ION-TRANSPORTING ACTIVITY IN THE MURINE COLONIC EPITHELIUM OF NORMAL ANIMALS AND ANIMALS WITH CYSTIC-FIBROSIS

Electrogenic ion transport in the isolated colonic epithelium from nor mal and transgenic mice with cystic fibrosis (CF mice) has been invest igated under short-circuit current (I-sc) conditions. Normal tissues s howed chloride secretion in response to carbachol or forskolin, which was sensitive to the Na-K-2CI cotransport inhibitor, frusemide. Respon ses to both agents were maintained for at least 12 h in vitro, but the responses to carbachol changed in format throughout this period. By c ontrast CF colons failed to show the normal secretory responses to car bachol and forskolin, most preparations showing a decrease in I-sc tha t was immediately reversed by frusemide. In CF colons addition of Ba2 ions or tetraethylammonium (TEA(+)) to the apical bathing solution an tagonised the reduction in I-sc caused by the secretagogues. It is con cluded that the reduction in I-sc in CF colons is due to electrogenic K+ secretion and this was confirmed by flux studies using rubidium-86. In normal colons exposed to TEA(+) the responses to forskolin were gr eater, but not significantly so, presumably because the minor K+-secre tory responses are dominated by major chloride-secretory responses. Ag ain rubidium-86 fluxes showed an increase of K+ secretion in normal co lons receiving forskolin. Since the amiloride-sensitive current was no t different in CF and normal colons there was no evidence that the CF mice were stressed in a way that increased mineralocorticoid levels an d hence K+ secretion. Knowledge of the phenotype of the colonic epithe lium of the CF mouse sets the baseline from which attempts at gene the rapy for the gut must be judged.