Activation of prostaglandin EP receptors by lubiprostone in rat and human stomach and colon

Abstract

Background and purpose: Lubiprostone (Amitiza), a possible ClC-2 channel opener derived from prostaglandin E 1 and indicated for the treatment of constipation, increases chloride ion transport and fluid secretion into the intestinal lumen. As lubiprostone may also directly modulate gastrointestinal motility, we investigated its actions and the possible involvement of prostaglandin EP receptor activation on rat and human isolated gastrointestinal preparations. Experimental approach: Rat and human isolated preparations were mounted in tissue baths for isometric recording. The effects of lubiprostone on muscle tension and on electrically stimulated, neuronal contractions were investigated in the absence and presence of EP receptor antagonists. Key results: In rat and human stomach longitudinal muscle, lubiprostone induced a contraction (pEC 50 of 7.0±0.0, n ¼ 4 and 6.4 ± 0.2, n ¼ 3, respectively), which was inhibited by pretreatment with the EP 1 receptor antagonist, EP 1 A 300 nM (pEC 50 reduced to 6.2±0.2, n ¼ 6), but not by the EP 3 or EP 4 receptor antagonists (L-798106 and GW627368X, respectively, 1 mM, P40.05). Lubiprostone also reduced electrically stimulated, neuronal contractions in rat and human colon circular muscle preparations (pIC 50 of 8.9±0.4, n ¼ 7 and 8.7±0.9, n ¼ 6, respectively), an effect mediated pre-junctionally. This effect was reduced by the EP 4 receptor antagonist (pIC 50 of 6.7 ± 1.1, n ¼ 7 and 7.7 ± 0.4, n ¼ 6, respectively) but not by EP 1 or EP 3 receptor antagonists. Conclusions and implications:In rats and humans, lubiprostone contracts stomach longitudinal muscle and inhibits neuronally mediated contractions of colon circular muscle. Experiments are now needed to determine if this additional activity of lubiprostone contributes to its clinical efficacy and/or side-effect profile.

Stimulation of mucosal secretion by lubiprostone (SPI-0211) in guinea pig small intestine and colon

“…Our results do not support the suggestion in the reports of Bassil et al (3,4) that actions of lubiprostone on gastrointestinal motility and perhaps mucosal secretion reflect stimulation of prostaglandin EP receptors. We found that intraneuronal microelectrodes recorded excitatory responses (i.e., membrane depolarization and spike discharge) in submucosal ganglion cells in response to each of three different prostaglandins.…”

“…Signal transduction for M 3 -mediated activation of Cl Ϫ secretion involves elevation of Ca 2ϩ in the enterocytes and stimulation of PKC (19). Absence of evidence for opening of ClC-2 channels by elevation of intracellular Ca 2ϩ makes ClC-2 an unlikely candidate for explanation of the enhancing effects of lubiprostone on the muscarinic-evoked first phase.…”

“…In preparations from rats and humans, lubiprostone was reported to contract the stomach longitudinal muscle coat and inhibit neuronally mediated contractions of the colonic circular muscle coat. These actions were reported to be suppressed by an EP 1 receptor antagonist and an EP 4 receptor antagonist, respectively, which suggest that lubiprostone might act like a prostaglandin to stimulate EP receptors (3,4). We tested this suggestion by comparing the electrophysiological responses of submucosal ganglion cells evoked by prostaglandins with responses evoked by lubiprostone.…”

Lubiprostone: Clinical applications beyond constipation

“…This is especially true if the lubiprostone is administered prior to bowel cleansing with the agents such as polyethylene glycol electrolyte (PEG-E) [3] . Lubiprostone also enhances and stimulates contraction in colonic as well as gastric muscles and may, thus, further contribute as a prokinetic agent [4] . Besides these effects, lubiprostone also causes hyperpolarization in other tissues such as uterine muscle cells [5] .…”

Emerging Pharmacologic Therapies for Constipation-predominant Irritable Bowel Syndrome and Chronic Constipation

“…33 Lubiprostone also enhances and stimulates contraction in colonic as well as gastric muscles through prostaglandin E receptors, suggesting direct effects on GI motility. 34,35 This drug has been approved by the Food and Drug Administration (FDA) as a treatment for women and men with chronic constipation at a dose of 24 μg, twice daily, and for women with IBS-C at a dose of 8 μg, twice daily. Lubiprostone is contraindicated in mechanical GI obstruction and is FDA pregnancy category C. Lubiprostone has been consistently demonstrated to be superior to placebo for increasing the number of SBMs, improving stool consistency, reducing straining, bloating and overall constipation symptoms in several large, multicenter RCTs involving CC and IBS-C. 23,[36][37][38][39][40] One phase III trial in CC involved 242 patients (average age: 48 years; 89% female; 88% Caucasian) who received either lubiprostone 24 μg twice daily or placebo with food for a period of 4 weeks with a primary efficacy end point of number of SBM at 1 week of treatment.…”