title: Anti-diarrheal mechanism of the traditional remedy Uzara via reduction of active chloride secretion.
abstract: OBJECTIVE
  The root extract of the African Uzara plant is used in traditional medicine as anti-diarrheal drug. It is known to act via inhibition of intestinal motility, but malabsorptive or antisecretory mechanisms are unknown yet.
  
  
  METHODS
  HT-29/B6 cells and human colonic biopsies were studied in Ussing experiments in vitro. Uzara was tested on basal as well as on forskolin- or cholera toxin-induced Cl(-) secretion by measuring short-circuit current (I(SC)) and tracer fluxes of (22)Na(+) and (36)Cl(-). Para- and transcellular resistances were determined by two-path impedance spectroscopy. Enzymatic activity of the Na(+)/K(+)-ATPase and intracellular cAMP levels (ELISA) were measured.
  
  
  RESULTS
  In HT-29/B6 cells, Uzara inhibited forskolin- as well as cholera toxin-induced I(SC) within 60 minutes indicating reduced active chloride secretion. Similar results were obtained in human colonic biopsies pre-stimulated with forskolin. In HT-29/B6, the effect of Uzara on the forskolin-induced I(SC) was time- and dose-dependent. Analyses of the cellular mechanisms of this Uzara effect revealed inhibition of the Na(+)/K(+)-ATPase, a decrease in forskolin-induced cAMP production and a decrease in paracellular resistance. Tracer flux experiments indicate that the dominant effect is the inhibition of the Na(+)/K(+)-ATPase.
  
  
  CONCLUSIONS
  Uzara exerts anti-diarrheal effects via inhibition of active chloride secretion. This inhibition is mainly due to an inhibition of the Na(+)/K(+)-ATPase and to a lesser extent to a decrease in intracellular cAMP responses and paracellular resistance. The results imply that Uzara is suitable for treating acute secretory diarrhea.
authors.affiliation: Department of Gastroenterology, Section of General Medicine and Nutrition, Charité, Campus Benjamin Franklin, Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany. joerg.schulzke@charite.de
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Schulzke
authors.forename: Susanne
authors.initials: S
authors.lastname: Andres
authors.forename: Maren
authors.initials: M
authors.lastname: Amasheh
authors.forename: Anja
authors.initials: A
authors.lastname: Fromm
authors.forename: Dorothee
authors.initials: D
authors.lastname: Günzel
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000930:Antidiarrheals / Q000494:pharmacology*; D029062:Apocynaceae / Q000737:chemistry*; D001692:Biological Transport / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D017097:Electric Impedance; D005260:Female; D019073:HT29 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008519:Medicine, Traditional; D008875:Middle Aged; D009761:Nystatin / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D000930:Antidiarrheals; D002712:Chlorides; D010936:Plant Extracts; D009761:Nystatin; D005576:Colforsin; D010042:Ouabain; D002217:Carbachol; D002772:Cholera Toxin; D012964:Sodium; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid