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Am J Physiol Gastrointest Liver Physiol 276: G58-G63, 1999;
0193-1857/99 $5.00
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Vol. 276, Issue 1, G58-G63, January 1999

A novel plant-derived inhibitor of cAMP-mediated fluid and chloride secretion

S. E. Gabriel1,2, S. E. Davenport2, R. J. Steagall2, V. Vimal3, T. Carlson3, and E. J. Rozhon3

1 Department of Pediatric Gastroenterology and the 2 Cystic Fibrosis/Pulmonary Research and Clinical Treatment Center, University of North Carolina, Chapel Hill, North Carolina 27599; and 3 SHAMAN Pharmaceuticals Inc., South San Francisco, California 94080

We have identified an agent (SP-303) that shows efficacy against in vivo cholera toxin-induced fluid secretion and in vitro cAMP-mediated Cl- secretion. Administration of cholera toxin to adult mice results in an increase in fluid accumulation (FA) in the small intestine (FA ratio = 0.63 vs. 1.86 in control vs. cholera toxin-treated animals, respectively). This elevation in FA induced by cholera toxin was significantly reduced (FA ratio = 0.70) in animals treated with a 100 mg/kg dose of SP-303 at the same time as the cholera treatment. Moreover, when SP-303 was administered 3 h after cholera toxin, a dose-dependent inhibition of FA levels was observed with a half-maximal inhibitory dose of 10 mg/kg. In Ussing chamber studies of Caco-2 or T84 monolayer preparations, SP-303 had a significant effect on both basal current and forskolin-stimulated Cl- current. SP-303 also induced an increase in resistance that paralleled the observed decrease in current. These data suggest that SP-303 has an inhibitory effect on cAMP-mediated Cl- and fluid secretion. Thus SP-303 may prove to be a useful broad-spectrum antidiarrheal agent.

cystic fibrosis transmembrane conductance regulator; secretory diarrhea; chloride channel


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