title: Deoxycholic acid (DOC) affects the transport properties of distal colon.
abstract: Secondary bile acids can induce diarrhea. In the present study we examined the effects of deoxycholic acid (DOC) on equivalent short-circuit current (Isc) in rabbit colon and the cellular mechanisms involved in DOC action (rabbit and rat). Luminal DOC inhibited amiloride-sensitive Na+ absorption. In the presence of amiloride luminal DOC had a concentration dependent effect on Isc. Low concentrations (1-10 micromol/l) induced a lumen-positive current (51+/-3 microA/cm2, 10 micromol/l, n=7) which was inhibited by luminal Ba2+ suggesting the activation of a luminal K+ conductance. Higher luminal concentrations induced a lumen-negative current (-76+/-9 microA/cm2, 100 micromol/l, n=11). Basolateral application of DOC, also in the presence of amiloride, only induced lumen-negative Isc, (-58+/-10 microA/cm2, 100 micromol/l, n=6, EC50= 3 micromol/l). This current could be abolished completely by the K+ channel blocker 293B, a selective inhibitor of cAMP-dependent Cl- secretion. This action of DOC on Isc was additive to the effect of carbachol (CCH) but not additive to that of cAMP. In intact rat colon mucosa pre-treated with DOC a significant increase in cAMP production was observed. Fura-2 measurements of cytosolic Ca2+ activity ([Ca2+]i) in isolated colonic crypts (rabbit and rat) showed that 100 micromol/l DOC induced a weak [Ca2+]i increase. Whole-cell measurements of membrane voltage in isolated rat colonic crypts revealed a hyperpolarization by DOC (4.9+/-0.8 mV, 100 micromol/l, n=8) but a depolarization by prostaglandin E2 (PGE2, via cAMP) (24+/-7 mV, n=8). The present data show that DOC acts at more than one target in the colon: in the intact mucosa it activates luminal K+ channels and Cl- secretion and this is paralleled by an increase in cAMP production. In isolated crypts DOC probably activates a Ca(2+)-regulated K+ conductance but has no effect on cAMP. Hence DOC probably activates ion channels or channel-regulating factors in colonocytes and acts on non-epithelial cells to activate Cl- secretion indirectly.
authors.affiliation: Centro de Química Fina e Biotecnologia, Departamento de Química, Universidade Nova de Lisboa, Monte da Caparica, Portugal.
authors.forename: A C
authors.initials: AC
authors.lastname: Mauricio
authors.forename: M
authors.initials: M
authors.lastname: Slawik
authors.forename: D
authors.initials: D
authors.lastname: Heitzmann
authors.forename: T
authors.initials: T
authors.lastname: von Hahn
authors.forename: R
authors.initials: R
authors.lastname: Warth
authors.forename: M
authors.initials: M
authors.lastname: Bleich
authors.forename: R
authors.initials: R
authors.lastname: Greger
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003106:Colon / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003840:Deoxycholic Acid / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology; D053503:Epithelial Sodium Channels; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism; D013424:Sulfanilamides / Q000494:pharmacology; D013777:Tetrazoles; D013876:Thiophenes; D000096926:Benzenesulfonamides
chemical_list: D000584:Amiloride; D002118:Calcium; D018118:Chloride Channels; D002712:Chlorides; D000242:Cyclic AMP; D003840:Deoxycholic Acid; D003902:Detergents; D015232:Dinoprostone; D004232:Diuretics; D053503:Epithelial Sodium Channels; D005456:Fluorescent Dyes; D016257:Fura-2; D015221:Potassium Channels; D015222:Sodium Channels; D013424:Sulfanilamides; C018222:azosemide; D013777:Tetrazoles; D013876:Thiophenes; D000096926:Benzenesulfonamides