Defective cholinergic Cl- secretion and detection of K+ secretion in rectal biopsies from cystic fibrosis patients

Rectal biopsies from cystic fibrosis (CF) patients show defective cAMP-acti vated Cl- secretion and an inverse response of the short-circuit current (I -sc) toward stimulation with carbachol (CCh). Alternative Cl- channels are found in airway epithelia and have been attributed to residual Cl- secretio n in CF colon. The aim of the present study was to investigate ion conducta nces causing reversed I-sc upon cholinergic stimulation. Furthermore, the p utative role of an alternative Ca2+-dependent Cl- conductance in human dist al colon was examined. Cholinergic ion secretion was assessed in the absenc e and presence of cAMP-dependent stimulation. Transepithelial voltage and I -sc were measured in rectal biopsies from non-CF and CF individuals by mean s of a perfused micro-Ussing chamber. Under baseline conditions, CCh induce d a positive I-sc in CF rectal biopsies but caused a negative I-sc in non-C F subjects. The CCh-induced negative I-sc in non-CF biopsies was gradually reversed to a positive response by incubating the biopsies in indomethacin. The positive I-sc was significantly enhanced in CF and was caused by activ ation of a luminal K+ conductance, as shown by the use of the K+ channel bl ockers Ba2+ and tetraethylammonium. Moreover, a cAMP-dependent luminal K+ c onductance was detected in CF individuals. We conclude that the cystic fibr osis transmembrane conductance regulator is the predominant Cl- channel in human distal colon. Unlike human airways, no evidence was found for an alte rnative Cl- conductance in native tissues from CF patients. Furthermore, we demonstrated that both Ca2+- and cAMP-dependent K+ secretion are present i n human distal colon, which are unmasked in rectal biopsies from CF patient s.