Abstract
Background and PurposeThe 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.Experimental ApproachHT-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 (ISC) and tracer fluxes of 22Na+ and 36Cl−. 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.Key ResultsIn HT-29/B6 cells, Uzara inhibited forskolin- as well as cholera toxin-induced ISC 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 ISC 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.Conclusion and ImplicationsUzara 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.
Highlights
Diarrheal diseases have a major impact on morbidity and mortality worldwide
Monolayers of HT-29/B6 cells were mounted into Ussing chambers
When forskolin (10 mM, basolaterally) was applied, ISC rapidly increased to 59.964.0 mA/cm2 equivalent to a net transport of monovalent ions of 2.2360.15 mmol/(h?cm2) (n = 6) and remained on this level for at least 80 min (Fig. 1A, P,0.001)
Summary
The subclass of secretory diarrhea is typically induced by bacterial pathogens like enterotoxic E. coli or, in the worst case, Vibrio cholerae. It is characterized by active secretion of chloride and/or bicarbonate into the intestine and subsequently by a loss of fluid [1]. Electrogenic chloride secretion is the predominant anion secretory process. It is the result of the action of four membrane transporters acting in concert. The Na+/K+-ATPase provides the driving force for this chloride uptake by discharging sodium across the basolateral membrane. Enzymatic activity of the Na+/K+-ATPase and intracellular cAMP levels (ELISA) were measured
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