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

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 278; no. 4; pp. G617 - G624
• Main Authors: Mall, M., Wissner, A., Seydewitz, H. H., Kuehr, J., Brandis, M., Greger, R., Kunzelmann, K.
• Format: Journal Article
• Language: English
• Published: United States 01.04.2000
• Subjects: Adolescent; Adult; Biopsy; Carbachol - pharmacology; Child; Child, Preschool; Chlorides - metabolism; Cholinergic Agonists - pharmacology; Cholinergic Fibers - metabolism; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - biosynthesis; Cyclic AMP - physiology; Cyclooxygenase Inhibitors - pharmacology; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Humans; Indomethacin - pharmacology; Infant; Middle Aged; Phenotype; Potassium - metabolism; Rectum - metabolism; Rectum - pathology; Reference Values
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.2000.278.4.G617

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 Ca 2+ -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 Ba 2+ 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 Ca 2+ - and cAMP-dependent K + secretion are present in human distal colon, which are unmasked in rectal biopsies from CF patients.