Disturbances of colonic ion secretion in inflammation: role of the enteric nervous system and cAMP.
We used the trinitrobenzenesulphonic acid (TNBS) rat model of experimental colitis to study the alterations in electrogenic ion transport in the inflamed distal colon. The distal colon exhibited decreased basal transport and reduced short-circuit current responses to carbachol and isobutylmethylxanthine (IBMX). The concentration/response curve for IBMX was also shifted to the right. Ion substitution experiments indicated that electrogenic transport was attributable chiefly to Cl(-) secretion. The mucosal layer of the inflamed distal colon (devoid of the submucosa) exhibited normal maximal responses to carbachol and IBMX, although the concentration/response curve for the latter was again shifted to the right. Tetrodotoxin markedly increased the response of the normal distal colon to both secretagogues and nullified the inhibition of the response to carbachol, but not that to IBMX, in the inflamed colon. The response of the mucosal preparation to 8-bromoadenosine 3',5'-cyclic monophosphate was similar in the normal and inflamed intestine, while the G protein activator NaF had a greater effect in the latter. The expression of the cystic fibrosis transmembrane conductance regulator (CFTR), as assessed by Northern blotting, was unchanged. cAMP levels in isolated colonocytes were markedly reduced by inflammation. We conclude that colonic inflammation produces disturbances of the enteric nervous system resulting in defective mucosal cAMP production and inhibition of ionic secretion.
Sánchez de Medina
F
F
Department of Pharmacology, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. fsanchez@ugr.es
Pérez
R
R
Martínez-Augustin
O
O
González
R
R
Lorente
M D
MD
Gálvez
J
J
Zarzuelo
A
A
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D003106:Colon / Q000276:immunology / Q000294:innervation* / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D017615:Enteric Nervous System / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D007413:Intestinal Mucosa / Q000276:immunology / Q000294:innervation / Q000378:metabolism; D007477:Ions / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid
D000779:Anesthetics, Local; D018679:Cholinergic Agonists; D007477:Ions; D010726:Phosphodiesterase Inhibitors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D013779:Tetrodotoxin; D014302:Trinitrobenzenesulfonic Acid; D002217:Carbachol; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine