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 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.
Mall
M
M
Universitäts-Kinderklinik, Albert-Ludwigs-Universität Freiburg, 79106 Freiburg, Germany. mmall@ruf.uni-freiburg.de
Wissner
A
A
Seydewitz
H H
HH
Kuehr
J
J
Brandis
M
M
Greger
R
R
Kunzelmann
K
K
D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002217:Carbachol / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000378:metabolism*; D018679:Cholinergic Agonists / Q000494:pharmacology; D002799:Cholinergic Fibers / Q000378:metabolism*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007223:Infant; D008875:Middle Aged; D010641:Phenotype; D011188:Potassium / Q000378:metabolism*; D012007:Rectum / Q000378:metabolism* / Q000473:pathology; D012016:Reference Values
D002712:Chlorides; D018679:Cholinergic Agonists; D016861:Cyclooxygenase Inhibitors; D002217:Carbachol; D000242:Cyclic AMP; D011188:Potassium; D007213:Indomethacin