Mechanisms of Action of Zinc on Intestinal Epithelial Electrogenic Ion Secretion: Insights into its Anti-Diarrheal Actions

Objectives  Zinc is a useful addition to oral rehydration therapy for acute diarrhoea. We have assessed the mechanism of its epithelial antisecretory action when intestinal epithelial tight junctions were pharmacologically opened.

Methods  Rat isolated ileal and colonic mucosae were mounted in Ussing chambers and exposed to ZnSO4 (Zn2+) in the presence of secretagogues and inhibition of short circuit current (Isc) was measured.

Key findings  Pre-incubation with basolateral but not apical Zn2+ reduced Isc stimulated by forskolin, carbachol and A23187. In the presence of the tight junction-opener, cytochalasin D, antisecretory effects of apically-applied Zn2+ were enabled in colon and ileum. The apparent permeability coefficient (Papp) of Zn2+ was increased 1.4- and 2.4-fold across rat ileum and colon, respectively, by cytochalasin D. Basolateral addition of Zn2+ also reduced the Isc stimulated by nystatin in rat colon, confirming K channel inhibition. In comparison with other inhibitors, Zn2+ was a relatively weak blocker of basolateral KATP and K Ca2+ channels. Exposure of ileum and colon to Zn2+ for 60 min had minimal effects on epithelial histology.

Conclusions  Antisecretory effects of Zn2+ on intestinal epithelia arose in part through nonselective blockade of basolateral K channels, which was enabled when tight junctions were open.