Abstract
Background: As the signal transduction of 5-HT4 receptors on cholinergic neurons innervating smooth muscle is controlled by phosphodiesterase (PDE) 4 in porcine stomach and colon, and human large intestine, the in vivo gastroprokinetic effects of a 5-HT4 receptor agonist might be enhanced by combination with a selective PDE4 inhibitor. The presence of 5-HT4 receptors on cholinergic neurons towards murine gastrointestinal circular muscle was recently shown. If the control of this receptor pathway by PDE4 is also present in mice, this might be a good model for in vivo testing of the combination therapy. Therefore this study investigates the role of cAMP catalyzing PDEs in smooth muscle cell activity and in the intraneuronal signal transduction of the 5-HT4 receptors in the gastrointestinal tract of C57Bl/6J mice.Methods: In circular smooth muscle strips from murine fundus, jejunum, and colon, submaximal cholinergic contractions were induced by either electrical field stimulation (EFS) or by carbachol (muscarinic receptor agonist). The influence of the PDE inhibitors IBMX (non-selective), vinpocetine (PDE1), EHNA (PDE2), cilostamide (PDE3), and rolipram (PDE4) was tested on these contractions and on the facilitating effect of a submaximal concentration of prucalopride (5-HT4 receptor agonist) on EFS-induced contractions.Results: In the three gastrointestinal regions, IBMX and cilostamide concentration-dependently decreased carbachol- as well as EFS-induced contractions. Some inhibitory effect was also observed with rolipram. In the fundus a non-significant trend for an enhancement of the facilitating effect of prucalopride on EFS-induced contractions was observed with IBMX, but none of the selective PDE inhibitors enhanced the facilitating effect of prucalopride in fundus, jejunum or colon.Conclusion: In analogy with the porcine gastrointestinal tract, in murine fundus, jejunum, and colon circular smooth muscle PDE3 is the main regulator of the cAMP turnover, with some contribution of PDE4. In contrast to the porcine gastrointestinal tract, the in vitro facilitation of electrically induced cholinergic contractions by 5-HT4 receptor stimulation could not be enhanced by specific PDE inhibition. The C57Bl/6J murine model is thus not suitable for in vivo testing of a 5-HT4 receptor agonist combined with a selective PDE4 inhibitor.
Highlights
The gastrointestinal (GI) prokinetic properties of 5-HT4 receptor agonists, developed for GI hypomotility disorders like gastroparesis and constipation (Galligan and Vanner, 2005), are related to interaction with stimulating 5-HT4 receptors on cholinergic neurons innervating the GI smooth muscle layer (Gershon and Tack, 2007)
We recently showed that PDE4 inhibition with rolipram or roflumilast enhances the facilitating effect of the 5-HT4 receptor agonist prucalopride on acetylcholine release in circular muscle strips of human large intestine (Pauwelyn et al, 2018)
The aim of this study was to investigate whether the intraneuronal pathway of 5-HT4 receptors, enhancing cholinergic neurotransmission towards the circular muscle layer of murine gastric fundus, jejunum, and colon is regulated by PDEs and possibly more particular by PDE4, in view of its role in the signal transduction pathway of facilitating 5-HT4 receptors in circular muscle of porcine stomach and colon, and human large intestine (Priem et al, 2012, 2013; Lefebvre et al, 2016; Pauwelyn et al, 2018). 5-HT4 receptors signal via cAMP; the classic PDEs 1, 2, and 3 are able to metabolize cAMP as well as cGMP, while PDE4 is cAMP specific (Maurice et al, 2003; Lugnier, 2006)
Summary
The gastrointestinal (GI) prokinetic properties of 5-HT4 receptor agonists, developed for GI hypomotility disorders like gastroparesis and constipation (Galligan and Vanner, 2005), are related to interaction with stimulating 5-HT4 receptors on cholinergic neurons innervating the GI smooth muscle layer (Gershon and Tack, 2007). We recently showed that PDE4 inhibition with rolipram or roflumilast enhances the facilitating effect of the 5-HT4 receptor agonist prucalopride on acetylcholine release in circular muscle strips of human large intestine (Pauwelyn et al, 2018) This suggests the possible usefulness of combining a 5-HT4 receptor agonist with a PDE4 inhibitor in man, allowing enhanced GI prokinetic effects of the 5-HT4 receptor agonist in low dose. PDEs. As the signal transduction of 5-HT4 receptors on cholinergic neurons innervating smooth muscle is controlled by phosphodiesterase (PDE) 4 in porcine stomach and colon, and human large intestine, the in vivo gastroprokinetic effects of a 5-HT4 receptor agonist might be enhanced by combination with a selective PDE4 inhibitor. This study investigates the role of cAMP catalyzing PDEs in smooth muscle cell activity and in the intraneuronal signal transduction of the 5-HT4 receptors in the gastrointestinal tract of C57Bl/6J mice
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