Glibenclamide Inhibits an Outwardly Rectifying Chloride Channel in M-1 Mouse Cortical Collecting Duct Cells

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Abstract
As previously reported, an outwardly rectifying chloride conductance contributes to the whole-cell conductance of M-l mouse cortical collecting duct cells and appears to be inhibited by glibenclamide, a known blocker of ATP-sensitive K channels [Korbmacher et al: J Gen Physiol 1993;102:761-793]. Glibenclamide has also been shown to inhibit chloride currents in fibroblasts transfected with the cystic fibrosis transmembrane regulator (CFTR) gene [Sheppard and Welsh: J Gen Physiol 1992;100:573-591]. The aim of the present study was to identify chloride channels in excised inside-out membrane patches of M-l cells and to test their sensitivity to glibenclamide. Typical outwardly rectifying chloride channels were detected with inward and outward chord conductances of 16.7 ± 1.1 and 49.6 ± 2.1 pS, respectively (n = 14). Kinetic analyses revealed the presence of one open time constant (τo = 35 ms) and three closed time constant (τc1 = 0.14 ms; τc2 = 1.97 ms; τc3 = 94 ms). Channel activity was not affected by cytosolic calcium removal (n = 8). Cytoplasmic application of 100 µM glibenclamide reversibly reduced channel open probability (PO) from 0.92 ± 0.02 to 0.24 ± 0.06 (n = 4, p < 0.001) by means of a flicker block. Glibenclamide decreased τO, reduced the observation frequency of τc1 and increased the observation frequency of τc2 The inhibitory effect of glibenclamide was concentration-dependent with an IC50 of 36 µM. In conclusion, we have identified an outwardly rectifying chloride channel in M-l mouse cortical collecting duct cells and have characterized its inhibition by glibenclamide. Its sensitivity to this inhibitor suggests that glibenclamide is not a useful pharmacological tool to discriminate between CFTR-like chloride channels and other types of chloride channels.

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