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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Rutaecarpine Induces Chloride Secretion across Rat Isolated Distal Colon

Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (D.Z.W., Z.B.H.); and E-Institute of Traditional Chinese Medicine Internal Medicine, Shanghai Municipal Education Commission, Shanghai, China (D.Z.W.)

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 E₂ 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 Ca²⁺ 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 Ba²⁺ ions and chromanol 293B. The evidence derived from present study suggests that Rut-stimulated Cl^– secretion is mediated by generation of endogenous prostaglandin E₂ 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.

Address correspondence to: Dr. ZhiBi Hu, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rd., Zhangjiang Hi-tech Park, Shanghai 201203, People's Republic of China. E-mail: zhibihu{at}hotmail.com