Novel calmodulin antagonist CGS 9343B inhibits secretory diarrhea.
The goal of this study was to determine whether secretory diarrhea could be ameliorated by pharmacological alteration of the second messenger systems which mediate intestinal fluid and electrolyte transport. Calmodulin is an important intermediate in the mucosal signal-transduction pathways that regulate intestinal NaCl transport. We tested a selective inhibitor of calmodulin, CGS 9343B, for antidiarrheal activity in two different models of secretory diarrhea. Diarrhea was induced in mice by p.o. administration of castor oil (0.6 ml) and in rats by i.p. injection of PGE2 (150 micrograms). We compared the antidiarrheal effects of CGS 9343B to other prototype antidiarrheal agents including morphine, loperamide and chlorpromazine in the castor oil-induced model of secretory diarrhea in mice. CGS 9343B was the most potent of these agents, eliminating diarrhea in 100% of mice at a dose of 1 mg/kg (p.o.). Morphine, loperamide and chlorpromazine were 3 to 10 times weaker than CGS 9343B. In this model, we measured changes in the amount of feces eliminated (grams) and loss of body weight (grams) as indicators of the rate of intestinal propulsion, based on the assumption that reduced fecal passage and concomitantly smaller weight loss represented reduced propulsion of intestinal contents, or constipation. Although the other agents caused equal degrees of constipation and antidiarrheal activity, CGS 9343B did not exert any significant antipropulsive effects at antidiarrheal doses in castor oil-treated mice. To further differentiate these agents on the basis of antipropulsive activity, we compared them for effects on the rate of transit of a p.o. administered radioactive marker in normal mice (noncastor oil-treated).(ABSTRACT TRUNCATED AT 250 WORDS)
Shook
J E
JE
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson.
Burks
T F
TF
Wasley
J W
JW
Norman
J A
JA
D000700:Analgesics; D000818:Animals; D000930:Antidiarrheals; D001562:Benzimidazoles / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002746:Chlorpromazine / Q000494:pharmacology; D005772:Gastrointestinal Transit / Q000187:drug effects*; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000700:Analgesics; D000930:Antidiarrheals; D001562:Benzimidazoles; D002147:Calmodulin; C052087:CGS 9343B; D008139:Loperamide; D009020:Morphine; D002746:Chlorpromazine