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Background and Purpose  For decades, inhibitors of the cystic fibrosis transmembrane conductance regulator ( CFTR ) chloride channel have been used as tools to investigate the role and function of  CFTR  conductance in cystic fibrosis research. In the early 2000s, two new and potent inhibitors of  CFTR ,  CFTR  inh ‐172 and  GlyH ‐101, were described and are now widely used to inhibit specifically  CFTR . However, despite some evidence, the effects of both drugs on other types of   Cl   − ‐conductance have been overlooked. In this context, we explore the specificity and the cellular toxicity of both inhibitors in  CFTR ‐expressing and non– CFTR ‐expressing cells.    Experimental Approach  Using patch‐clamp technique, we tested the effects of  CFTR  inh ‐172 and  GlyH ‐101 inhibitors on three distinct types of   Cl   −  currents: the  CFTR ‐like conductance, the volume‐sensitive outwardly rectifying   Cl   −  conductance ( VSORC ) and finally the   Ca   2+ ‐dependent   Cl   −  conductance ( CaCC ). We also explored the effect of both inhibitors on cell viability using live/dead and cell proliferation assays in two different cell lines.    Key Results  We confirmed that these two compounds were potent inhibitors of the  CFTR ‐mediated   Cl   −  conductance. However, GlyH ‐101 also inhibited the  VSORC  conductance and the  CaCC  at concentrations used to inhibit  CFTR . The  CFTR  inh ‐172 did not affect the  CaCC  but did inhibit the  VSORC,  at concentrations higher than 5 µM. Neither inhibitor (20 µM; 24 h exposure) affected cell viability, but both were cytotoxic at higher concentrations.    Conclusions and Implications  Both inhibitors affected Cl −  conductances apart from CFTR. Our results provided insights into their use in mouse models.

Revisiting CFTR inhibition: a comparative study of CFTR inh ‐172 and GlyH ‐101 inhibitors