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Comparative Study
. 2008 May;154(1):126-35.
doi: 10.1038/bjp.2008.84. Epub 2008 Mar 10.

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

A K Bassil  1 , R A Borman, E M Jarvie, R J McArthur-Wilson, R Thangiah, E Z H Sung, K Lee, G J Sanger
Affiliations
Comparative Study

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

A K Bassil et al. Br J Pharmacol. 2008 May.

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=4 and 6.4+/-0.2, n=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=6), but not by the EP(3) or EP(4) receptor antagonists (L-798106 and GW627368X, respectively, 1 microM, P>0.05). Lubiprostone also reduced electrically stimulated, neuronal contractions in rat and human colon circular muscle preparations (pIC(50) of 8.9+/-0.4, n=7 and 8.7+/-0.9, n=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=7 and 7.7+/-0.4, n=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.

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Figures

Figure 1
Figure 1
Original trace showing baseline responses of the rat fore-stomach longitudinal muscle to different concentrations of lubiprostone and the concentration–contractile response curve of this tissue to lubiprostone, where the response is expressed as a percentage of the contraction induced by 1 μM prostaglandin E2 (PGE2). Each point represents the mean and vertical lines show s.e.mean.
Figure 2
Figure 2
Original trace showing baseline responses of the rat fore-stomach longitudinal muscle to different concentrations of lubiprostone and the concentration–contractile response curve of this tissue to lubiprostone in the presence of vehicle or (a) EP1 receptor antagonist, EP1A (30 nM, 300 nM and 3 μM); (b) either EP3 receptor antagonist, L-798106 or EP4 receptor antagonist, GW627368X (1 μM). The responses are expressed as a percentage of the contraction induced by 1 μM prostaglandin E2 (PGE2). Each point represents the mean and vertical lines show s.e.mean.
Figure 3
Figure 3
Concentration–contractile response curves of rat fore-stomach circular muscle to lubiprostone in the presence of vehicle or (a) EP1, (b) EP3 or (c) EP4 receptor antagonists (EP1A, L-798106 and GW627368X, respectively, 1 μM). The responses are expressed as a percentage of the contraction induced by 1 μM prostaglandin E2 (PGE2). Each point represents the mean and vertical lines show s.e.mean.
Figure 4
Figure 4
Concentration–contractile response curves of rat colon longitudinal muscle to lubiprostone in the presence of vehicle or (a) EP1, (b) EP3 or (c) EP4 receptor antagonists (EP1A, L-798106 and GW627368X, respectively, 1 μM). The responses are expressed as a percentage of the contraction induced by 1 μM prostaglandin E2 (PGE2). Each point represents the mean and vertical lines show s.e.mean.
Figure 5
Figure 5
Concentration–response curves for the effect of lubiprostone on electrical field stimulation (EFS)-evoked contractions of rat colon circular muscle in the presence of vehicle or (a) EP1, (b) EP3 or (c) EP4 receptor antagonists (EP1A, L-798106 and GW627368X, respectively, 1 μM). Each point represents the mean and vertical lines show s.e.mean.
Figure 6
Figure 6
Concentration–contractile response curves of human proximal stomach longitudinal muscle to lubiprostone in the presence of vehicle or (a) EP1, (b) EP3 or (c) EP4 receptor antagonists (EP1A, L-798106 and GW627368X, respectively, 1 μM). The responses are expressed as a percentage of the contraction induced by 1 μM prostaglandin E2 (PGE2). Each point represents the mean and vertical lines show s.e.mean.
Figure 7
Figure 7
Concentration–response curves for the effect of lubiprostone on electrical field stimulation (EFS)-evoked contractions of human colon circular muscle in the presence of vehicle or (a) EP1, (b) EP3 or (c) EP4 receptor antagonists (EP1A, L-798106 and GW627368X, respectively, 1 μM). Each point represents the mean and vertical lines show s.e.mean.
Figure 8
Figure 8
Concentration–response curves for the effect of lubiprostone on electrical field stimulation (EFS)-evoked contractions of human colon longitudinal muscle in the presence of vehicle or (a) EP1, (b) EP3 or (c) EP4 receptor antagonists (EP1A, L-798106 and GW627368X, respectively, 1 μM). Each point represents the mean and vertical lines show s.e.mean.
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References

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