Deoxycholic acid (DOC) affects the transport properties of distal colon.
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.
Mauricio
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AC
Centro de Química Fina e Biotecnologia, Departamento de Química, Universidade Nova de Lisboa, Monte da Caparica, Portugal.
Slawik
M
M
Heitzmann
D
D
von Hahn
T
T
Warth
R
R
Bleich
M
M
Greger
R
R
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
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