Secretory diarrhea warrants global health research because it is a leading cause of childhood morbidity and Mortality in developing countries. While diarrhea can be treated with oral re-hydration solution (ORS), inclusion of .Zn2+ with ORS has been shown to reduce the duration of acute diarrhea. However, how Zn2+ improves diarrhea is not known. In secretory diarrhea, there is an excessive intestinal cr secretion which is stimulated by the elevation of intracellular cAMP and Ca2+ concentrations. It is also not known whether Zn2+ is effective against either or both of these two secretagogues. Forskolin/cAMP stimulated Cl- secretion in intestinal T84 cells is a sustained event. However, in the presence of Zn2+, it becomes transient and reduced in duration. We hypothesize that when Zn2+ and FSK are added simultaneously to T84 cells, they act synergistically to elevate [Ca2+]j which initially stimulates cr secretion. 2n2+ subsequently limits FSK stimulated cr secretion by blocking cAMP-stimulated K+ channel activity and generating the negative signal, Ins(3,4,5,6)P4 which is a potent inhibitor of Ca2+ activated cr channel on the apical membrane. Inhibiting cAMP-stimulated K+ channel inhibits the driving force for cr secretion and thus reduces cr secretion in response to FSK. Our model explains how Zn2+ improves diarrhea by reducing its duration and suggests that Zn2+ is therapeutically important as an anti-diarrheal compound that improves excessive cAMP¬mediated Cl- secretion (diarrhea). We believe that Zn2+ has substantial benefit in terms of inhibition of anion secretion and reduction of disease duration combined with low cost.
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Project Abstract
