Luminal 5-HT stimulates colonic bicarbonate secretion in rats

Area of Science:

• Gastroenterology
• Neurogastroenterology
• Molecular Pharmacology

Background:

• 5-hydroxytryptamine (5-HT), a bioactive monoamine, plays a role in functional gastrointestinal disorders.
• 5-HT is synthesized, stored, and released in the rat proximal colon, but its effect on colonic anion secretion is not fully understood.

Purpose of the Study:

• To investigate the effects of luminal 5-HT on colonic anion secretion.
• To identify the specific 5-HT receptor subtype involved in mediating this response.
• To explore the role of nitric oxide (NO) in regulating 5-HT-evoked colonic secretion.

Main Methods:

• Short-circuit current (Isc) measurements in rat proximal colon preparations to assess ion transport.
• In vitro and in vivo measurement of total CO2 output.
• Immunohistochemistry to localize 5-HT4, NOS1, and NOS2.
• Pharmacological blockade using selective receptor antagonists and inhibitors.

Main Results:

• Luminal 5-HT significantly increased Isc in a sustained manner, indicating enhanced ion transport.
• The 5-HT-evoked response was dependent on bicarbonate (HCO3-) and sensitive to acetazolamide, suggesting electrogenic HCO3- secretion.
• The 5-HT4 receptor antagonist GR113808, but not antagonists for other 5-HT receptors, inhibited the 5-HT-evoked Isc.
• Nitric oxide (NO) synthesized in the submucosa, via NOS1 and NOS2, suppressed mucosal anion secretion, as evidenced by enhanced 5-HT-evoked secretion upon submucosa removal or NOS inhibition.
• Luminal 5-HT-evoked HCO3- secretion was confirmed in vivo and inhibited by GR113808.

Conclusions:

• A novel apical 5-HT4 receptor-mediated pathway for bicarbonate secretion exists in the proximal colon.
• An NO-dependent inhibitory mechanism modulates this secretory pathway.
• Luminal 5-HT-evoked bicarbonate secretion may be crucial for maintaining mucosal integrity by regulating luminal pH.