J Neurogastroenterol Motil.  2013 Jul;19(3):312-318.

Lubiprostone Increases Small Intestinal Smooth Muscle Contractions Through a Prostaglandin E Receptor 1 (EP1)-mediated Pathway

• Chan WW
• Mashimo H

Abstract

BACKGROUND/AIMS
Lubiprostone, a chloride channel type 2 (ClC-2) activator, was thought to treat constipation by enhancing intestinal secretion. It has been associated with increased intestinal transit and delayed gastric emptying. Structurally similar to prostones with up to 54% prostaglandin E2 activity on prostaglandin E receptor 1 (EP1), lubiprostone may also exert EP1-mediated procontractile effect on intestinal smooth muscles. We investigated lubiprostone's effects on intestinal smooth muscle contractions and pyloric sphincter tone.
METHODS
Isolated murine small intestinal (longitudinal and circular) and pyloric tissues were mounted in organ baths with modified Krebs solution for isometric recording. Basal muscle tension and response to electrical field stimulation (EFS; 2 ms pulses/10 V/6 Hz/30 sec train) were measured with lubiprostone (10(-10)-10(-5) M) +/- EP1 antagonist. Significance was established using Student t test and P < 0.05.
RESULTS
Lubiprostone had no effect on the basal tension or EFS-induced contractions of longitudinal muscles. With circular muscles, lubiprostone caused a dose-dependent increase in EFS-induced contractions (2.11 +/- 0.88 to 4.43 +/- 1.38 N/g, P = 0.020) that was inhibited by pretreatment with EP1 antagonist (1.69 +/- 0.70 vs. 4.43 +/- 1.38 N/g, P = 0.030). Lubiprostone had no effect on circular muscle basal tension, but it induced a dose-dependent increase in pyloric basal tone (1.07 +/- 0.01 to 1.97 +/- 0.86 fold increase, P < 0.05) that was inhibited by EP1 antagonist.
CONCLUSIONS
In mice, lubiprostone caused a dose-dependent and EP1-mediated increase in contractility of circular but not longitudinal small intestinal smooth muscles, and in basal tone of the pylorus. These findings suggest another mechanism for lubiprostone's observed clinical effects on gastrointestinal motility.

Keyword

Gastrointestinal motility; Intestine, small; Lubiprostone; Receptors, prostaglandin E

MeSH Terms

Alprostadil
Animals
Baths
Chloride Channels
Constipation
Contracts
Dinoprostone
Gastric Emptying
Gastrointestinal Motility
Humans
Intestinal Secretions
Intestine, Small
Isotonic Solutions
Mice
Muscle Tonus
Muscle, Smooth
Muscles
Pylorus
Receptors, Prostaglandin E
Receptors, Prostaglandin E, EP1 Subtype
Lubiprostone
Alprostadil
Chloride Channels
Dinoprostone
Isotonic Solutions
Receptors, Prostaglandin E
Receptors, Prostaglandin E, EP1 Subtype