<abstract xmlns="http://www.w3.org/1999/xhtml">

<sec><h3>Background</h3>
<p>The family of calcium-activated chloride channels, TMEM16, plays a significant role in contributing to the pathogenesis of airway inflammatory diseases. Targeting these ion channels and aiming to modulate them may provide an interesting new approach to the therapy of these potentially fatal diseases.</p>
</sec>
<sec><h3>Methods</h3>
<p>We tested this hypothesis in both healthy and ovalbumin (OVA)-sensitized male Dunkin-Hartley guinea pigs. The ion channel activity was modulated by TMEM16A-nonselective (benzbromarone) and TMEM16A-selective blockers (CaCCinh-A01). <italic>In vivo</italic> airway reactivity, induced by histamine and methacholine, was expressed as specific airway resistance (sRaw) values. The number of citric acid-induced coughs was counted using a double-chambered body plethysmograph, and the frequency of ciliary beating (CBF) was assessed <italic>in vitro</italic> by brushing method. For comparison, salbutamol and codeine were tested under the same conditions.</p>
</sec>
<sec><h3>Results</h3>
<p>The results showed significant differences in the responses of unsensitized and sensitized airways to both TMEM16 blockers administered. CaCCinh-A01 and benzbromarone significantly reduced the number of cough efforts in the group of OVA-sensitized guinea pigs. Significant improvement in sRaw values could be observed in OVA-sensitized TMEM16 blocker–treated animals compared to salbutamol when challenged with inhalational histamine, and the outcome was similar to salbutamol when challenged with methacholine. CBF was significantly inhibited in animals sensitized to OVA treated with selective inhibition of TMEM16A.</p>
</sec>
<sec><h3>Conclusions</h3>
<p>The results demonstrated that treatment with blockers of TMEM16 can reduce both cough effort and sRaw, and the difference between TMEM16A-selective and TMEM16A-nonselective blocking is only negligibly in favor of CaCCinh-A01. It is also worthwhile to note the impairment of CBF in OVA-sensitized animals treated with CaCCinh-A01.</p>
</sec>
</abstract>

Background
The family of calcium-activated chloride channels, TMEM16, plays a significant role in contributing to the pathogenesis of airway inflammatory diseases. Targeting these ion channels and aiming to modulate them may provide an interesting new approach to the therapy of these potentially fatal diseases.

Methods
We tested this hypothesis in both healthy and ovalbumin (OVA)-sensitized male Dunkin-Hartley guinea pigs. The ion channel activity was modulated by TMEM16A-nonselective (benzbromarone) and TMEM16A-selective blockers (CaCCinh-A01). In vivo airway reactivity, induced by histamine and methacholine, was expressed as specific airway resistance (sRaw) values. The number of citric acid-induced coughs was counted using a double-chambered body plethysmograph, and the frequency of ciliary beating (CBF) was assessed in vitro by brushing method. For comparison, salbutamol and codeine were tested under the same conditions.

Results
The results showed significant differences in the responses of unsensitized and sensitized airways to both TMEM16 blockers administered. CaCCinh-A01 and benzbromarone significantly reduced the number of cough efforts in the group of OVA-sensitized guinea pigs. Significant improvement in sRaw values could be observed in OVA-sensitized TMEM16 blocker–treated animals compared to salbutamol when challenged with inhalational histamine, and the outcome was similar to salbutamol when challenged with methacholine. CBF was significantly inhibited in animals sensitized to OVA treated with selective inhibition of TMEM16A.

Conclusions
The results demonstrated that treatment with blockers of TMEM16 can reduce both cough effort and sRaw, and the difference between TMEM16A-selective and TMEM16A-nonselective blocking is only negligibly in favor of CaCCinh-A01. It is also worthwhile to note the impairment of CBF in OVA-sensitized animals treated with CaCCinh-A01.

Experimental evaluation of the nonselective and selective TMEM16 family calcium-activated chloride channel blockers in the airways

Comenius University in Bratislava Jessenius Faculty of Medicine in Martin: Univerzita Komenskeho v Bratislave Jesseniova Lekarska Fakulta v Martine

Biomedical Center (Biomed Martin), Jessenius School of Medicine

European Pharmaceutical Journal

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Background
The family of calcium-activated chloride channels, TMEM16, plays a significant role in contributing to the pathogenesis of airway inflammatory...

Experimental evaluation of the nonselective and selective TMEM16 family calcium-activated chloride channel blockers in the airways

Article Category: Original Paper

Published Online: Sep 30, 2023

Page range: 1 - 7

Received: May 19, 2023

Accepted: Aug 14, 2023

DOI: https://doi.org/10.2478/afpuc-2023-0016

Keywords
calcium-activated chloride channels, TMEM16A channel, cough reflex, bronchoconstriction, mucociliary clearance, guinea pigs

© 2023 J. Mažerik et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Experimental evaluation of the nonselective and selective TMEM16 family calcium-activated chloride channel blockers in the airways

Article Category: Original Paper

Published Online: Sep 30, 2023

Page range: 1 - 7

Received: May 19, 2023

Accepted: Aug 14, 2023

DOI: https://doi.org/10.2478/afpuc-2023-0016

Keywordscalcium-activated chloride channels, TMEM16A channel, cough reflex, bronchoconstriction, mucociliary clearance, guinea pigs

© 2023 J. Mažerik et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
calcium-activated chloride channels, TMEM16A channel, cough reflex, bronchoconstriction, mucociliary clearance, guinea pigs