Inhibition of cholera-toxin-stimulated intestinal secretion by CGS 9343B in rats: a specific calmodulin inhibitor.
In this study, the effect of CGS 9343B on cholera-toxin-stimulated intestinal secretion in rats was determined using in vivo isolated loops. This recently developed compound is a potent and specific inhibitor of calmodulin, but not of protein kinase C. At a luminal dose of 15 mg/kg, CGS 9343B has little effect on basal intestinal absorption but completely inhibited the secretory effects of cholera toxin. The less specific calmodulin inhibitor, trifluoperazine, has a similar antisecretory effect, but unlike with CGS 9343B, severe toxicity was noted at luminal doses of 7.5 mg/kg. In animals where two intestinal loops were created, one with cholera toxin alone and the other with CGS 9343B and cholera toxin, significant inhibition of secretion was observed in both loops, consistent with a systemic effect of this compound. Finally, both CGS 9343B and trifluoperazine inhibited choleratoxin stimulated increases in mucosal cyclic AMP content, whereas basal levels were unaffected. We conclude that CGS 9343B significantly inhibits choleratoxin-stimulated intestinal secretions, possibly by inhibition of calmodulin-dependent adenylate cyclase activity. Its lack of major toxicity at therapeutic doses makes this compound potentially useful for the treatment of enterotoxigenic diarrheal diseases.
Fedorak
R N
RN
Department of Medicine, University of Alberta, Edmonton, Canada.
Kotake
A
A
Douglas
F
F
Chang
E B
EB
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002772:Cholera Toxin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology; D007419:Intestinal Secretions / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D014268:Trifluoperazine / Q000494:pharmacology
D001562:Benzimidazoles; D002147:Calmodulin; C052087:CGS 9343B; D014268:Trifluoperazine; D002772:Cholera Toxin; D000242:Cyclic AMP; D002118:Calcium