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Stereospecific actions of misoprostol on rat colonic electrolyte transport
S Won-Kim1, J F Kachur, T S Gaginella
1Gastrointestinal Diseases Research, Searle Research & Development, Skokie, IL 60077.
Abstract:
Misoprostol (Miso) produces a mild, transient diarrhea in some patients, which is believed to be partly due to intraluminal fluid accumulation. To better understand this diarrheagenic action, we compared the effects of Miso, its 4 stereoisomers (11R16R, 11R16S, 11S16S, 11S16R), misoprostol free acid (Miso-FA), and 16,16-dimethyl PGE2 (dmPGE2) on rat colonic electrolyte transport in vitro. Increases in short-circuit current (Isc) were measured (after serosal addition) in segments of mucosa stripped of muscularis and mounted in Ussing chambers. The rank order of apparent potencies, in terms of threshold, were (microM): 11R, 16S (1.2) approximately dmPGE2 (1.0) > Miso-FA (10.0) approximately Miso >> 11R, 16R; 11S, 16R; 11S, 16S (all inactive at 100 microM). The response to dmPGE2 and Miso was attenuated in the presence of the Na+/K+/Cl- co-transport inhibitor bumetanide (100 microM). Pretreatment with atropine (0.1 microM) did not affect the Isc response to Miso, Miso-FA, or dmPGE2. Tetrodotoxin partially attenuated (39 +/- 9% inhibition) the response to Miso-FA, but did not affect Miso or dmPGE2. In conclusion, Miso increases Cl- secretion across rat colonic mucosa through a direct action on epithelial cells. The activity resides in the 11R,16S isomer, thus implying a stereospecific interaction at PGE receptors. The effect of Miso to stimulate epithelial Cl- secretion might contribute to its diarrheagenic action in vivo.
Insights
Misoprostol (Miso) causes diarrhea by increasing chloride secretion in the colon. This effect is stereospecific, with the 11R,16S isomer being the most potent, suggesting a direct action on epithelial cells.
Area of Science:
- Gastroenterology
- Pharmacology
- Molecular Biology
Background:
- Misoprostol (Miso) is known to cause diarrhea, potentially due to increased fluid in the intestines.
- Understanding the mechanism of Miso-induced diarrhea is crucial for patient management.
Purpose of the Study:
- To investigate the effects of Misoprostol and its stereoisomers on electrolyte transport in rat colonic mucosa.
- To elucidate the specific isomer responsible for Miso's diarrheagenic action.
Main Methods:
- In vitro Ussing chamber technique to measure short-circuit current (Isc) in rat colonic mucosa.
- Comparison of Miso, its four stereoisomers, misoprostol free acid (Miso-FA), and 16,16-dimethyl PGE2 (dmPGE2).
- Assessment of the roles of bumetanide, atropine, and tetrodotoxin in Miso's effects.
Main Results:
- The 11R,16S isomer of Miso and dmPGE2 were the most potent in increasing Isc.
- Misoprostol free acid and Miso showed moderate activity, while other isomers were inactive.
- The response to dmPGE2 and Miso was partially mediated by Na+/K+/Cl- co-transport and neuronal pathways.
Conclusions:
- Misoprostol stimulates chloride secretion in rat colonic epithelium via a direct, stereospecific interaction with prostaglandin E receptors.
- The 11R,16S isomer is primarily responsible for this effect.
- This epithelial chloride secretion likely contributes to Misoprostol's diarrheagenic side effect in vivo.