CFTR IS REQUIRED FOR CAMP INHIBITION OF INTESTINAL NA-FIBROSIS MOUSE MODEL( ABSORPTION IN A CYSTIC)

Acute adenosine 3',5'-cyclic monophosphate (cAMP) stimulation of intes tinal epithelium induces net transepithelial Cl- secretion and inhibit s neutral coupled NaCl absorption. To investigate the role that the cy stic fibrosis transmembrane conductance regulator (CFTR) plays in thes e events, we measured bioelectric changes and radioisotopic NaCl flux across jejunal tissues from gene-targeted cftr ''knockout'' mice [cftr (-/-) homozygotes] and their normal littermates [cftr(+/+) homozygotes and cftr(+/-) heterozygotes]. Before stimulation, the short-circuit c urrent (I-sc, an index of Cl- secretion) of the cftr(-/-) jejunum was essentially zero and significantly less than in the cftr(+/+) or cftr( +/-) intestine. Acute cAMP stimulation had little effect on the bioele ctric parameters of the cftr(-/-) intestine but induced a marked incre ase of I-sc and decrease of total tissue conductance in both the cftr( +/+) and cftr (+/-) intestine. Differences in the magnitude of the cAM P-induced I-sc between the cftr(+/+) and cftr(+/-) intestine were only observed when the cell-to-lumen anion concentration gradient was maxi mized by removal of permeant anions from the luminal bath. Radioisotop e flux measurements revealed that Na+ and Cl- were absorbed equally ac ross the cpr(-/-) jejunum under basal conditions. In cftr(+/+) and cft r(+/-) intestine, Na+ was absorbed at a similar rate, but net Cl- abso rption was reduced from that in cftr(-/-) intestine by an amount appro ximating the I-sc. Acute cAMP stimulation of the cftr(+/+) and cftr(+/ -) intestine abolished net NaCl absorption and induced electrogenic Cl - secretion. In contrast, net NaCl absorption was unchanged from the p receding flux period in the cftr(-/-)jejunum. The data suggest that CF TR not only mediates cAMP-induced transepithelial Cl- secretion but is also required for cAMP inhibition of neutral NaCl absorption in the i ntestine.