Zinc as a Potential Enteroprotector in Oral Rehydration Solutions: Its Role in Nitric Oxide Metabolism

Abstract

Zinc has been recognized as an antioxidant with potential for chronic and acute effects. Oxidative damage produced by free radicals, including nitric oxide (NO), is responsible for certain types of intestinal malabsorption syndromes and diarrhea. Under physiologic or mildly stimulatory conditions for NO synthesis, the small intestine characteristically is in a proabsorptive state; however, an excessive production of NO triggers formation of cyclic nucleotides, which cause secretion and malabsorption. In this study, we hypothesized that low-molecular-weight, soluble zinc chelates could modulate the effects of induced NO excess on the small intestine. In vitro experiments demonstrated that zinccitrate or zinc-histidine at Ն0.66 mM, as well as a known NO scavenger, 2-[carboxyphenyl]-4,4,4,4-tetramethylimidazoline-1-oxyl-3-oxide, at 2 M, were effective at removing chemically generated NO. In vivo jejunal perfusions, conducted in healthy rats under anesthesia, showed that c-PTIO reduced the proabsorptive effects produced by 1 mM L-arginine, the precursor of NO. In a standard oral rehydration solution, 1 mM zinc-citrate partially reversed the antiabsorptive effects on potassium caused by an excess of NO generated from 20 mM L-arginine but did not alter sodium or water absorption. The data are consistent with the view that soluble zinc compounds incorporated into an oral rehydration solution may deserve further attention as a means to scavenge NO with fluids used for the treatment of chronic or acute diarrhea, especially in malnourished children who are often zinc deficient. The importance of NO as a second messenger has become fully recognized in the last several years, especially in regard to endothelial tissue responses to endogenous stimuli (1). A reduction of NO synthesis from Arg in endothelia may lead to cell contraction, increased vascular protein leakage, and inflammation (2, 3). The latter may be linked to free radical formation. The severity of chronic ileitis has been associated with the extent of NO synthesis by inducible NO synthase (iNOS) in the intestine (4). This may play a role on the integrity of the mucosal barrier, compromised in that condition. Proinflammatory cytokines up-regulate iNOS, as experimentally shown in chemically induced colitis injury (5), after injection of IL-1␣ (6) and in cancer patients receiving IL-2 (7). Animal and human studies support the view that zinc has anti-inflammatory properties. In rats with 2,4,6-trinitrobenzenesulfonic acid-induced colitis, zinc sulfate enemas produced a decrease in the lesion area and in other markers of inflammation (8). In another context, zinc ions have been considered an important anti-inflammatory factor because they appear to block human rhinovirus docking on intercellular adhesion molecule-1 (ICAM-1) on somatic cells, thus interrupting the inflammatory process (9). Experiments on rats injected with lipopolysaccharide (LPS) to induce inflammation showed that endogenous zinc inhibited LPS or IL-1-induced NO formation, as well as reduced the act...

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