A novel plant-derived inhibitor of cAMP-mediated fluid and chloride secretion.
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.
Gabriel
S E
SE
Department of Pediatric Gastroenterology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Davenport
S E
SE
Steagall
R J
RJ
Vimal
V
V
Carlson
T
T
Rozhon
E J
EJ
D000818:Animals; D001704:Biopolymers / Q000494:pharmacology*; D001826:Body Fluids / Q000187:drug effects / Q000378:metabolism*; D018938:Caco-2 Cells; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D002712:Chlorides / Q000037:antagonists & inhibitors*; D002772:Cholera Toxin / Q000008:administration & dosage / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004553:Electric Conductivity; D017097:Electric Impedance; D005260:Female; D006801:Humans; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044945:Proanthocyanidins
D001704:Biopolymers; D002392:Catechin; D002712:Chlorides; D002772:Cholera Toxin; D005576:Colforsin; D000242:Cyclic AMP; C546704:crofelemer; D044945:Proanthocyanidins