Chromanol 293B, a blocker of the slow delayed rectifier K+ current (IKs), inhibits the CFTR Cl- current

The cystic fibrosis transmembrane conductance regulator (CFTR) and the sulphonylurea receptor subunit (SUR) of the K-ATP channel are both members of the ATP-binding cassette (ABC) protein superfamily. Many compounds that open or block the K-ATP channel by binding to SUR also inhibit the CFTR Cl- current (I-CFTR); an example in point is the chromanol-type K-ATP channel opener, cromakalim. The structurally related chromanol 293B (trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane), a blocker of the slow component of the delayed rectifier K+ current (I-Ks) in the heart, is also a weak inhibitor of K-ATP This suggests that 293B may affect also I-CFTR. We have addressed this question with human CFTR expressed in Xenopus oocytes. In two-electrode voltage-clamp experiments, 293B inhibited I-CFTR with an IC50-value of 19 muM and Hill coefficient of 1.0; the inhibition was weakened by increasing concentrations of isobutylmethylxanthine (IBMX). Patch-clamp recordings gave an IC50-value of 30 muM but showed a unusual variability in the sensitivity to 293B. The data show that 293B inhibits I-CFTR and suggest that the mechanism of inhibition may depend on the phosphorylation state of the CFTR protein. The concentrations required for inhibition of I-CFTR are three- to fivefold higher than those reported for inhibition of KvLQT1 + minK expressed in Xenopus oocytes. Since CFTR is expressed also in cardiac myocytes, the effects of 293B in these cells must be analysed with caution.