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Octreotide inhibition of serotonin-induced ileal chloride secretion
R D Hurst1, G H Ballantyne, I M Modlin
1Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Abstract:
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.
Insights
Octreotide effectively treats carcinoid syndrome diarrhea by directly inhibiting serotonin-stimulated intestinal chloride secretion at the mucosal level, likely via G-protein signaling.
Area of Science:
- Gastroenterology
- Pharmacology
- Molecular Biology
Background:
- Malignant carcinoid syndrome causes secretory diarrhea due to tumor release of serotonin (5HT).
- Octreotide (synthetic miniature somatostatin, SMS) alleviates this diarrhea, even with persistent high 5HT levels.
- This suggests SMS may directly impact intestinal ion secretion.
Purpose of the Study:
- To investigate if octreotide (SMS) directly inhibits mediator-stimulated intestinal ion secretion at the mucosal level.
- To determine the mechanism of octreotide's inhibitory effect on serotonin-induced intestinal secretion.
Main Methods:
- Rabbit ileal mucosa mounted in Ussing chambers to measure short-circuit current (delta Isc) as an indicator of ion secretion.
- Application of serotonin (5HT) to stimulate ion secretion and assessment of inhibition by octreotide (SMS).
- Investigation of the role of G-proteins using pertussis toxin pretreatment.
Main Results:
- Serotonin (5HT) significantly stimulated electrogenic chloride secretion in rabbit ileum.
- Octreotide (SMS) significantly inhibited this 5HT-stimulated chloride secretion.
- The inhibitory effect of SMS was dependent on G-protein signaling, as it was blocked by pertussis toxin.
Conclusions:
- Octreotide directly inhibits serotonin-stimulated electrogenic chloride secretion at the intestinal mucosal level.
- This inhibition is mediated by the activation of the inhibitory subunit of membrane-bound GTP-binding regulatory proteins.
- These findings provide evidence for octreotide's direct action on intestinal ion secretion in ameliorating carcinoid diarrhea.