Octreotide inhibition of serotonin-induced ileal chloride secretion.
Octreotide (SMS, synthetic miniature somatostatin) effectively alleviates the secretory diarrhea of the malignant carcinoid syndrome. Although SMS inhibits tumor release of serotonin (5HT) and other bioactive agents, it also inhibits the diarrhea in patients who continue to exhibit elevated serum levels of 5HT. This observation suggest that SMS may 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 changes in short circuit current (delta Isc) were observed as an indicator of mucosal ion secretion. The application of pathophysiologic concentrations of 5HT (10(-5) M) to the mucosal preps resulted in a delta Isc of 52 +/- 6 microA/cm2. This 5HT-stimulated delta Isc was significantly 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 concentration of SMS (10(-8) M) resulted in a significant inhibition of 5HT-stimulated electrogenic Cl- secretion (9 +/- 1 microA/cm2) (P < 0.005). This inhibitory effect of SMS was not seen in tissue pretreated with pertussis toxin. The results of these experiments demonstrate that octreotide inhibits 5HT-stimulated electrogenic chloride secretion at the mucosal level. Additionally this inhibitory effect of octreotide is likely mediated by activation of the inhibitory subunit of membrane-bound GTP-binding regulatory proteins. These results thus provide experimental evidence in support of the ability of SMS to ameliorate the carcinoid diarrhea by a direct effect on stimulated mucosal ion secretion.
Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
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Hurst
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Ballantyne
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Modlin
D000818:Animals; D001693:Biological Transport, Active; D002712:Chlorides / Q000378:metabolism*; D046508:Culture Techniques; D004553:Electric Conductivity; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015282:Octreotide / Q000494:pharmacology*; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D002712:Chlorides; D012702:Serotonin Antagonists; D012701:Serotonin; D015282:Octreotide