No evidence for direct activation of the cystic fibrosis transmembrane conductance regulator by 8-cyclopentyl-1,3-dipropylxanthine.

8-Cyclopentyl-1,3-dipropylxanthine (CPX) is a selective A1-adenosine receptor antagonist which has been reported to activate Cl- efflux at very low concentrations in cells carrying the cystic fibrosis (CF) defect, but not in cells expressing the wild-type form of the CF transmembrane conductance regulator (CFTR). CPX was suggested as a new therapeutic drug for the treatment of CF. In the present study, we examined the effects of CPX on various types of recombinant cells (Xenopus oocytes, Chinese hamster ovary cells, CF tracheal cells) and native non-CF and CF respiratory epithelial cells. CPX did not activate a whole-cell conductance when applied at concentrations ranging from 1 nmol/l to 100 micromol/l in oocytes injected with water or expressing either wild-type CFTR or mutant deltaF508-CFTR. Correspondingly, CPX (10 micromol/l) did not activate whole-cell conductance in non-CF or CF respiratory epithelial cells and Chinese hamster ovary cells expressing either wild-type CFTR or deltaF508-CFTR. Instead, CPX depolarized Vm by inhibition of a K+ conductance in CF respiratory epithelial cells. At 10 micromol/l CPX marginally decreased intracellular pH in respiratory epithelial cells, independent of expression of wild-type CFTR or mutant CFTR. According to these data, CPX-induced 36Cl efflux reported in previous studies cannot be attributed to direct activation of deltaF508-CFTR Cl- conductance and is probably related to the CPX-induced changes in intracellular pH.