Oxidants potentiate Ca(2+)- and cAMP-stimulated Cl(-) secretion in intestinal epithelial T84 cells.
OBJECTIVE
Diarrhea is one of the major complications of inflammatory bowel disease. The role of oxidants in promoting net intestinal secretion is important, but the cellular mechanisms underlying their effects are unclear. We examined the effects and defined the cellular actions of the oxidant monochloramine (NH(2)Cl) on anion secretion in human colonic T84 cells.


METHODS
Effects of NH(2)Cl on basal and agonist-stimulated short-circuit current (Isc) of T84 monolayers were determined. Apical Cl(-) and basolateral K(+) conductances were measured by efflux of (125)I(-) and (86)Rb(+), respectively.


RESULTS
NH(2)Cl alone had little effect on Isc and (125)I(-) efflux. However, pretreatment with NH(2)Cl led to a concentration-dependent potentiation of the Ca(2+)-mediated Isc and of submaximal cAMP-mediated responses. These effects were associated with increased basolateral K(+) channel conductance and were blocked by increasing cellular Ca(2+) buffering capacity with Quin-2. Whole-cell voltage clamp experiments showed that NH(2)Cl potentiated Ca(2+) activation of basolateral K(+) channel conductance.


CONCLUSIONS
Oxidants potentiate both Ca(2+)- and cAMP-stimulated Cl(-) secretion by a direct effect on calcium-activated basolateral K(+) channel conductance, lowering its Ca(2+) activation threshold. This effect may play an important role in amplifying and prolonging the secretory response of inflamed intestinal mucosa and enhancing the severity of diarrhea.
Sugi
K
K
The Martin Boyer Laboratories, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Musch
M W
MW
Di
A
A
Nelson
D J
DJ
Chang
E B
EB
D000634:Aminoquinolines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002700:Chloramines / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D003967:Diarrhea / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D007457:Iodine Radioisotopes; D007502:Iron Chelating Agents / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D016877:Oxidants / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D012414:Rubidium Radioisotopes
D000634:Aminoquinolines; D002700:Chloramines; D002712:Chlorides; D007457:Iodine Radioisotopes; D007502:Iron Chelating Agents; D016877:Oxidants; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; D000242:Cyclic AMP; C030816:chloramine; C035739:Quin2; D011188:Potassium; D002118:Calcium