Investigation of neurogenic excitatory and inhibitory motor responses and their control by 5-HT4 receptors in circular smooth muscle of pig descending colon

Abstract: The aim of this study was to investigate whether the pig colon descendens might be a good model for the responses mediated via the different locations of human colonic 5-HT4 receptors. The intrinsic excitatory and inhibitory motor neurotransmission in pig colon descendens was therefore first characterized. In circular smooth muscle strips, electrical field stimulation (EFS) at basal tone induced only in the combined presence of the NO synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) and the SK channel blocker apamin voltage-dependent on-contractions. These on-contractions were largely reduced by the neuronal conductance blocker tetrodotoxin (TTX) and by the muscarinic receptor antagonist atropine, illustrating activation of cholinergic neurons. The 5-HT4 receptor agonist prucalopride facilitated submaximal EFS-evoked cholinergic contractions and this effect was prevented by the 5-HT4 receptor antagonist GR113808, supporting the presence of facilitating 5-HT4 receptors on the cholinergic nerve endings innervating circular muscle in pig colon descendens. Relaxations were induced by EFS in strips pre-contracted with substance P in the presence of atropine. The responses at lower stimulation voltages were abolished by TTX. L-NAME or apamin alone did not influence or only moderately reduced the relaxations, but L-NAME plus apamin abolished the relaxations at lower stimulation voltages, suggesting that NO and ATP act as inhibitory neurotransmitters in a redundant way. Prucalopride did not influence the EFS-induced relaxations at lower stimulation voltage, nor did it per se relax contracted circular muscle strips. No evidence for relaxing 5-HT4 receptors, either on inhibitory neurons or on the muscle cells was thus obtained in pig colon descendens circular muscle. [Copyright &y& Elsevier]