Regulation of intestinal Cl- and HCO3-secretion by uroguanylin
Joo, N.S.; London, R.M.; Kim, H.D.; Forte, L.R.; Clarke, L.L.
American Journal of Physiology 274(4): G633-G644
1998
ISSN/ISBN: 0002-9513 PMID: 9575844 Document Number: 495066
Uroguanylin is an intestinal peptide hormone that may regulate epithelial ion transport by activating a receptor guanylyl cyclase on the luminal surface of the intestine. In this study, we examined the action of uroguanylin on anion transport in different segments of freshly excised mouse intestine, using voltage-clamped Ussing chambers. Uroguanylin induced larger increases in short-circuit current (Isc) in proximal duodenum and cecum compared with jejunum, ileum, and distal colon. The acidification of the lumen of the proximal duodenum (pH 5.0-5.5) enhanced the stimulatory action of uroguanylin. In physiological Ringer solution, a significant fraction of the Isc, stimulated by uroguanylin was insensitive to bumetanide and dependent on HCO3- in the bathing medium. Experiments using pH-stat titration revealed that uroguanylin stimulates serosal-to-luminal HCO3- secretion (JO3fwdarws-lHCOl3-) together with a larger increase in Isc. Both Jsfwdarw1HCO3- and Isc were significantly augmented when luminal pH was reduced to pH 5.15. Uroguanylin also stimulated the JHCO3-s-I and Isc across the cecum, but luminal acidity caused a generalized decrease in the bioelectric responsiveness to agonist stimulation. In cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice, the duodenal Isc response to uroguanylin was markedly reduced, but not eliminated, despite having a similar density of functional receptors. It was concluded that uroguanylin is most effective in acidic regions of the small intestine, where it stimulates both HCO3- and Cl- secretion primarily via a CFTR-dependent mechanism.