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Calcimimetic inhibits the effect of Cholera Toxin in Rat Small Bowel
Syed M Alam1, Stanley J Dudrick1, John Geibel2
1Department of Surgery, Saint Mary's Health System, Waterbury, CT;2Department of Surgery, Yale University School of Medicine, New Haven, CT
Introduction: Cholera is a life-threatening secretory diarrhea caused by cholera enterotoxin (CT) binding to the plasma membrane of intestinal epithelial cells, resulting in excessive fluid and electrolyte secretion. The aim of the present study was to demonstrate that the calcimimetic R-568 can prevent the CT induced fluid movement.
Methods: Isolated 15 cm loops of rat small bowel were used in this study. Microelectrodes and 2 mm tubes were inserted at the proximal and distal ends of the loop and fixed in place using 3.0 silk sutures, allowing for continuous recording and perfusion. Fluid secretion was determined by the change in voltage across the electrode (movement of Cl- ions from cell to lumen). In one series the lumen was infused with cholera toxin for 5 minutes before stopping the luminal infusion; recordings were made at 15 minute intervals for 90 minutes. In a separate series, two sequential loops (CT, CT plus calcimimetic) of bowel were examined. Both cholera and the R-568 compound were mixed individually in 0.5 Normal Saline for infusion.
Results: Addition of CT to perfused loops resulted in a continuous increase in voltage, indicative of fluid secretion from blood to lumen. This was confirmed by increased loop diameter. Pre-addition or concomitant addition of the calcimimetic R-568 prevented CT induced fluid secretion.
Conclusion: Cholera toxin causes increased salt and fluid secretion in isolated rat ileal loops as evidenced by the increase in voltage and luminal diameter in the perfused loops. Pre-treatment with a calcimimetic can completely prevent fluid secretion in the presence of CT. These data suggest that calcimimetics may be potent therapeutic agents for the treatment of bacterial induced secretory diarrhea.
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