Background and purpose: To characterize the in vitro motor patterns and the neurotransmitters released by enteric motor neurons (EMNs) in the human sigmoid colon. Experimental approach: Sigmoid circular strips were studied in organ baths. EMNs were stimulated by electrical field stimulation (EFS) and through nicotinic ACh receptors. Key results: Strips developed weak spontaneous rhythmic contractions (3.67 ± 0.49 g, 2.54 ± 0.15 min) unaffected by the neurotoxin tetrodotoxin (TTX; 1 mM). EFS induced strong contractions during (on, 56%) or after electrical stimulus (off, 44%), both abolished by TTX. Nicotine (1-100 mM) inhibited spontaneous contractions. Latency of off-contractions and nicotine responses were reduced by N G -nitro-L-arginine (1 mM) and blocked after further addition of apamin (1 mM) or the P2Y 1 receptor antagonist MRS 2179 (10 mM) and were unaffected by the P2X antagonist NF279 (10 mM) or a-chymotrypsin (10 U mL À1 ). Amplitude of on-and off-contractions was reduced by atropine (1 mM) and the selective NK 2 receptor antagonist Bz-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH 2 (1 mM). MRS 2179 reduced the amplitude of EFS on-and off-contractions without altering direct muscular contractions induced by ACh (1 nM-1 mM) or substance P (1 nM-10 mM). Conclusions and implications: Latency of EFS-induced off-contractions and inhibition of spontaneous motility by nicotine are caused by stimulation of inhibitory EMNs coreleasing NO and a purine acting at muscular P2Y 1 receptors through apaminsensitive K þ channels. EFS-induced on-and off-contractions are caused by stimulation of excitatory EMNs coreleasing ACh and tachykinins acting on muscular muscarinic and NK 2 receptors. Prejunctional P2Y 1 receptors might modulate the activity of excitatory EMNs. P2Y 1 and NK 2 receptors might be therapeutic targets for colonic motor disorders.
The neurotransmitters mediating relaxation of lower esophageal sphincter (LES) were studied using circular LES strips from adult pigs in organ baths. LES relaxation by sodium nitroprusside (1 nM-3 M), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP; 1 nM-1 M), ATP (10 M-30 mM), and tricarbonyldichlororuthenum dimer (1 M-1 mM) was unaffected by tetrodotoxin (1 M) or L-N G -nitroarginine methyl ester (L-NAME; 100 M). Calcitonin gene-related peptide (CGRP; 1 nM-1 M) did not affect LES tone. ATP relaxation was blocked by 1 M apamin and the P2Y 1 antagonist MRS 2179 (N 6 -methyl 2Ј-deoxyadenosine 3Ј,5Ј-bisphosphate; 10 M). Apamin inhibited PACAP relaxation. VIP and PACAP relaxation was blocked by 10 U/ml ␣-chymotrypsin. L-NAME (Ϫ62.52 Ϯ 13.13%) and 1H-[1,2,4]oxadiazole-[4,3-␣]quinoxalin-1-one (ODQ; 10 M, Ϫ67.67 Ϯ 6.80%) similarly inhibited electrical LES relaxation, and apamin blocked non-nitrergic relaxation. Nicotine relaxation (100 M) was inhibited by L-NAME (Ϫ60.37 Ϯ 10.8%) and ODQ (Ϫ41.90 Ϯ 7.89%), and apamin also blocked non-nitrergic relaxation. Non-nitrergic and apamin-sensitive LES relaxation by electrical stimulation or nicotine was strongly inhibited by MRS 2179, slightly inhibited by ␣-chymotrypsin and the P2X 1,2,3 receptor antagonist NF 279 (8,8¢-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt; 10 M), and unaffected by tin protoporphyrin IX (100 M). Porcine LES relaxation after stimulation of intrinsic inhibitory motor neurons is mediated by two main neuromuscular pathways: nitric oxide through guanylate cyclase signaling and apamin-insensitive mechanisms and by non-nitrergic apamin-sensitive neurotransmission mainly mediated by ATP, ADP, or a related purine acting on P2Y 1 receptors and a minor contribution of purinergic P2X 1,2,3 receptors and PACAP. Nitrergic and purinergic cotransmitters show parallel effects of similar magnitude without major interplay. Our study shows no role for CGRP and only a minor one for VIP and carbon monoxide in porcine LES relaxation.The lower esophageal sphincter (LES) acts as a barrier at the gastroesophageal junction (GEJ). Basal tone of LES is primarily myogenic in origin and is modulated by a combination of hormonal factors and neurogenic mechanisms that involve local enteric motor neurons and extrinsic nerves and are not yet fully understood. Nonadrenergic, noncholinergic enteric motor neurons are the final step in the inhibitory vagal pathway to LES, allowing swallowing-induced and transient LES relaxation that causes physiologic gastroesophageal reflux and belching (Chang et al., 2003). Vasoactive intestinal peptide (VIP), nitric oxide, ATP, pituitary adenylate cyclase-activating peptide (PACAP), carbon monoxide, and calcitonin gene-related peptide (CGRP) have been
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