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Am J Physiol Gastrointest Liver Physiol 274: G633-G644, 1998;
0193-1857/98 $5.00
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Vol. 274, Issue 4, G633-G644, April 1998

Regulation of intestinal Clminus and HCO<SUP>−</SUP><SUB>3</SUB> secretion by uroguanylin

Nam Soo Joo1, Roslyn M. London1,2, Hyun Dju Kim1, Leonard R. Forte1,2, and Lane L. Clarke3,4

1 Department of Pharmacology, School of Medicine, 3 Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, and the 4 Dalton Cardiovascular Research Center, University of Missouri and 2 The Truman Veterans Affairs Medical Center, Columbia, Missouri 65212

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 HCO<SUP>−</SUP><SUB>3</SUB> in the bathing medium. Experiments using pH-stat titration revealed that uroguanylin stimulates serosal-to-luminal HCO<SUP>−</SUP><SUB>3</SUB> secretion (<IT>J</IT><SUP>HCO<SUP>−</SUP><SUB>3</SUB></SUP><SUB>s→l</SUB>) together with a larger increase in Isc. Both <IT>J</IT><SUP>HCO<SUP>−</SUP><SUB>3</SUB></SUP><SUB>s→l</SUB> and Isc were significantly augmented when luminal pH was reduced to pH 5.15. Uroguanylin also stimulated the <IT>J</IT><SUP>HCO<SUP>−</SUP><SUB>3</SUB></SUP><SUB>s→l</SUB> 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 HCO<SUP>−</SUP><SUB>3</SUB> and Cl- secretion primarily via a CFTR-dependent mechanism.

cyclic GMP; bicarbonate transport; chloride transport; cystic fibrosis; cystic fibrosis transmembrane conductance regulator; guanylyl cyclase; mouse intestine; proximal duodenum


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