treated with the TMEM16A antagonists: benzbromarone, T16Ainh-A01, <italic>N</italic>-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid, or B25. In separate studies, guinea pig tracheal rings were contracted with acetylcholine and then exposed to increasing concentrations of isoproterenol (0.01 nM to 10 μM) ± benzbromarone. Plasma membrane potential and intracellular calcium concentrations were measured in human ASM cells.</p> </sec> <sec> <title>Results:</title> <p>Benzbromarone was the most potent TMEM16A antagonist tested for relaxing an acetylcholine -induced contraction in guinea pig tracheal rings (n = 6). Further studies were carried out to investigate the clinical utility of benzbromarone. In human ASM, benzbromarone relaxed either an acetylcholine- or a leukotriene D<sub>4</sub>–induced contraction (n = 8). Benzbromarone was also effective in relaxing peripheral airways (n = 9) and potentiating relaxation by β agonists (n = 5 to 10). In cellular mechanistic studies, benzbromarone hyperpolarized human ASM cells (n = 9 to 12) and attenuated intracellular calcium flux from both the plasma membrane and the sarcoplasmic reticulum (n = 6 to 12).</p> </sec> <sec> <title>Conclusion:</title> <p>TMEM16A antagonists work synergistically with β agonists and through a novel pathway of interrupting ion flux at both the plasma membrane and sarcoplasmic reticulum to acutely relax human ASM.</p> </sec> </abstract>