Zinc supplementation in oral rehydration solutions: experimental assessment and mechanisms of action

Background: Zinc deficiency is associated with chronic diarrhea. This condition is generally linked to an overproduction of nitric oxide (NO), which induces secretion and cellular damage as a free radical. Use of oral rehydration solutions (ORS) is an important part of diarrhea treatment, especially early in infancy and for patients with cholera. The presence of zinc in an ORS could be a positive factor in recovery from diarrheal disease. Objective: This study was undertaken to determine whether zinc added to an ORS could regulate the synthesis of NO metabolites in the lumen of zinc deficient rat intestine, acting as a gastrointestinal protector and thus accelerating normalization of intestinal function and zinc status. Methods: The effects of zinc on NO metabolism were studied in young male rats fed a zinc deficient diet for three weeks to mimic the condition of patients with recurrent diarrheal episodes. During the fourth week of the zinc deficient feedings, experimental diarrhea was induced using cathartics (magnesium citrate plus phenolphthalein) that exacerbate NO production. A standard ORS with or without 1 mM zinc was given to the rats for the last two days. A control group received a zinc sufficient diet. Rats were killed at each stage. Intestinal nitric oxide synthase (NOS) was assayed, cecal fluid contents were analyzed for nitrates and nitrites, intestinal histology was examined, and activation of nuclear factor NF-kappaB DNA binding activity was determined. Results: Rats fed the zinc-deficient diet for three weeks gained less weight than rats fed a normal zinc content diet and had a lower plasma zinc than controls (51.6 +/- 5.4 [n = 10] vs. 143.6 +/- 7.2 microgram/dL [n = 11], p < 0.05). Recovery with ORS+Zn resulted in a higher plasma zinc than with the ORS-Zn (ORS+Zn: 186.5 +/- 12.2; ORS-Zn: 57.5 +/- 6.6 microgram/dL, p < 0.05). The zinc-deficient diet did not alter mucosal NOS, as compared to the values of rats fed a normal diet. However, those animals which received five days of cathartic fluids had a small intestinal NOS higher than that of all other groups. Either ORS+Zn or ORS-Zn normalized NOS activity, regardless of cathartic treatment. The rats fed the zinc deficient diet had generally a higher content of NO metabolites in the cecum than rats fed a normal diet. After recovery with either type of ORS, rats given the cathartic remained with higher cecal NO metabolite concentrations than rats that had no induced diarrhea. After recovery with ORS+Zn, intestinal villi showed significant expansion of the lamina propria, an indication of greater absorption of fluid, while with ORS-Zn this was not present. Small intestinal homogenates of rats recovering with ORS+Zn had a decreased NF-kappaB DNA binding activity than tissues from rats consuming ORS-Zn. Conclusions: The results are consistent with the hypothesis that addition of Zn to an ORS may contribute to improving the physiologic status of the small intestine and potentially reduce the risks of recurrent diarrhea episodes.