Krisanaklan Reduces Intestinal Anion and Fluid Secretion Through Inhibition of Na⁺/K⁺-ATPase and K⁺ Channel Activity

Krisanaklan (KK) is a traditional herbal remedy used to treat an array of gastrointestinal complaints, including infectious, secretory diarrhea (SD). We assessed the effect of KK on anion and fluid secretion across intestinal epithelia, and delineated its mode of action. KK inhibited cholera toxin/cAMP-dependent anion secretion across intestinal epithelial monolayers and native intestinal epithelium ex vivo. Similarly, KK reduced cAMP-dependent fluid secretion in intestinal organoids. KK inhibited Na⁺,K⁺-ATPase (NKA)-mediated, ouabain-sensitive ion transport and channel-mediated K⁺ efflux across the basolateral plasma membrane but did not block cAMP-dependent anion transport across the apical plasma membrane. KK also inhibited ouabain-insensitive ATPase activity, but did not affect cAMP-dependent protein phosphorylation. KK reduced carrier-mediated amino acid uptake in Caco-2 cells and Na⁺-coupled glucose transport in porcine intestine. Further, KK inhibited cGMP- and Ca²⁺-linked anion secretion across intestinal epithelial monolayers. We conclude that KK blocks intestinal epithelial anion and fluid secretion by inhibition of the NKA and K⁺ channels. Consequently, KK may ameliorate SD caused by enteric microbial pathogens. However, by inhibiting the activity of Na⁺-dependent solute carriers, it is also predicted to counteract oral rehydration therapy, the current mainstay for SD therapy.