OCTREOTIDE INHIBITION OF SEROTONIN-INDUCED ILEAL CHLORIDE SECRETION

Octreotide (SMS, synthetic miniature somatostatin) effectively allevia tes the secretory diarrhea of the malignant carcinoid syndrome. Althou gh SMS inhibits tumor release of serotonin (5HT) and other bioactive a gents, it also inhibits the diarrhea in patients who continue to exhib it elevated serum levels of 5HT. This observation suggests that SMS ma y directly inhibit mediator-stimulated intestinal ion secretion at the mucosal level. To test this hypothesis, intestinal ion secretion was studied in rabbit ileal mucosa mounted in Ussing chambers. Maximal cha nges in short circuit current (Delta I-se) were observed as an indicat or of mucosal ion secretion. The application of pathophysiologic conce ntrations of 5HT (10(-5) M) to the mucosal preps resulted in a Delta I -se of 52 +/- 6 mu A/cm(2). This 5HT-stimulated Delta I-se was signifi cantly inhibited by serosal furosemide (10(-3) M) or use of a chloride -depleted medium, indicating that 5HT stimulates electrogenic chloride secretion in the rabbit ileum. Pretreatment with a therapeutic concen tration of SMS (10(-8) M) resulted in a significant inhibition of 5HT- stimulated electrogenic Cl- secretion (9 +/- 1 mu A/cm(2)) (P < 0.005) . This inhibitory effect of SMS was not seen in tissue pretreated with pertussis toxin. The results of these experiments demonstrate that oc treotide inhibits 5HT-stimulated electrogenic chloride secretion at th e mucosal level. Additionally this inhibitory effect of octreotide is likely mediated by activation of the inhibitory subunit of membrane-bo und GTP-binding regulatory proteins. These results thus provide experi mental evidence in support of the ability of SMS to ameliorate the car cinoid diarrhea by a direct effect on stimulated mucosal ion secretion . (C) 1995 Academic Press, Inc.