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-activated 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- secretion in CF colon. The aim of the present study was to investigate ion conductances causing reversed I-sc upon cholinergic stimulation. Furthermore, the putative role of an alternative Ca2+-dependent Cl- conductance in human distal colon was examined. Cholinergic ion secretion was assessed in the absence and presence of cAMP-dependent stimulation. Transepithelial voltage and I-sc were measured in rectal biopsies from non-CF and CF individuals by means of a perfused micro-Ussing chamber. Under baseline conditions, CCh induced a positive I-sc in CF rectal biopsies but caused a negative I-sc in non-CF 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 activation of a luminal K+ conductance, as shown by the use of the K+ channel blockers Ba2+ and tetraethylammonium. Moreover, a cAMP-dependent luminal K+ conductance was detected in CF individuals. We conclude that the cystic fibrosis transmembrane conductance regulator is the predominant Cl- channel in human distal colon. Unlike human airways, no evidence was found for an alternative Cl- conductance in native tissues from CF patients. Furthermore, we demonstrated that both Ca2+- and cAMP-dependent K+ secretion are present in human distal colon, which are unmasked in rectal biopsies from CF patients.