EBIO, an agent causing maintained epithelial chloride secretion by co-ordinate actions at both apical and basolateral membranes.
The effect of 1-ethyl-2-benzimidazolone (EBIO) on electrogenic chloride secretion in murine colonic and nasal epithelium was investigated by the short-circuit technique. In the colon, EBIO produces a sustained current increase in the presence of amiloride, which is sensitive to furosemide. In nasal epithelium EBIO causes only a small, transient current increase. Sustained increases in current were obtained in response to forskolin in both epithelia. To examine the mechanisms by which EBIO increases chloride secretion, the effects on intracellular mediators were measured in colonic crypts. There was no effect on [Ca(2+)]i but cAMP content was increased, more so in the presence of IBMX, indicating a direct effect on adenylate cyclase. In colonic epithelia in which the apical surface was permeabilized by nystatin, and the tissue subjected to an apical to basolateral K(+) gradient, EBIO caused a current increase that was entirely sensitive to charybdotoxin (ChTX). In similarly permeabilized colons Br-cAMP caused a current increase that was entirely sensitive to 293B. Thus EBIO increases chloride secretion in the colon by coordinated actions at both the apical and basolateral faces of the cells. These include direct and indirect actions on Ca(2+)-sensitive and cAMP-sensitive K(+) channels respectively, and indirect actions on the basolateral cotransporter and apical CFTR chloride channels via cAMP. In CF colonic epithelia EBIO did not evoke chloride secretion. It is not clear why the nasal epithelium responds poorly to EBIO whereas it gives a sustained response to the related compound chlorzoxazone.
MacVinish
L J
LJ
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ, UK.
Keogh
J
J
Cuthbert
A W
AW
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D018999:Charybdotoxin / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D002753:Chlorzoxazone / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009297:Nasal Mucosa / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism
D001562:Benzimidazoles; D002120:Calcium Channel Agonists; D002712:Chlorides; D009125:Muscle Relaxants, Central; D015221:Potassium Channels; D018999:Charybdotoxin; D005576:Colforsin; D000242:Cyclic AMP; D002753:Chlorzoxazone; C102635:1-ethyl-2-benzimidazolinone