Mechanisms of action of zinc on rat intestinal epithelial electrogenic ion secretion: Insights into its antidiarrhoeal actions

Abstract

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 ZnSO 4 (Zn 2+) in the presence of secretagogues and inhibition of short circuit current (I sc) was measured. Key findings Pre-incubation with basolateral but not apical Zn 2+ reduced I sc stimulated by forskolin, carbachol and A23187. In the presence of the tight junction-opener, cytochalasin D, antisecretory effects of apically-applied Zn 2+ were enabled in colon and ileum. The apparent permeability coefficient (P app) of Zn 2+ was increased 1.4- and 2.4-fold across rat ileum and colon, respectively, by cytochalasin D. Basolateral addition of Zn 2+ also reduced the I sc stimulated by nystatin in rat colon, confirming K channel inhibition. In comparison with other inhibitors, Zn 2+ was a relatively weak blocker of basolateral K ATP and K Ca2+ channels. Exposure of ileum and colon to Zn 2+ for 60 min had minimal effects on epithelial histology. Conclusions Antisecretory effects of Zn 2+ on intestinal epithelia arose in part through nonselective blockade of basolateral K channels, which was enabled when tight junctions were open. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.