Mechanisms of action of zinc on rat intestinal epithelial electrogenic ion secretion: insights into its antidiarrhoeal actions.
ABSTRACT 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.
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.
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.
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.
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ABSTRACT: This study addressed the mechanisms by which dietary zinc affects diarrhoea and aimed to study possible interactions between zinc status and the presence of zinc in vitro on secretagogue-induced secretion from piglet intestinal epithelium in Ussing chambers. In addition, it was studied from which side of the epithelium zinc would perform an effect and if copper caused similar effects. Twenty-four piglets (28 days of age) were weaned and fed diets containing 100 or 2500 mg zinc/kg (as ZnO) for 5 or 6 days (12 piglets per group). Intestinal epithelium underwent the following 5 treatments: zinc at the mucosal side (M(Zn)), zinc at the serosal side (S(Zn)), zinc at both sides (MS(Zn)), copper at both sides (MS(Cu)) or water at both sides (control). Provoked secretion in terms of short circuit responses to serotonin (5-HT) and vasoactive intestinal peptide (VIP) were measured. Zinc at the serosal or both sides of the epithelium reduced the 5-HT induced secretion (P<0.001); however, due to interactions (P=0.05) the effect of zinc in vitro was only present in the ZnO(100) group. The secretion caused by VIP was not affected by the diet (P=0.33), but zinc at the serosal side or both sides reduced the response to VIP (P<0.001). Copper reduced the 5-HT and VIP induced secretion to a larger extent than zinc. However, copper also disturbed intestinal barrier function as demonstrated by increased transepithelial conductance and increased short circuit current, which was unaffected by zinc. In conclusion, zinc at the serosal side of piglet small intestinal epithelium attenuated 5-HT and VIP induced secretion in vitro. These in vitro studies indicate that in vivo there will be no positive acute effect of increasing luminal Zn concentration on secretagogue-induced chloride secretion and that zinc status at the serosal side of the epithelium has to be increased to reduce secretagogue-induced chloride secretion and thereby diarrhoea.Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 01/2008; 149(1):51-8. · 2.20 Impact Factor
- Journal of Biological Chemistry 09/2006; 281(34):24085-9. · 4.65 Impact Factor
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ABSTRACT: The Vibrio cholerae bacterium causes devastating diarrhea when it infects the human intestine. The key event is adenosine diphosphate (ADP)-ribosylation of the human signaling protein GSalpha, catalyzed by the cholera toxin A1 subunit (CTA1). This reaction is allosterically activated by human ADP-ribosylation factors (ARFs), a family of essential and ubiquitous G proteins. Crystal structures of a CTA1:ARF6-GTP (guanosine triphosphate) complex reveal that binding of the human activator elicits dramatic changes in CTA1 loop regions that allow nicotinamide adenine dinucleotide (NAD+) to bind to the active site. The extensive toxin:ARF-GTP interface surface mimics ARF-GTP recognition of normal cellular protein partners, which suggests that the toxin has evolved to exploit promiscuous binding properties of ARFs.Science 09/2005; 309(5737):1093-6. · 31.20 Impact Factor