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Aim: Our aim was to determine mechanisms of action of the gasotransmitter hydrogen sulfide (H(2)S) on contractile activity in circular muscle of rat jejunum., Methods: Jejunal circular muscle strips were prepared to measure isometric contractions. Effects of sodium hydrosulfide (NaHS), a H(2)S donor, were evaluated on spontaneous contractile activity and after pre-contraction with bethanechol. L-cysteine was evaluated as an endogenous H(2)S donor. We evaluated extrinsic nerves, enteric nervous system, visceral afferent nerves, nitric oxide, K(ATP)+ and K(Ca)+ channels, and myosin light chain phosphatase on action of H(2)S using non-adrenergic/non-cholinergic conditions, tetrodotoxin, capsaicin, L-N(G)-nitro arginine (L-NNA), glibenclamide, apamin, and calyculin A, respectively, and electrical field stimulation (EFS)., Results: NaHS dose-dependently and reversibly inhibited spontaneous and bethanechol-stimulated contractile activity (p < 0.05). L-cysteine had a dose-dependent inhibitory effect. Non-adrenergic/non-cholinergic conditions, tetrodotoxin, capsaicin, L-NNA, or apamin had no effect on contractile inhibition by NaHS; in contrast, low-dose glibenclamide and calyculin A prevented NaHS-induced inhibition. We could not demonstrate H(2)S release by EFS., Conclusions: H(2)S inhibits contractile activity of jejunal circular muscle dose-dependently, in part by K(ATP)+ channels and via myosin light chain phosphatase, but not via pathways mediated by the extrinsic or enteric nervous system, visceral afferent nerves, nitric oxide, or K(Ca)+ channels.

Background: There is limited information on medications with promotility effects on the esophagus. Studies in healthy volunteers have shown the potential role of the direct cholinergic agonist bethanechol and the serotonin receptor agonist buspirone in improving esophageal motility. It has been also shown that an acetylcholinesterase inhibitor, the short-acting drug edrophonium administered intravenously caused a greater increase in the esophageal contraction amplitude and duration than bethanechol. Edrophonium cannot be used as a promotility therapy owing to short duration of action and lack of oral administration. The use of another acetylcholinesterase inhibitor pyridostygmine with longer duration of action has not been studied. The aim of the study was to evaluate the effect of oral pyridostygmine (60 mg), buspirone (20 mg), and bethanechol (25 mg) on esophageal function assessed by combined multichannel intraluminal impedance-esophageal manometry., Materials and Methods: Ten healthy volunteers were enrolled in a double blind randomized 3-period crossover study. Multichannel intraluminal impedance-esophageal manometry recorded esophageal pressures and bolus transit data during 6 liquid and 6 viscous swallows at baseline and 20, 40, and 60 minutes after the randomized oral administration of each drug., Results: Blinded analysis found significant increases in mean distal esophageal amplitude for liquid swallows from baseline to 60 minutes postdosing after pyridostygmine (87.6 vs. 118.0 mm Hg, P<0.001), buspirone (85.1 vs. 101.9 mm Hg, P<0.05), and bethanechol (87.6 vs. 118.8 mm Hg, P<0.01). Only pyridostygmine showed a significant decrease in mean distal onset velocity for liquid swallows at 60 minutes postdosing (3.4 vs. 2.3 cm/s, P<0.01) and increase in total bolus transit time at 60 minutes postdosing (7.9 vs. 9.3 s, P<0.05). All 3 agents significantly increased mean lower esophageal sphincter residual pressure for liquid swallows at 20, 40, and 60 minutes postdosing. Increased lower esophageal sphincter resting pressure was not significant. Similar results were found with viscous swallows., Conclusions: Oral pyridostygmine, buspirone, and bethanechol enhance esophageal motility with pyridostygmine appearing to have the greatest effect. A potential effect on improving esophageal function and symptoms in patients requires further study.

Our primary purpose was to characterize vagal pathways controlling gastric motility by microinjecting l-glutamate into the dorsal motor nucleus of the vagus (DMV) in the rat. An intragastric balloon was used to monitor motility. In 39 out of 43 experiments, microinjection of l-glutamate into different areas of the DMV rostral to calamus scriptorius (CS) resulted in vagally mediated excitatory effects on motility. We observed little evidence for inhibitory effects, even with intravenous atropine or with activation of gastric muscle muscarinic receptors by intravenous bethanechol. Inhibition of nitric oxide synthase with N(omega)-nitro-l-arginine methyl ester (l-NAME) HCl did not augment DMV-evoked excitatory effects on gastric motility. Microinjection of l-glutamate into the DMV caudal to CS produced vagally mediated gastric inhibition that was resistant to l-NAME. l-Glutamate microinjected into the medial subnucleus of the tractus solitarius (mNTS) also produced vagally mediated inhibition of gastric motility. Motility responses evoked from the DMV were always blocked by ipsilateral vagotomy, while responses evoked from the mNTS required bilateral vagotomy to be blocked. Microinjection of oxytocin into the DMV inhibited gastric motility, but the effect was never blocked by ipsilateral vagotomy, suggesting that the effect may have been due to diffusion of oxytocin to the mNTS. Microinjection of substance P and N-methyl-d-aspartate into the DMV also produced inhibitory effects attributable to excitation of nearby mNTS neurons. Our results do not support previous studies indicating parallel vagal excitatory and inhibitory pathways originating in the DMV rostral to CS. Our results do support previous findings of vagal inhibitory pathways originating in the DMV caudal to CS.

The goal of this study was to investigate the effect of bethanechol (BeCh) on contractility patterns of smooth muscle preparations of equine duodenum descendens, jejunum, caecum and pelvic flexure in vitro. Concentration-response relationships were developed for BeCh using in vitro assays with and without preincubation of muscarinic (M) receptor antagonists for M2 and M3 receptors. BeCh induced a significant, concentration-dependent increase in contractile response in equine intestine in specimens with circular orientation. The maximal effect was largest for jejunal specimens with no difference in EC50 within the different locations investigated. The M2 antagonist, AF-DX 116, caused a rightward shift of the concentration-response curve and the M3 antagonist, 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide), almost completely inhibited the effect of BeCh over the entire concentration-response curve. These data provide evidence that, although the effect of BeCh is predominantly mediated by M3 receptors, M2 muscarinic receptors also play a role in BeCh-induced contraction in specimens of equine intestine. The involvement of other muscarinic receptor subtypes cannot be excluded. Further studies are necessary to understand the effect of BeCh in vivo including diseased animals.

The present study investigated how a cholinergic agonist modifies interdigestive motility and secretion of the upper gastrointestinal tract and how muscarinic and cholecystokinin receptor blockade interfere with this direct cholinergic stimulation. In eight healthy volunteers, gastrointestinal motor and secretory responses to bethanechol (12.5, 25, and 50 micrograms kg-1 h-1) with and without a background of atropine (5 micrograms kg-1 h-1) or loxiglumide (10 mg kg-1 h-1) were studied. Stepdoses of bethanechol caused a parallel stimulation of antroduodenal motility and gastropancreatic secretion (P < 0.01) without inducing a fed pattern. However, duration of phase I was shortened (P < 0.05). Only high doses of bethanechol enhanced gastrin (P < 0.05), cholecystokinin (P < 0.05), and pancreatic polypeptide (P < 0.01) release. Atropine completely antagonized motor and secretory responses to cholinergic stimulation. Loxiglumide left cholinergically stimulated motility and pancreatic enzyme secretion unaltered. With co-infusion of bethanechol and loxiglumide, PP release dropped by 63% (P < 0.01); gastric acid output, gastrin and CCK release increased by 56%, 16%, and 25%, respectively (P < 0.05). We conclude that stimulation by a cholinergic agonist preserves the interdigestive pattern. Low dose muscarinic receptor blockade abolishes cholinergic stimulation over the full dose range. Inhibition of somatostatin release would explain stimulation of gastrin release and gastric acid secretion with co-infusion of bethanechol and loxiglumide. Endogenous CCK appears to interact with direct cholinergic stimulation at the pancreatic PP cell and the gastric D-cell but not at pancreatic acinar and antroduodenal smooth muscle cells.