REGULATION OF INTESTINAL CL- AND HCO3- SECRETION BY UROGUANYLIN

Uroguanylin is an intestinal peptide hormone that may regulate epithel ial ion transport by activating a receptor guanylyl cyclase on the lum inal surface of the intestine. In this study, we examined the action o f uroguanylin on anion transport in different segments of freshly exci sed mouse intestine, using voltage-clamped Ussing chambers. Uroguanyli n induced larger increases in short-circuit current (I-sc) in proximal duodenum and cecum compared with jejunum, ileum, and distal colon. Th e acidification of the lumen of the proximal duodenum (pH 5.0-5.5) enh anced the stimulatory action of uroguanylin. In physiological Ringer s olution, a significant fraction of the I-sc stimulated by uroguanylin was insensitive to bumetanide and dependent on HCO3- in the bathing me dium. Experiments using pH-stat titration revealed that uroguanylin st imulates serosal-to-luminal HCO3- secretion (J(s->l)(HCO3-)) together with a larger increase in I-sc. Both J(s->l)(HCO3-) and I-sc were sign ificantly augmented when luminal pH was reduced to pH 5.15. Uroguanyli n also stimulated the J(s->l)(HCO3-) and I-sc across the cecum, but lu minal acidity caused a generalized decrease in the bioelectric respons iveness to agonist stimulation. In cystic fibrosis transmembrane condu ctance regulator (CFTR) knockout mice, the duodenal I-sc response to u roguanylin was markedly reduced, but not eliminated, despite having a similar density of functional receptors. It was concluded that uroguan ylin is most effective in acidic regions of the small intestine, where it stimulates both HCO3- and Cl- secretion primarily via a CFTR-depen dent mechanism.