CFTR-mediated inhibition of epithelial Na1 conductance in human colon is defective in cystic fibrosis

Mall, M., M. Bleich, J. Kuehr, M. Brandis, R. Greger, and K. Kunzelmann. CFTR-mediated inhibition of epithelial Na1 conductance in human colon is defective in cystic fibrosis. Am. J. Physiol. 277 (Gastrointest. Liver Physiol. 40): G709–G716, 1999.—Cystic fibrosis (CF) patients show characteristic defects in epithelial ion transport, such as failure in cAMP-dependent Cl2 secretion. Because the cystic fibrosis transmembrane conductance regulator (CFTR) also functions as a downregulator of epithelial Na1 channels (ENaC), enhanced Na1 conductance was found in the airways of CF patients. Here, we examined whether enhanced epithelial Na1 conductance is also present in the colonic epithelium of CF patients and examined the underlying mechanisms. Thus transepithelial voltages were measured, and equivalent shortcircuit currents (Isc-eq) were determined by means of a novel type of Ussing chamber. Non-CF tissues demonstrated cAMPdependent Cl2 secretion that was absent in biopsies of CF patients. Correspondingly, Isc-eq was inhibited in non-CF but not in CF epithelia when synthesis of endogenous prostaglandins was blocked by indomethacin. In the presence of indomethacin, a larger portion of amiloride-sensitive Isc-eq was detected in CF tissues, suggesting enhanced ENaC conductance in colonic mucosa of CF patients. Increase of intracellular cAMP by forskolin and IBMX inhibited amiloridesensitive ENaC currents in non-CF tissues but not in CF biopsies. Therefore, enhanced epithelial Na1 conductance is present in the CF colon and is probably due to missing downregulation by CFTR.