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

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.