| 18187619 |
Wu D, Hu Z: Rutaecarpine induces chloride secretion across rat isolated distal colon. . J Pharmacol Exp Ther. 2008 Apr;325(1):256-66. Epub 2008 Jan 10.
The present study evaluated the effect of rutaecarpine (Rut) on Cl (-) secretion across rat distal colonic mucosa. Basolateral application of Rut elicited an increase in short-circuit current (I (SC)) response in a concentration-dependent manner. Evidence that Rut-stimulated I (SC) was due to Cl (-) secretion is based on 1) inhibition of current by bumetanide; 2) Cl (-) channel blockers diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)-benzoic acid, and glibenclamide; and 3) removal of Cl (-) ions in bath solution. Determination of neurogenic blockers on Rut-induced I (SC) indicated that pretreatment of tissues with tetrodotoxin or indomethacin, but not atropine or hexamethonium, inhibited Rut-induced response. Treatment with Rut led to release and synthesis of prostaglandin E (2) in rat colonic mucosa. Rut-stimulated I (SC) was markedly reduced by pretreatment with MDL-12,330A [cis-N-[2-phenylcyclopentyl]-azacyclotridec-1-en-2-amine] and N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide (H-89), but not with 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, bisindolylmaleimide, and thapsigargin. Elimination of the extracellular Ca (2+) also did not alter Rut response. Rut treatment resulted in the increase in intracellular cAMP levels and the activation of protein kinase A. Depolarizing the basolateral membrane with high K (+) showed that Rut-stimulated apical Cl (-) current was largely prevented by cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors. Permeabilizing apical membrane with nystatin revealed that Rut-stimulated basolateral K (+) current was specifically inhibited by Ba (2+) ions and chromanol 293B. The evidence derived from present study suggests that Rut-stimulated Cl (-) secretion is mediated by generation of endogenous prostaglandin E (2) and that it also involves the stimulation of cAMP and protein kinase A pathways, which subsequently lead to the activation of apical Cl (-) channels, mostly the CFTR and basolateral cAMP-dependent K (+) channels. |
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