Regional functional specialization and inhibitory nitrergic and nonnitrergic coneurotransmission in the human...

The aim of this study was to explore the myenteric mechanisms of control of human esophageal motility and the effect of nitrergic and nonnitrergic neurotransmitters. Human circular esophageal strips were studied in organ baths and with microelectrodes. Responses following electrical field stimulation (EFS) of enteric motoneurons (EMNs) or through nicotinic acetylcholine receptors were compared in the esophageal body (EB) and in clasp and sling regions in the lower esophageal sphincter (LES). In clasp LES strips: 1) sodium nitroprusside (1 nM to 100 μM), adenosine-5'-[β-thio]diphosphate trilithium salt (1-100 μM), and vasoactive intestinal peptide (1 nM to 1 μM) caused a relaxation; 2) 1 mM N(ω)-nitro-L-arginine (L-NNA) shifted the EFS "on"-relaxation to an "off"-relaxation, partly antagonized by 10 μM 2'-deoxy-N(6)-methyladenosine 3',5'-bisphosphate tetrasodium salt (MRS2179) or 10 U/ml α-chymotrypsin; and 3) nicotine-relaxation (100 μM) was mainly antagonized by L-NNA, and only partly by MRS2179 or α-chymotrypsin. In sling LES fibers, EFS and nicotine relaxation was abolished by L-NNA. In the EB, L-NNA blocked the latency period, and MRS2179 reduced "off"-contraction. The amplitude of cholinergic contraction decreased from the EB to both LES sides. EFS induced a monophasic inhibitory junction potential in clasp, sling, and EB fibers abolished by L-NNA. Our study shows a regional specialization to stimulation of EMNs in the human esophagus, with stronger inhibitory responses in clasp LES fibers and stronger cholinergic excitatory responses in the EB. Inhibitory responses are mainly triggered by nitrergic EMNs mediating the inhibitory junction potentials in the LES and EB, EFS on-relaxation in clasp and sling LES sides, and latency in the EB. We also found a minor role for purines (through P2Y(1) receptors) and vasoactive intestinal peptide-mediating part of nonnitrergic clasp LES relaxation.