Synergy between 5-HT4 receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle

Abstract

Background

Gastroprokinetic properties of 5-HT₄ receptor agonists, such as prucalopride, are attributed to activation of 5-HT₄ receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase (PDE) 4 has been shown to control the signaling pathway of these 5-HT₄ receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT₄ receptors in human large intestine.

Methods

Circular smooth muscle strips were prepared from human large intestine; after incubation with [³H]-choline, electrically induced tritium outflow was determined as a measure for acetylcholine release. The influence of PDE inhibition on the facilitating effect of prucalopride on electrically induced acetylcholine release was studied.

Key Results

The non-selective PDE inhibitor IBMX enhanced the facilitating effect of prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence, while rolipram and roflumilast (PDE4) enhanced the prucalopride-induced facilitation to the same extent as IBMX.

Conclusions & Inferences

In human large intestinal circular muscle, the intracellular pathway of 5-HT₄ receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5-HT₄ receptor agonism and PDE4 inhibition is confirmed in a functional assay with electrically induced cholinergic contractions of human large intestinal circular smooth muscle strips, combination of a selective 5-HT₄ receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5-HT₄ receptor agonist in the large intestine.

In human large intestinal circular smooth muscle strips, the facilitating effect of the 5-HT₄ receptor agonist prucalopride on electrically induced acetylcholine release was enhanced by non-selective phosphodiesterase (PDE) inhibition with IBMX. The selective PDE4 inhibitors rolipram and roflumilast mimicked the effect of IBMX, while inhibitors of PDE1 (vinpocetine), PDE2 (EHNA) and PDE3 (cilostamide) did not.

The signaling pathway of 5-HT₄ receptors facilitating cholinergic neurotransmission towards human large intestinal circular smooth muscle is thus controlled by PDE₄. If the synergy between 5-HT₄ receptor agonism and PDE4 inhibition is confirmed in a functional assay with electrically induced cholinergic contractions, combination of a 5-HT₄ receptor agonist with a selective PDE4 inhibitor might also in vivo enhance the prokinetic effect of the 5-HT₄ receptor agonist.

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