Search

We studied the inhibitory actions of docosahexaenoic acid (DHA) on the contractions induced by carbachol (CCh), angiotensin II (Ang II), and bradykinin (BK) in guinea pig (GP) gastric fundus smooth muscle (GFSM), particularly focusing on the possible inhibition of store-operated Ca 2+ channels (SOCCs). DHA significantly suppressed the contractions induced by CCh, Ang II, and BK; the inhibition of BK-induced contractions was the strongest. Although all contractions were greatly dependent on external Ca 2+ , more than 80% of BK-induced contractions remained even in the presence of verapamil, a voltage-dependent Ca 2+ channel inhibitor. BK-induced contractions in the presence of verapamil were not suppressed by LOE-908 (a receptor-operated Ca 2+ channel (ROCC) inhibitor) but were suppressed by SKF-96365 (an SOCC and ROCC inhibitor). BK-induced contractions in the presence of verapamil plus LOE-908 were strongly inhibited by DHA. Furthermore, DHA inhibited GFSM contractions induced by cyclopiazonic acid (CPA) in the presence of verapamil plus LOE-908 and inhibited the intracellular Ca 2+ increase due to Ca 2+ addition in CPA-treated 293T cells. These findings indicate that Ca 2+ influx through SOCCs plays a crucial role in BK-induced contraction in GP GFSM and that this inhibition by DHA is a new mechanism by which this fatty acid inhibits GFSM contractions., (© 2024. The Author(s).)

This study tested the effects of β-methylphenylethylamine (β-MPEA) and octopamine on contractile parameters of the gastrointestinal tract in rats. We hypothesized that some of their effects result from interactions with trace amine (TA)-associated receptors or serotoninergic 5-hydroxytryptamine (5-HT) receptors. β-MPEA-induced contractions in rat gastric fundus strips under resting tonus conditions, but induced relaxation in preparations that were previously contracted with carbachol. Octopamine relaxed gastric fundus strips maintained at resting tonus or contracted with carbachol. The contractile effect of β-MPEA was reduced by cyproheptadine and methiothepin, antagonists of excitatory 5-HT receptors. The relaxing effect of β-MPEA on gastric fundus was insensitive to pretreatment with N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide (EPPTB) and tropisetron, antagonists of TA 1 and 5-HT 4 receptors, respectively. Both EPPTB and tropisetron inhibited the relaxant effects of octopamine on carbachol-contracted preparations. Contrarily, EPPTB did not reduce the relaxant effects of RO5263397 (TA 1 agonist) or zacopride (5-HT 4 agonist). Octopamine, but not β-MPEA, delayed the gastrointestinal transit of a liquid test meal in awaken rats. In isolated preparations of the small intestine under resting conditions, β-MPEA did not alter the basal tonus, but octopamine relaxed it. Intestinal preparations previously contracted with carbachol relaxed after the addition of octopamine and decreased the magnitude of their spontaneous rhythmic contractions in a tropisetron-dependent manner. Thus, β-MPEA and octopamine exerted pharmacological actions on the rat gastrointestinal tract. The excitatory effects of β-MPEA involved 5-HT receptors. Octopamine inhibited the rat gut contractility through the likely involvement of 5-HT 4 and TA receptors. Overall, octopamine effectively inhibited rat gastrointestinal transit., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Transient outward, or "A-type," currents are rapidly inactivating voltage-gated potassium currents that operate at negative membrane potentials. A-type currents have not been reported in the gastric fundus, a tonic smooth muscle. We used whole cell voltage clamp to identify and characterize A-type currents in smooth muscle cells (SMCs) isolated from murine fundus. A-type currents were robust in these cells with peak amplitudes averaging 1.5 nA at 0 mV. Inactivation was rapid with a time constant of 71 ms at 0 mV; recovery from inactivation at -80 mV was similarly rapid with a time constant of 75 ms. A-type currents in fundus were blocked by 4-aminopyridine (4-AP), flecainide, and phrixotoxin-1 (PaTX1). Remaining currents after 4-AP and PaTX1 displayed half-activation potentials that were shifted to more positive potentials and showed incomplete inactivation. Currents after tetraethylammonium (TEA) displayed half inactivation at -48.1 ± 1.0 mV. Conventional microelectrode and contractile experiments on intact fundus muscles showed that 4-AP depolarized membrane potential and increased tone under conditions in which enteric neurotransmission was blocked. These data suggest that A-type K + channels in fundus SMCs are likely active at physiological membrane potentials, and sustained activation of A-type channels contributes to the negative membrane potentials of this tonic smooth muscle. Quantitative analysis of Kv4 expression showed that Kcnd3 was dominantly expressed in fundus SMCs. These data were confirmed by immunohistochemistry, which revealed Kv4.3-like immunoreactivity within the tunica muscularis. These observations indicate that Kv4 channels likely form the A-type current in murine fundus SMCs.

Pseudo-signet ring parietal cell vacuolation has been described as a mimic of invasive signet ring cell carcinoma. Moreover, signet ring cell carcinoma has been described in a fundic gland polyp. This case demonstrates parietal cell vacuolation in a fundic gland polyp in a patient on a long-term proton pump inhibitor.

Some adipokines, such as adiponectin (ADPN), other than being implicated in the central regulation of feeding behavior, may influence gastric motor responses, which are a source of peripheral signals that also influence food intake. The present study aims to elucidate the signaling pathways through which ADPN exerts its actions in the mouse gastric fundus. To this purpose, we used a multidisciplinary approach. The mechanical results showed that ADPN caused a decay of the strip basal tension, which was abolished by the nitric oxide (NO) synthesis inhibitor, L-N G -nitro arginine (L-NNA). The electrophysiological experiments confirmed that all ADPN effects were abolished by L-NNA, except for the reduction of Ca 2+ current, which was instead prevented by the inhibitor of AMP-activated protein kinase (AMPK), dorsomorphin. The activation of the AMPK signaling by ADPN was confirmed by immunofluorescence analysis, which also revealed the ADPN R1 receptor (AdipoR1) expression in glial cells of the myenteric plexus. In conclusion, our results indicate that ADPN exerts an inhibitory action on the gastric smooth muscle by acting on AdipoR1 and involving the AMPK signaling pathway at the peripheral level. These findings provide novel bases for considering AMPK as a possible pharmacologic target for the potential treatment of obesity and eating disorders.

Endokinin A/B (EKA/B), the common C-terminal decapeptide in endokinins A and B, is a preferred ligand of the NK1 receptor and regulates pain and itch. The study focused on the effects of EKA/B on rat gastric motility in vivo and in vitro. Gastric emptying was measured to evaluate gastric motility in vivo . Intragastric pressure and the contraction of gastric muscle strips were measured to evaluate gastric motility in vitro. Moreover, various neural blocking agents and neurokinin receptor antagonists were applied to explore the mechanisms. TAC4 and TACR1 mRNAs were expressed throughout rat stomach. EKA/B promoted gastric emptying by intraperitoneal injection in vivo. Correspondingly, EKA/B also increased intragastric pressure in vitro. Additionally, EKA/B contracted the gastric muscle strips from the fundus but not from the corpus or antrum. Further studies revealed that the contraction induced by EKA/B on muscle strips from the fundus could be significantly reduced by NK1 receptor antagonist SR140333 but not by NK2 receptor antagonist, NK3 receptor antagonist, or the neural blocking agents used. Our results suggested that EKA/B might stimulate gastric motility mainly through the direct activation of myogenic NK1 receptors located in the fundus.

Class-I-antiarrhythmics like ajmaline are known to alter smooth muscle function, which may cause alterations in gastrointestinal motility. The effects of ajmaline on isolated gastric and portal vein smooth muscle and the underlying mechanisms are unknown. We studied the effects of ajmaline on the contractile patterns of isolated preparations of gastric antrum and portal vein from Wistar rats. The organ bath technique was used to measure spontaneous or pharmacologically induced isometric contractions. Changes in force observed after application of ajmaline or under control conditions are reported as % of the amplitude of an initial K + -induced contraction. Electric field stimulation was used to study neurogenic relaxations of gastric fundus smooth muscle. Ajmaline increased the amplitude of spontaneous contractions of muscle strips (portal vein: control 31.1 ± 15.2%, with 100 μM ajmaline 76.6 ± 32.3%, n = 9, p < 0.01; gastric antrum: control 9.5 ± 1.6%, with 100 μM ajmaline 63.9 ± 9.96%, n = 14, p < 0.01). The frequency of spontaneous activity was reduced in portal vein, but not in gastric antrum strips. The effects of ajmaline were not blocked by tetrodotoxin, L-nitroarginine methyl ester, or atropine. Ajmaline abolished coordinated neurogenic relaxations triggered by electric field stimulation and partly reversed the inhibition of GA spontaneous activity caused by the gap junction blocker carbenoxolone. Ajmaline enhances the amplitude of spontaneous contractions in rat gastric and portal vein smooth muscle. This effect may be accompanied, but not caused by an inhibition of enteric neurotransmission. Enhanced syncytial coupling as indicated by its ability to antagonize the effects of carbenoxolone is likely to underlie the enhancement of contractility.

It is generally considered that enteric neuropathy is one of the causative factors in diabetic gastroparesis. Our previous study demonstrated that there is a loss of NOS neurons in diabetic mice. However, the underlying mechanism remains unclear. The present study was designed to clarify the relationship between neuronal P2X7R and NOS neuron damage. The effect of P2X7R on diabetes-induced gastric NOS neurons damage and its mechanism were investigated by using quantitative RT-PCR，immunofluorescence, western blot, isometric force recording, intracellular calcium ([Ca 2+ ]i) measurement and whole-cell patch clamp techniques. The immunohistochemistry and western blot results showed that nNOS expression was significantly down-regulated in diabetic mice, meanwhile, electric field stimulation-induced NOS sensitive relaxation was significantly suppressed. Myenteric neurons expressed P2X7R and pannexin1, and the mRNA and protein level of P2X7R and pannexin1 were up-regulated in diabetic mice. BzATP, a P2X7R activator, evoked [Ca 2+ ]i increase in Hek293 cells with heterologous expression of P2X7R (Hek293-P2X7R cells) and the same dose of ATP-induced [Ca 2+ ]i was more obvious in Hek293-P2X7R cells than in Hek293 cells. Application of BzATP activated an inward current of Hek293-P2X7R in a dose dependent manner. Hek293-P2X7R but not untransfected Hek293 cells could take up of YO-PRO-1. In addition, the uptake of YO-PRO-1 by Hek293-P2X7R was blocked by oxATP, a P2X7 antagonist and CBX, a pannexin1 inhibitor. The results suggest that the P2X7R of enteric neurons may be involved in diabetes-induced NOS neuron damage via combining with pannexin-1 to form transmembrane pores which induce macromolecular substances and calcium into the cells., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Statins are determined to have various pleiotropic effects apart from their lipid-lowering properties. Herein, we investigated the direct effects of atorvastatin on gastric smooth muscle tone. Atorvastatin effectively relaxed isolated rat gastric fundus strips precontracted with acetylcholine, potassium chloride, and serotonin. Incubation of the strips with nitric oxide synthase inhibitor, l-NOARG (10 -4 M, 20 min), l-type voltage-operated Ca 2+ channel (VOCC) blocker, nifedipine (10 -6 M, 30 min), K ATP channel blocker, glibenclamide (10 -5 M, 30 min), or precursor of cholesterol, mevalonate (10 -2 M, 45 min) did not change the relaxations to atorvastatin. However, pretreatment of fundus strips with atorvastatin (3×10 -5 -3×10 -4 M, 30 min) inhibited the contractions to calcium chloride (10 -4 -10 -1 M), acetylcholine (10 -4 M), and caffeine (20 mM) in the calcium-free medium. Moreover, atorvastatin reduced the contractions induced by sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA) inhibitor, cyclopiazonic acid (10 -7 -3×10 -5 M). The current study demonstrated that atorvastatin produces an acute relaxant effect on gastric fundus strips, which appears to be mediated by several Ca 2+ -signalling mechanisms such as the blockade of l-type VOCC-independent Ca 2+ entry, decrease in smooth muscle Ca 2+ sensitivity, inhibition of IP 3 - and ryanodine-sensitive intracellular stores to mediate Ca 2+ release, as well as the activation of SERCA. This acute relaxing effect seems unlikely to be related with nitric oxide, K ATP channels, and the mevalonate pathway.

Background: Acotiamide, a prokinetic agent was shown to be efficacious in the treatment of functional dyspepsia (FD). The exact mechanism of action is incompletely elucidated., Methods: This randomized, placebo-controlled, cross-over study aimed to examine the effect of acotiamide on gastric motility, measured as intragastric pressure, gastric emptying (GE) rate and gastrointestinal (GI) symptom perception in healthy volunteers (HVs). Participants were treated with acotiamide (100 mg tid) and placebo for 3 weeks, separated by a 1-week washout period. A daily symptom diary was collected during both treatments. At the end of each treatment period, GE rate and gastric motility were assessed with a 13 C-octanoic acid breath test and high-resolution manometry during nutrient infusion, respectively. GI symptom levels were scored during high-resolution manometry. Data were analyzed using mixed models. The study was registered as NCT03402984., Key Results: Twenty HVs (10 female, 25 ± 4.1 years, 22.58 ± 2.73 kg/m 2 ) participated in the study. There was no difference in GE half time between both treatments (P = 0.92). Acotiamide had no effect on fundic pressures before and after nutrient infusion (P = 0.91). However, postprandial antral pressures remained significantly lower compared to placebo (P = 0.015). There was no significant difference in hunger, satiation and GI symptoms scores assessed during IGP measurement and by the daily diary (P > 0.12 for all)., Conclusion: Acotiamide is associated with lower antral pressures after nutrient intake, whereas it has no effect on fundic pressures, GE rate and symptom perceptions in HVs. Studies in FD need to elucidate whether lower antral pressures induced by acotiamide underlie postprandial symptom improvement in FD., (© 2019 John Wiley & Sons Ltd.)

β-Phenylethylamine (β-PEA) is a trace amine with chemical proximity to biogenic amines and amphetamines. It is an endogenous agonist of trace amine-associated receptors (TAARs) that acts as a neuromodulator of classic neurotransmitters in the central nervous system. At high concentrations, β-PEA contracts smooth muscle, and a role for TAARs in these responses has been postulated. The high dietary intake of trace amines has been associated with such symptoms as hypertension and migraine, especially after the intake of foods containing such compounds. In gastrointestinal tissues, TAAR expression was reported, although the effect of β-PEA on gastric contractile behaviour is unknown. Here, isolated strips that were obtained from the rat gastric fundus were stimulated with high micromolar concentrations of β-PEA. Under resting tonus, β-PEA induced contractions. In contrast, when the strips were previously contracted with KCl, a relaxant response to β-PEA was observed. The contractile effect of β-PEA was inhibited by 5-hydroxytryptamine (5-HT) receptor antagonists (i.e., cyproheptadine and ketanserin) but not by the TAAR 1 antagonist EPPTB. In gastric fundus strips that were previously contracted with 80 mmol/L KCl, the relaxant effect of β-PEA intensified in the presence of 5-HT receptor antagonists, which was inhibited by EPPTB and the adenylyl cyclase inhibitor MDL-12,330A. The guanylyl cyclase inhibitor ODQ did not alter the relaxant effects of β-PEA. In conclusion, β-PEA exerted dual contractile and relaxant effects on rat gastric fundus. The contractile effect appeared to involve the recruitment of 5-HT receptors, and the relaxant effect of β-PEA on KCl-elicited contractions likely involved TAAR 1 ., (© 2018 John Wiley & Sons Australia, Ltd.)

Background: Sphingosine and its metabolite sphingosine phosphate (S1P) regulate a multitude of biological functions, including the contractile state of smooth. Gastrointestinal side effects have been reported in patients treated with FTY720, a sphingosine analog that is approved for the treatment of multiple sclerosis. The aim of this study was to characterize the effects of FTY720 on rat gastric fundus smooth muscle under basal conditions and during activation induced by high-K + solution., Methods: Isometric contractions of isolated circular strips of gastric fundus smooth muscle were recorded using the organ bath method. The effects of FTY720 or vehicle were recorded under control conditions and in the presence of indomethacin, L-NAME, HA-1100, nifedipine, JTE-013, and suramin. Tone and contractions recorded in the presence of FTY720 or vehicle are reported as % of the amplitude of an initial high-K + contraction obtained under control conditions., Key Results: From a concentration of 10 μmol L -1 onwards, FTY720 increased the tone, reaching 8.9% ± 7.5% at 100 μmol L -1 (P < .05). With indomethacin in the solution, the effects of FTY720 were enhanced (32.1% ± 7.7%; P < .001). The FTY720-induced increase in tone was abolished in the absence of extracellular Ca 2+ and reduced by nifedipine, HA-1100, JTE-013, and suramin. Furthermore, FTY720 increased high-K + contractions in the presence of indomethacin., Conclusions & Inferences: FTY720 increases tone and contractile responses to depolarization in gastric fundus smooth muscle by triggering calcium entry and calcium sensitization in a S1P receptor-dependent manner. Taken together, the experimental results presented in this work suggest that FTY720 may increase gastric tone and contractility in patients., (© 2018 John Wiley & Sons Ltd.)

Aqueous extract of the spines of the brown bullhead catfish (Ameiurus nebulosus Lesueur, 1819) caused contraction of the guinea-pig small intestine in vitro, a widely-used preparation in pharmacology. The action is dependent on extracellular Ca 2+ , and probably takes place on the smooth muscle cells. Mouse gastrointestinal preparations were also contracted by the extract. Stings by the spines of this fish species causes a painful sensation in man. We tested the effect of an extract of spines in isolated organ experiments on innervated smooth muscle preparations. In the guinea-pig ileum, the response to the extract was abolished by the Ca 2+ -channel blocker nifedipine, but only slightly reduced by atropine (a muscarine receptor antagonist) or tetrodotoxin (TTX; a blocker axonal conduction) or antagonists for P 2X purinoceptors. Blocking of serotonin or histamine H 1 receptors, tachykinin NK 1 receptors, functional impairment of capsaicin-sensitive sensory nerve endings or inhibition of cyclo-oxygenases failed to influence the contractile effect of the extract. No inhibitory action of the extract was detected on the ileum subject to electrical motor nerve stimulation.

Background: Resveratrol is a polyphenolic compound that can be isolated from plants and also is a constituent of red wine. Resveratrol induces relaxation of vascular smooth muscle and may prevent cardiovascular diseases., Purpose: Impaired gastric accommodation plays an important role in functional dyspepsia and fundic relaxation and is a therapeutic target of functional dyspepsia. Although drugs for fundic relaxation have been developed, these types of drugs are still rare. The purpose of this study was to investigate the relaxant effects of resveratrol in the guinea pig fundus., Study Design: We studied the relaxant effects of resveratrol in the guinea pig fundus. In addition, we investigated the mechanism of resveratrol-induced relaxation on the guinea pig fundus by using tetraethylammonium (a non-selective potassium channel blocker), apamine (a selective inhibitor of the small conductance calcium-activated potassium channel), iberiotoxin (an inhibitor of large conductance calcium-activated potassium channels), glibenclamide (an ATP-sensitive potassium channel blocker), KT 5720 (a cAMP-dependent protein kinase A inhibitor), KT 5823 (a cGMP-dependent protein kinase G inhibitor), NG-nitro-L-arginine (a competitive inhibitor of nitric oxide synthase), tetrodotoxin (a selective neuronal Na + channel blocker), ω-conotoxin GVIA (a selective neuronal Ca 2+ channel blocker) and G-15 (a G-protein coupled estrogen receptor antagonist)., Results: The results of this study showed that resveratrol has potent and dose-dependent relaxant effects on the guinea pig fundic muscle. In addition, the results showed that resveratrol-induced relaxation of the guinea pig fundus occurs through nitric oxide and ATP-sensitive potassium channels., Conclusion: This study provides the first evidence concerning the relaxant effects of resveratrol in the guinea pig fundic muscle strips. Furthermore, resveratrol may be a potential drug to relieve gastrointestinal dyspepsia., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

New Findings: What is the central question of this study? Acute acidosis that results from short-term exercise is involved in delayed gastric emptying in rats and the lower responsiveness of gastric fundus strips to carbachol. Does extracellular acidosis decrease responsiveness to carbachol in tissues of sedentary rats? How? What is the main finding and its importance? Extracellular acidosis inhibits cholinergic signalling in the rat gastric fundus by selectively influencing the G q/11 protein signalling pathway. Acute acidosis that results from short-term exercise delays gastric emptying in rats and decreases the responsiveness to carbachol in gastric fundus strips. The regulation of cytosolic Ca 2+ concentrations appears to be a mechanism of action of acidosis. The present study investigated the way in which acidosis interferes with gastric smooth muscle contractions. Rat gastric fundus isolated strips at pH 6.0 presented a lower magnitude of carbachol-induced contractions compared with preparations at pH 7.4. This lower magnitude was absent in carbachol-stimulated duodenum and KCl-stimulated gastric fundus strips. In Ca 2+ -free conditions, repeated contractions that were induced by carbachol progressively decreased, with no influence of extracellular pH. In fundus strips, CaCl 2 -induced contractions were lower at pH 6.0 than at pH 7.4 but only when stimulated in the combined presence of carbachol and verapamil. In contrast, verapamil-sensitive contractions that were induced by CaCl 2 in the presence of KCl did not change with pH acidification. In Ca 2+ store-depleted preparations that were treated with thapsigargin, the contractions that were induced by extracellular Ca 2+ restoration were smaller at pH 6.0 than at pH 7.4, but relaxation that was induced by SKF-96365 (an inhibitor of store-operated Ca 2+ entry) was unaltered by extracellular acidification. At pH 6.0, the phospholipase C inhibitor U-73122 relaxed carbachol-induced contractions less than at pH 7.4, and this phenomenon was absent in tissue that was treated with the RhoA kinase blocker Y-27632. Thus, extracellular acidosis inhibited pharmacomechanical coupling in gastric fundus by selectively inhibiting the G q/11 protein signalling pathway, whereas electromechanical coupling remained functionally preserved., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

Background: In the gastrointestinal tract of several species, facilitating 5-HT 4 receptors were proposed on myenteric cholinergic neurons innervating smooth muscle by in vitro study of the effect of the selective 5-HT 4 receptor agonist prucalopride on submaximal cholinergic contractions. This was not yet established in the murine gastrointestinal tract., Methods: In circular smooth muscle strips from murine fundus, jejunum and colon, contractions were induced by electrical field stimulation in the presence of guanethidine, L-NAME and for colon also MRS 2500. Submaximal contractions were induced to study the influence of prucalopride., Key Results: Electrical field stimulation at reduced voltage induced reproducible submaximal neurogenic and cholinergic contractions as the contractions were abolished by tetrodotoxin and atropine. Hexamethonium had no systematic inhibitory effect but mecamylamine reduced the responses, suggesting that part of the cholinergic response is due to activation of preganglionic neurons. Prucalopride concentration-dependently increased the submaximal cholinergic contractions in the three tissue types, reaching maximum from 0.03 μmol/L onwards. The facilitation in the different series with 0.03 μmol/L prucalopride ranged from 41% to 104%, 30% to 76% and 24% to 74% in fundus, jejunum, and colon, respectively. The effect of 0.03 μmol/L prucalopride was concentration-dependently inhibited by GR 113808., Conclusions & Inferences: In the murine gastrointestinal tract, activation of 5-HT 4 receptors with prucalopride enhances cholinergic contractions, illustrating facilitation of myenteric cholinergic neurotransmission. The degree of enhancement with prucalopride is of similar magnitude as previously reported in other species, but the effective concentrations are lower than those needed in the gastrointestinal tract of other species., (© 2017 John Wiley & Sons Ltd.)

New Findings: What is the central question of this study? The present study investigated the relationship between H 2 S and NO in regulation of gastric fundus tension. What is the main finding and its importance? Endogenous or exogenous H 2 S and NO have opposite effects on fundus tension, and H 2 S-induced gastric fundus tension enhancements are mediated by inhibition of NO generation through the phosphoinositide 3-kinase/Akt pathway. These results are very important in exploring the mechanism of physiological accommodation and accommodation disorder. Hydrogen sulphide (H 2 S) is considered a new gasotransmitter, along with NO and CO. It was recently confirmed that H 2 S and NO play important roles in the regulation of gastrointestinal smooth muscle tension. The present study was designed to elucidate the interactions between H 2 S and NO with respect to the regulation of gastric fundus smooth muscle tension using Western blotting, physiological and electrochemical techniques. Real-time H 2 S and NO generation was detected in gastric smooth muscle tissue. NaHS, an H 2 S donor, enhanced fundus smooth muscle tension, whereas SNP, an NO donor, decreased fundus smooth muscle tension in a dose-dependent manner. NaHS-induced increases in fundus smooth muscle tension were suppressed by l-NAME, an NO synthase inhibitor. Aminooxyacetic acid (AOAA), a cystathionine β-synthase inhibitor, exerted inhibitory effects on fundus smooth muscle tension; these effects were also suppressed by l-NAME. Real-time NO generation was significantly potentiated by AOAA. Endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 and Akt phosphorylation at serine 308 and threonine 473 were significantly inhibited by NaHS. LY294002, a phosphoinositide 3-kinase inhibitor, blocked these NaHS-mediated effects. However, eNOS phosphorylation at serine 1177 and Akt phosphorylation at serine 308 and threonine 473 were significantly potentiated by AOAA. Cystathionine β-synthase siRNA interference significantly increased eNOS phosphorylation at serine 1177 and Akt phosphorylation at serine 308 and threonine 473. Cystathionine β-synthase siRNA interference also increased total eNOS protein expression levels but did not significantly change total Akt kinase protein expression levels. These results suggest that H 2 S-induced enhancement of gastric fundus tension is mediated by inhibition of NO generation through the phosphoinositide 3-kinase/Akt pathway., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

Objectives: The aim of this study was to evaluate anticholinergic, antihistaminic, and antiserotonergic activity of the n-hexane extract of the seeds of Zanthoxylum alatum (ZAHE) on isolated ileum of rat and guinea pig and fundus of rat., Materials and Methods: ZAHE was prepared using soxhlet extraction and cumulative concentration response curves were constructed using various doses on the tissues for acetylcholine (ACh), 5-hydroxytryptamine (5-HT), and histamine with or without n-hexane extract. Atropine, ketanserin, and pheniramine maleate were used as antagonists for ACh, serotonin, and histamine, respectively., Results: ZAHE-induced concentration-dependent inhibition of isolated ileum and fundus in rat and ileum of guinea pig. The half maximal effective concentration (EC 50 ) of ACh in the presence of atropine (10 -6 M; P < 0.05) and ZAHE (1000 μg/ml; P < 0.01) was significantly higher than EC 50 of ACh alone. The EC 50 of 5-HT in the presence of ketanserin (10 -5 M; P < 0.01) and ZAHE (1000 μg/ml; P < 0.05) was higher than EC 50 of 5-HT alone. Similarly, the EC 50 of histamine in the presence of pheniramine maleate (10 -6 M; P < 0.01) and ZAHE (300 μg/ml; P < 0.01 and 1000 μg/ml; P < 0.05) was also significantly higher than EC 50 of histamine alone., Conclusion: From the study, it was observed that ZAHE shows significant anticholinergic, antiserotonergic, and antihistaminic activity. The study provides sufficient evidence that the seeds can be used in gastric disorders, cough, chest infection, etc., as per folklore claims., Competing Interests: There are no conflicts of interest.

Background: Peptic ulcer diseases are common and are induced by many factors, including stress, smoking, and ingestion of non-steroidal anti-inflammatory drugs. Quercetin is considered to be an anti-oxidant with healing effects on many experimental toxic injuries. The present study aimed to explore the possible effect of quercetin on acute gastric ulcer induced by indomethacin in rats., Materials and Methods: Three groups received indomethacin (30 mg/kg body weight) orally by orogastric gavage on two consecutive days. The rats received famotidine (50 mg/kg body weight), quercetin (50 mg/kg body weight), or vehicle alone for 15 consecutive days by oral gavage. The control group received no indomethacin but received vehicle for 15 days by oral gavage. The ulcer index, volume, and pH of gastric juice were measured, and the stomachs were examined by routine light microscopy., Results: Compared with the control group, the indomethacin-treated rats showed a marked damage of the gastric mucosal surface and a high ulcer index. In the famotidine- and quercetin-treated groups, significantly increased antioxidant enzyme activities were observed. The congestion, erosions, and necrosis were reduced with mild inflammatory cell infiltration while no major damage of endothelial cells was observed in the treated rats., Conclusions: The findings of the study show that quercetin had antioxidant effect and can protect gastric mucosa against indomethacin-induced gastric ulceration than famotidine.

Aim: The objective was to evaluate the effects of nitric oxide (NO) and hydrogen sulfide (H 2 S) donors and possible interactions between these two systems in modulating gastric function., Methods: Mice received saline, sodium nitroprusside (SNP), or sodium hydrosulfite (NaHS), and after 1 h, the animals were killed for immunofluorescence analysis of CSE or eNOS expressions, respectively. Other groups received saline, SNP, NaHS, Lawesson's reagent (H 2 S donor), PAG + SNP, L-NAME, L-NAME + NaHS, or L-NAME + Lawesson's reagent. Then, the gastric secretions (mucous and acid), gastric blood flow, gastric defense against ethanol, and gastric motility (gastric emptying and gastric contractility) were evaluated., Results: SNP and NaHS increased the expression of CSE or eNOS, respectively. SNP or Lawesson's reagent did not alter gastric acid secretion but increased mucus production, and these effects reverted with PAG and L-NAME treatment, respectively. SNP or NaHS increased gastric blood flow and protected the gastric mucosa against ethanol injury, and these effects reverted with PAG and L-NAME treatments, respectively. SNP delayed gastric emptying when compared with saline, and PAG partially reversed this effect. NaHS accelerate gastric emptying, and L-NAME partially reversed this effect. SNP and NaHS alone induced gastric fundus and pylorus relaxation. However, pretreatment with PAG or L-NAME reversed these relaxant effects only in the pylorus but not in the gastric fundus., Conclusion: NO and H 2 S interact in gastric physiological functions, and this "cross-talk" is important in the control of mucus secretion, gastric blood flow, gastric mucosal defense, and gastric motility, but not in the control of basal gastric acid secretion.

Purpose: To assess whether the number of fundal arteries embolized and use of gastroprotective agents have an impact on ghrelin suppression and gastric ulceration rates., Materials and Methods: Twenty-two healthy, growing swine (mean, 38.4 kg; range, 30.3-47.0 kg) were evaluated. Six control swine underwent a sham procedure. Gastric embolization was performed by the infusion of 40-µm microspheres selectively into some or all gastric arteries supplying the gastric fundus. In group 1, 6 swine underwent embolization of all 4 arteries to the gastric fundus. In group 2, 5 swine underwent embolization of 2 gastric fundal arteries. In group 3, 5 swine underwent embolization of 1 gastric fundal artery. Animals in groups 2 and 3 were treated with gastroprotective agents (sucralfate and omeprazole). Weight and fasting plasma ghrelin levels were analyzed at baseline and at week 4. Upon animal euthanasia, gross analysis was performed for identification of ulcers., Results: Only group 1 animals exhibited changes in serum ghrelin levels that rendered them significantly lower than those in control animals (P = .049). Group 3 animals exhibited marked elevations in serum ghrelin levels compared with control animals (P = .001). Gross pathologic evaluation revealed 0 ulcers in the control animals, 3 ulcers (50%) in group 1, 2 ulcers (40%) in group 2, and 2 ulcers (40%) in group 3., Conclusions: Administration of gastroprotective agents and embolization of fewer arteries to the gastric fundus did not prevent gastric ulceration in treated animals. Only animals that underwent embolization of all gastric arteries exhibited significant decreases in serum ghrelin levels., (Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.)

Angiotensin II (AngII) is the final active product of the renin enzymatic cascade, which is responsible for sustaining blood pressure. To investigate the effect of N-terminal cyclization on AT 1 activation and tachyphylaxis, we designed conformationally constrained analogues with an i-(i + 1) lactam bridge. All analogues presented the same binding coefficient and tachyphylactic index, but some of them such as Cyclo (0-1a) [Glu 0 , endo-(Lys 1a )]-AngII and Cyclo (0-1a) [Asp 0 , endo-(Orn 1a )]-AngII showed higher potency. The same tachyphylactic index presented by AngII and cyclic analogues was surprising. We expected a variation after the modification of AngII N-terminal region., (© 2016 John Wiley & Sons A/S.)

Background: A causal association between proton pump inhibitor (PPI) use and fundic gland polyps has been suggested, but the data are conflicting., Aim: To clarify the relationship through a meta-analysis of the existing data., Methods: A systematic retrieval and selection of records was performed. The main inclusion criteria were original studies reporting the prevalence of fundic gland polyps in PPI users or the reverse, compared to controls. Key outcomes were the odds ratios (OR) for fundic gland polyp prevalence in association with PPI use, prevalence of PPI use amongst subjects with fundic gland polyps and fundic gland polyp prevalence among PPI users. Statistical analysis was performed using Mix 2.0 Pro., Results: The initial search using electronic databases and manual searching retrieved 339 peer-reviewed articles and abstracts. Twenty articles met all inclusion and exclusion criteria, with a total of 40 218 subjects included. The meta-analysis of 12 studies revealed an increase in fundic gland polyps amongst PPI users compared to controls (OR 2.46, 95% CI 1.42-4.27, P = 0.001), particularly among individuals taking PPIs for at least 6 months (OR: 4.71, 95% CI 2.22-9.99, P < 0.001) or 12 months (OR: 5.32, 95% CI 2.58-10.99, P < 0.001)., Conclusions: Proton pump inhibitor usage is associated with a significantly increased prevalence of fundic gland polyps, and there is a trend for this to increase with longer length of PPI exposure. However, the meta-analysis is limited mainly to cohort studies., (© 2016 John Wiley & Sons Ltd.)

α -Terpineol is a monoterpene with smooth muscle relaxant properties. In this study, its effects on the gastric emptying rate of awake rats were evaluated with emphasis on the mode by which it induces gastrointestinal actions. Administered by gavage, α -terpineol (50 mg/kg) delayed gastric emptying of a liquid test meal at 10 min postprandial. Hexamethonium or guanethidine did not interfere with the retarding effect induced by α -terpineol, but atropine and L-N G -nitroarginine methyl ester abolished it. In vagotomized rats, α -terpineol did not delay gastric emptying. In isolated strips of gastric fundus, concentration-effect curves in response to carbamylcholine were higher in magnitude after treatment with the monoterpene. α -Terpineol (1 to 2000 µM) relaxed sustained contractions induced by carbamylcholine or a high K + concentration in a concentration-dependent manner. This relaxing effect was not affected by the presence of L-N G -nitroarginine methyl ester, 1 H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, tetraethylammonium, or atropine. Smooth muscle contractions induced by electrical field stimulation were inhibited by α -terpineol. In conclusion, α -terpineol induced gastric retention in awake rats through mechanisms that depended on intact vagal innervation to the stomach, which involved cholinergic/nitrergic signalling. Such a retarding effect induced by α -terpineol appears not to result from a direct action of the monoterpene on gastric smooth muscle cells., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Human gastric fundus relaxation is mediated by intrinsic inhibitory pathway. We investigated the roles of nitrergic and purinergic pathways, two known inhibitory factors in gastric motility, on spontaneous and nerve-evoked contractions in human gastric fundus muscles., Methods: Gastric fundus muscle strips (12 circular and 13 longitudinal) were obtained from patients without previous gastrointestinal motility disorder who underwent gastrectomy for stomach cancer. Using these specimens, we examined basal tone, peak, amplitude, and frequency of spontaneous contractions, and peak and nadir values under electrical field stimulation (EFS, 150 V, 0.3 ms, 10 Hz, 20 s). To examine responses to purinergic and nitrergic inhibition without cholinergic innervation, atropine (muscarinic antagonist, 1 μM), MRS2500 (a purinergic P2Y1 receptor antagonist, 1 μM), and N-nitro-L-arginine (L-NNA, a nitric oxide synthase inhibitor, 100 μM) were added sequentially for spontaneous and electrically-stimulated contractions. Tetrodotoxin was used to confirm any neuronal involvement., Results: In spontaneous contraction, L-NNA increased basal tone and peak in both muscle layers, while amplitude and frequency were unaffected. EFS (up to 10 Hz) uniformly induced initial contraction and subsequent relaxation in a frequency-dependent manner. Atropine abolished initial on-contraction and induced only relaxation during EFS. While MRS2500 showed no additional influence, L-NNA reversed relaxation (p = 0.012 in circular muscle, and p = 0.006 in longitudinal muscle). Tetrodotoxin abolished any EFS-induced motor response., Conclusions: The relaxation of human gastric fundus muscle is reduced by nitrergic inhibition. Hence, nitrergic pathway appears to be the main mechanism for the human gastric fundus relaxation., Competing Interests: The authors have declared that no competing interests exist.

Background: Levosulpiride is a 5HT4 agonist/D2 antagonist prokinetic agent used to improve gastric emptying in patients with functional dyspepsia or gastroparesis. The aim of this study was to characterize its effect on the main in vitro motility patterns in the human fundus, antrum, and jejunum., Methods: Circular muscle strips from human stomach (antrum and fundus) and jejunum, obtained from 46 patients undergoing bariatric surgery, were studied using organ baths. Enteric motor neurons (EMNs) were stimulated by electrical field stimulation (EFS)., Key Results: Levosulpiride, caused an increase in the EFS-induced cholinergic contractions in the gastric antrum (+37 ± 15.18% at 100 μM, pEC50 = 4.46 ± 0.14; p < 0.05, n = 8) and jejunum (+45.4 ± 22.03% at 100 μM, pEC50 = 3.78 ± 6.81; p < 0.05, n = 5), but not in the gastric fundus. It also caused a slight decrease in tone and frequency of spontaneous contractions in the jejunum, but did not have any major effect on tone or spontaneous contractions in the stomach. It did not have any effect on EFS-induced relaxations mediated by nitric oxide (NO) in the stomach (antrum and fundus) and by NO and ATP in the jejunum., Conclusions & Inferences: Our results suggest that the prokinetic effects of levosulpiride in humans are mainly due to the facilitation of the release of acetylcholine by enteric motor neurons in the gastric antrum and the jejunum., (© 2016 John Wiley & Sons Ltd.)

Background and Aims: Capsule endoscopy for visualization of the upper GI tract has thus far been experimental and potentially expensive. Our aim was to demonstrate the maneuverability and evaluate the ability to completely visualize and maintain views in the upper GI tract by using a simple magnetic-assisted capsule endoscopy (MACE) system., Methods: Twenty-six volunteers were recruited. The hand-held magnet was placed at strategic points on the body surface and rotated to hold and maneuver the capsule. The ability to view the upper GI tract landmarks was noted: esophagogastric junction (EGJ), cardia, fundus, body, incisura, antrum, and pylorus. Control was assessed by the ability to hold the capsule for 1 minute at 5 positions: the lower esophagus and 4 designated positions in the proximal and distal stomach and also traversing the stomach and through the pylorus. Volunteers subsequently underwent a standard gastroscopy., Results: The median data are as follows: age, 38 years (range 26-45 years); BMI, 24 (range 19-38); and procedure time, 24 minutes (range 12-39 minutes). Successful visualization of each landmark was EGJ, 92%; cardia, 88%; fundus, 96%; body, 100%; incisura, 96%; antrum, 96%; and pylorus, 100%; with fewer clear views of the EGJ and fundus. The capsule could be held in 88% of designated positions for 1 minute, moved from the fundus to the antrum in all cases, and traversed the pylorus in 50% (n = 13). An age of 40 years and older was associated with successful pyloric traversing (P = .04). There was positive concordance for 8 of 9 minor pathological findings on standard gastroscopy., Conclusion: MACE in the upper GI tract is feasible. There is a high degree of visualization and control, with some improvement required for optimizing proximal gastric views and traversing the pylorus., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus., (Copyright © 2016 the American Physiological Society.)

Background: Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone synthesized and secreted by the enteroendocrine 'L' cells able to exert intestine-trophic and anti-inflammatory effects. The antineoplastic drug cisplatin causes gastrointestinal alterations with clinical symptoms (nausea and vomiting) that greatly affect the therapy compliance. Experimentally, it has been reported that chronic cisplatin treatment caused mucosal damage and enteric neuropathy in the rat colon., Methods: We investigated, through a combined immunohistochemical and functional approach, whether [Gly(2) ]GLP-2, a GLP-2 analog, was able to counteract the detrimental effects of long-term cisplatin administration in the mucosa and myenteric neurons of mouse gastric fundus., Key Results: Morphological experiments showed a reduction in the epithelium thickness in cisplatin-treated mice, which was prevented by [Gly(2) ]GLP-2 co-treatment. Immunohistochemistry demonstrated that cisplatin caused a significant decrease in myenteric neurons, mainly those expressing neuronal nitric oxide synthase (nNOS), that was prevented by [Gly(2) ]GLP-2 co-treatment. In the functional experiments, [Gly(2) ]GLP-2 co-treatment counteracted the increase in amplitude of the neurally induced contractions observed in strips from cisplatin-treated animals. The NO synthesis inhibitor L-N(G) -nitro arginine caused an increase in amplitude of the contractile responses that was greater in preparations from cisplatin+[Gly(2) ]GLP-2 treated mice compared to the cisplatin-treated ones., Conclusions & Inferences: The results demonstrate that in cisplatin long-term treated mice [Gly(2) ]GLP-2 is able to counteract both the mucosal gastric fundus damage, by preventing the epithelium thickness decrease, and the neuropathy, by protecting the nNOS neurons. Taken together, the present data suggest that [Gly(2) ]GLP-2 could represent an effective strategy to overcome the distressing gastrointestinal symptoms present during the anti-neoplastic therapy., (© 2015 John Wiley & Sons Ltd.)

Background: Severe burn injury has been demonstrated to delay gastric emptying. The aim of this study was to investigate effects and cellular mechanisms of auricular electroacupuncture (AEA) at the acupoints innervated by the auricular branch of vagus nerve on burn-induced gastric dysmotility in rats., Methods: Propranolol (β-adrenoceptor antagonist) was injected intraperitoneally after the rats underwent burn injury. All experiments were performed 6 h following burn/sham burn injury. AEA was performed at bilateral auricular acupoints for 45 min. Electrocardiogram was recorded for 30 min. Plasma hormones were measured; cyclooxygenase (COX)-2 expressions in gastric tissue were measured using western blotting and real-time RT-PCR., Key Results: (i) Burn injury delayed gastric emptying (p = 0.006) and AEA increased gastric emptying by 49% (p = 0.045). (ii) Burn injury evoked a significant elevation in plasma noradrenaline, which was suppressed by AEA. (iii) Burn injury significantly increased protein and mRNA expressions of COX-2 in gastric fundus and antrum. AEA suppressed burn-induced increase in protein expressions, but not mRNA expressions of COX-2., Conclusions & Inferences: Burn injury delays gastric emptying by up-regulating COX-2 attributed to sympathetic overactivity. AEA improves burn-induced delay in gastric emptying, possibly mediated via the sympathetic-COX-2 pathway., (© 2015 John Wiley & Sons Ltd.)

Background: Ghrelin is a 28-amino acid peptide that is isolated mainly from the oxyntic glands of the stomach, especially fundus. Ghrelin administration, either centrally or peripherally, increases food intake and body weight in both rodents and humans. This study evaluates the effects of fundus resection and sclerosing agent injection on ghrelin level and weight loss., Material and Methods: Thirty rats were divided into three groups. In group 1, NaCl was injected into the submucosal space at the gastric fundus while in Group 2, a sclerosing agent was injected into the latter site. In group 3, gastric fundus was resected. Ghrelin levels and weight were recorded., Results: In group 1, rats continued gaining weight and ghrelin levels stayed stable. In group 2, rats' weight and ghrelin levels stayed stable and in group 3, while weight stayed stable, ghrelin levels decreased significantly., Conclusion: In rats, the resection of fundus stabilizes weight gain and decreases ghrelin levels. However, in sclerotherapy, although weight gain was stabilized, there was no decrease in ghrelin levels. In humans, the effect of fundus resection on weight gain can usher in a new era of investigation (Tab. 2, Ref. 16).

Telokin phosphorylation by cyclic GMP-dependent protein kinase facilitates smooth muscle relaxation. In this study we examined the relaxation of gastric fundus smooth muscles from basal tone, or pre-contracted with KCl or carbachol (CCh), and the phosphorylation of telokin S13, myosin light chain (MLC) S19, MYPT1 T853, T696, and CPI-17 T38 in response to 8-Bromo-cGMP, the NO donor sodium nitroprusside (SNP), or nitrergic neurotransmission. We compared MLC phosphorylation and the contraction and relaxation responses of gastric fundus smooth muscles from telokin-/- mice and their wild-type littermates to KCl or CCh, and 8-Bromo-cGMP, SNP, or nitrergic neurotransmission, respectively. We compared the relaxation responses and telokin phosphorylation of gastric fundus smooth muscles from wild-type mice and W/WV mice which lack ICC-IM, to 8-Bromo-cGMP, SNP, or nitrergic neurotransmission. We found that telokin S13 is basally phosphorylated and that 8-Bromo-cGMP and SNP increased basal telokin phosphorylation. In muscles pre-contracted with KCl or CCh, 8-Bromo-cGMP and SNP had no effect on CPI-17 or MYPT1 phosphorylation, but increased telokin phosphorylation and reduced MLC phosphorylation. In telokin-/- gastric fundus smooth muscles, basal tone and constitutive MLC S19 phosphorylation were increased. Pre-contracted telokin-/- gastric fundus smooth muscles have increased contractile responses to KCl, CCh, or cholinergic neurotransmission and reduced relaxation to 8-Bromo-cGMP, SNP, and nitrergic neurotransmission. However, basal telokin phosphorylation was not increased when muscles were stimulated with lower concentrations of SNP or when the muscles were stimulated by nitrergic neurotransmission. SNP, but not nitrergic neurotransmission, increased telokin Ser13 phosphorylation in both wild-type and W/WV gastric fundus smooth muscles. Our findings indicate that telokin may play a role in attenuating constitutive MLC phosphorylation and provide an additional mechanism to augment gastric fundus mechanical responses to inhibitory neurotransmission.

Background: Rikkunshito (RKT) is a gastroprotective herbal medicine. In this study, we investigated the role of RKT in the relaxation of the gastric body (fundus and corpus) and antrum., Methods: We used Suncus murinus, a unique small model animal with similar gastrointestinal motility to humans and dogs. RKT was added at 0.1, 1.0, and 5.0 mg/mL to induce relaxation in vitro; the outcome measure was the intensity of relaxation. The number of spontaneous antral contractions in the absence or the presence of RKT was also counted., Key Results: Rikkunshito induced the relaxation of the gastric body and antrum and decreased the number of spontaneous antral contractions in a dose-dependent manner. The responses to RKT (1.0 mg/mL) were not affected by pretreatment with atropine, N-nitro-l-arginine methyl ester, ritanserin, or ondansetron. On the other hand, timolol almost completely reversed the relaxation induced by RKT (1.0 mg/mL) on the gastric body and antrum and the occurrence of the spontaneous antral contractions. Both butoxamine, a β(2) -adrenoreceptor antagonist, and L 748337, a β(3) -adrenoreceptor antagonist, but not CGP 20712, a β(1) -adrenoreceptor antagonist, significantly reversed the RKT-induced (1.0 mg/mL) gastric relaxation., Conclusions & Inferences: These results indicate that RKT stimulates and modulates gastric relaxation through β(2) - and β(3) -adrenergic, but not β(1) -adrenergic, pathways in S. murinus., (© 2015 John Wiley & Sons Ltd.)

Esophageal atresia (EA) is characterized by esophageal and gastric motility changes secondary to developmental and postsurgical damage. This study evaluated the in vitro contractile profile of the distal esophagus and gastric fundus in an experimental model of EA induced by doxorubicin (DOXO). Wistar pregnant rats received DOXO 2.2 mg/kg on the 8th and 9th gestational days. On day 21.5, fetuses were collected, sacrificed, and divided into groups: control, DOXO without EA (DOXO-EA), and DOXO with EA (DOXO+EA). Strips from the distal esophagus and gastric fundus were mounted on a wire myograph and isolated organ-bath system, respectively, and subjected to increasing concentrations of carbamylcholine chloride (carbachol, CCh). The isolated esophagus was also stimulated with increasing concentrations of KCl. In esophagus, the concentration-effect curves were reduced in response to CCh in the DOXO+EA and DOXO-EA groups compared to the control group (P<0.05). The maximum effect values (Emax) for DOXO+EA and DOXO-EA were significantly lower than control (P<0.05), but the half-maximal effective concentration (EC50) values were not significantly different when the three groups were compared (P>0.05). In response to KCl, the distal esophagus samples in the three groups were not statistically different with regard to Emax or EC50 values (P>0.05). No significant difference was noted for EC50 or Emax values in fundic strips stimulated with CCh (P>0.05). In conclusion, exposure of dams to DOXO during gestation inhibited the contractile behavior of esophageal strips from offspring in response to CCh but not KCl, regardless of EA induction. The gastric fundus of DOXO-exposed offspring did not have altered contractile responsiveness to cholinergic stimulation.

Aim: To investigate the effect of hydrogen sulfide (H2S) on smooth muscle motility in the gastric fundus., Methods: The expression of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) in cultured smooth muscle cells from the gastric fundus was examined by the immunocytochemistry technique. The tension of the gastric fundus smooth muscle was recorded by an isometric force transducer under the condition of isometric contraction with each end of the smooth muscle strip tied with a silk thread. Intracellular recording was used to identify whether hydrogen sulfide affects the resting membrane potential of the gastric fundus in vitro. Cells were freshly separated from the gastric fundus of mice using a variety of enzyme digestion methods and whole-cell patch-clamp technique was used to find the effects of hydrogen sulfide on voltage-dependent potassium channel and calcium channel. Calcium imaging with fura-3AM loading was used to investigate the mechanism by which hydrogen sulfide regulates gastric fundus motility in cultured smooth muscle cells., Results: We found that both CBS and CSE were expressed in the cultured smooth muscle cells from the gastric fundus and that H2S increased the smooth muscle tension of the gastric fundus in mice at low concentrations. In addition, nicardipine and aminooxyacetic acid (AOAA), a CBS inhibitor, reduced the tension, whereas Nω-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase, increased the tension. The AOAA-induced relaxation was significantly recovered by H2S, and the NaHS-induced increase in tonic contraction was blocked by 5 mmol/L 4-aminopyridine and 1 μmol/L nicardipine. NaHS significantly depolarized the membrane potential and inhibited the voltage-dependent potassium currents. Moreover, NaHS increased L-type Ca(2+) currents and caused an elevation in intracellular calcium ([Ca(2+)]i)., Conclusion: These findings suggest that H2S may be an excitatory modulator in the gastric fundus in mice. The excitatory effect is mediated by voltage-dependent potassium and L-type calcium channels.

Background: To date, few animal experiments have been conducted to examine the effects and mechanisms of buspirone in inducing the relaxation of the gastric fundus. The aim of this study is to examine the effects and mechanisms of buspirone, 5-HT(1a) receptor agonist, in the accommodation of gastric fundus muscle in an animal experimental model using guinea pigs., Methods: In the current study, we performed an immunohistochemistry for 5-HT(1a) receptors in the tissue samples collected from the stomach of guinea pig, an ex vivo experiment to examine the electrical field stimulation (EFS)-induced relaxation of the circular muscle in the gastric fundus in guinea pigs and an in vivo experiment to measure the intragastric pressure through the insertion of the balloon catheter in the fundus., Key Results: Immunohistochemical stains for 5-HT(1a) receptor could confirm the expression of 5-HT(1a) receptor in guinea pig stomach. There was a significant dose-dependent inhibition of the EFS-induced relaxation of fundic muscle strips following the treatment with WAY-100635 (5-HT(1a) antagonist), but this was significantly improved following the treatment with buspirone. An in vivo measurement of the gastric fundic tone showed that there was a significant decrease in the intragastric pressure at same volume by pretreatment with buspirone as compared with the vehicle control, but this could be prevented with the treatment with WAY-100635., Conclusions & Inferences: Based on our results, it can be concluded that buspirone is effective in relaxing the gastric fundus via 5-HT(1a) receptor pathway in both in vitro and in vivo experimental models using guinea pigs., (© 2015 John Wiley & Sons Ltd.)

Objectives: The aim was to study interaction of aqueous leaf extract of Aegle marmelos (AM) with cholinergic, serotonergic, and adrenergic receptor systems using appropriate rat tissues-ileum, fundus and tracheal chain, respectively., Materials and Methods: Cumulative concentration-response curves (CRC) were constructed at various doses on each tissue for AM and respective standard agonist. The CRC was again plotted in presence and absence of respective standard antagonist to confirm the interaction of receptor system and AM., Results: AM induced concentration-dependent contractions in isolated rat ileum (0.2-6.4 mg/ml) and fundus (0.2-3.2 mg/ml) that were inhibited significantly (P < 0.05) in the presence of atropine (10(-7) M) and ketanserin (10(-6) M), respectively. The relaxant effect, produced by AM (0.2 mg/ml) on carbachol (10(-5) M) precontracted rat tracheal chain, was also inhibited significantly (P < 0.05) by propranolol (1 ng/ml)., Conclusion: It may be concluded that AM possesses agonistic activity on cholinergic, serotonergic and adrenergic receptors.

Background: Motilin agonists promote human gastric motility and cholinergic activity, but excitatory and inhibitory actions are reported in the esophagus. The effect of 5-HT₄ agonists in esophagus is also unclear. Perhaps the use of drugs with additional actions explains the variation. The aim, therefore, was to examine how motilin and prucalopride, selective motilin and 5-HT₄ receptor agonists, modulate neuromuscular functions in human esophagus and gastric fundus., Methods: Electrical field stimulation (EFS) evoked nerve-mediated contractions of circular and longitudinal muscle from human esophageal body and circular muscle from gastric fundus., Key Results: In esophageal circular muscle EFS evoked brief contraction, followed by another contraction on termination of EFS, each prevented by atropine. Nitric oxide synthase inhibition facilitated contraction during EFS and the overall contraction became monophasic. In esophagus longitudinal muscle and gastric fundus, EFS evoked cholinergically mediated, monophasic contractions, attenuated by simultaneous nitrergic activation. Motilin (100-300 nM) reduced esophagus circular muscle contractions during EFS, unaffected by L-NAME or apamin. Motilin 300 nM also reduced EFS-evoked contractions of longitudinal muscle. Similar concentrations of motilin facilitated cholinergic activity in the fundus and increased baseline muscle tension. Prucalopride facilitated EFS-evoked contractions in esophagus (tested at 30 μM) and fundus (0.1-30 μM)., Conclusions & Inferences: Selective motilin and 5-HT₄ agonists have different, region-dependent abilities to modulate human esophageal and stomach neuromuscular activity, exemplified by weak inhibition (motilin) or excitation (5-HT₄) in esophageal body and excitation for both in stomach. In different patients with motility dysfunctions, motilin and 5-HT₄ agonists may reduce gastro-esophageal reflux in different ways., (© 2014 John Wiley & Sons Ltd.)

Ghrelin is a multifunctional peptide that promotes an increase of food intake and stimulates GH secretion. Ghrelin secretion is regulated by nutritional status and nutrients. Although a high-protein (HP) diet increases plasma ghrelin secretion in mammals, the mechanisms and the roles of the elevated ghrelin concentrations due to a HP diet have not been fully established. To clarify the roles of elevated acylated ghrelin upon intake of a HP diet, we investigated the regulation of ghrelin concentrations in plasma and tissues in wethers fed with either the HP diet or the control (CNT) diet for 14 days, and examined the action of the elevated plasma ghrelin by using a ghrelin-receptor antagonist. The HP diet gradually increased the plasma acylated-ghrelin concentrations, but the CNT diet did not. Although the GH concentrations did not vary significantly across the groups, an injection of ghrelin-receptor antagonist enhanced insulin levels in circulation in the HP diet group. In the fundus region of the stomach, the ghrelin levels did not differ between the HP and CNT diet groups, whereas ghrelin O-acyltransferase mRNA levels were higher in the group fed with HP diet than those of the CNT diet group were. These results indicate that the HP diet elevated the plasma ghrelin levels by increasing its synthesis; this elevation strongly suppresses the appearance of insulin in the circulation of wethers, but it is not involved in GH secretion. Overall, our findings indicate a role of endogenous ghrelin action in secretion of insulin, which acts as a regulator after the consumption of a HP diet., (© 2014 Society for Endocrinology.)

The intracellular motor protein myosin Va is involved in nitrergic neurotransmission possibly by trafficking of neuronal nitric oxide synthase (nNOS) within the nerve terminals. In this study, we examined the role of myosin Va in the stomach and penis, proto-typical smooth muscle organs in which nitric oxide (NO) mediated relaxation is critical for function. We used confocal microscopy and co-immunoprecipitation of tissue from the gastric fundus (GF) and penile corpus cavernosum (CCP) to localize myosin Va with nNOS and demonstrate their molecular interaction. We utilized in vitro mechanical studies to test whether smooth muscle relaxations during nitrergic neuromuscular neurotransmission is altered in DBA (dilute, brown, non-agouti) mice which lack functional myosin Va. Myosin Va was localized in nNOS-positive nerve terminals and was co-immunoprecipitated with nNOS in both GF and CCP. In comparison to C57BL/6J wild type (WT) mice, electrical field stimulation (EFS) of precontracted smooth muscles of GF and CCP from DBA animals showed significant impairment of nitrergic relaxation. An NO donor, Sodium nitroprusside (SNP), caused comparable levels of relaxation in smooth muscles of WT and DBA mice. These normal postjunctional responses to SNP in DBA tissues suggest that impairment of smooth muscle relaxation resulted from inhibition of NO synthesis in prejunctional nerve terminals. Our results suggest that normal physiological processes of relaxation of gastric and cavernosal smooth muscles that facilitate food accommodation and penile erection, respectively, may be disrupted under conditions of myosin Va deficiency, resulting in complications like gastroparesis and erectile dysfunction.

Background: Sporadic fundic gland polyps (FGPs) are common gastric polyps. Some studies reported that FGPs dramatically increased due to proton pump inhibitors (PPIs) use and a decreased prevalence of Helicobacter pylori (H. pylori) infection in Western countries. However, data are still controversial. This study aimed to identify the relationships between these two factors and FGPs in China., Methods: Consecutive patients with FGPs detected were retrospectively analyzed. Data including patients' age, sex, symptoms, H. pylori infection, history of PPIs use, and the polyps were documented. Each patient was compared with two randomly selected age- and sex-matched controls with similar symptoms in the same period., Results: During the period from March 2011 to March 2012, a total of 328 patients were diagnosed as FGPs in 23 047 patients who underwent routine esophagogastroduodenoscopy and 656 patients without FGPs as controls. The mean age was (55.12±12.61) years, and 75.91% were women. The prevalence of H. pylori in patients with FGPs was significantly lower than in those without FGPs (22.30% (64/287) vs. 42.26% (224/530), P < 0.001, OR 0.392, 95% CI 0.283-0.544). Overall, a total of 54 patients with FGPs (54/328, 16.46%) and 136 patients without FGPs (136/656, 20.73%) received PPIs therapy (P = 0.110). According to the different duration of PPIs use, no significant differences of PPIs use were found between the cases and controls among all subgroups. Moreover, the PPIs use was also similar, regardless of age, sex, H. pylori infection, and the number of polyps., Conclusion: Sporadic FGPs may not be induced by PPIs therapy but negatively correlate with H. pylori infection in China, which is not the same with the data in Western countries.

Obestatin is a hormone released from the stomach deriving from the same peptide precursor as ghrelin. It is known to act as an anorectic hormone decreasing food intake, but contrasting results have been reported about the effects of obestatin on gastrointestinal motility. The aim of the present study was to investigate whether this peptide may act on the gastric longitudinal smooth muscle by using a combined mechanical and electrophysiological approach. When fundal strips from mice were mounted in organ baths for isometric recording of the mechanical activity, obestatin caused a tetrodotoxin-insensitive decrease of the basal tension and a reduction in amplitude of the neurally induced cholinergic contractile responses, even in the presence of the nitric oxide synthesis inhibitor N(G)-nitro-l-arginine. Obestatin reduced the amplitude of the response to the ganglionic stimulating agent dimethylphenyl piperazinium iodide but did not influence that to methacholine. In nonadrenergic, noncholinergic conditions, obestatin still decreased the basal tension of the preparations without influencing the neurally induced relaxant responses. For comparison, in circular fundal strips, obestatin had no effects. Notably, in the longitudinal antral ones, obestatin only caused a decrease of the basal tension. Electrophysiological experiments, performed by a single microelectrode inserted in a gastric longitudinal smooth muscle cell, showed that obestatin had similar effects in fundal and antral preparations: it decreased the resting specific membrane conductance, inhibited Ca(2+) currents, and positively shifted their voltage threshold of activation. In conclusion, the present results indicate that obestatin influences gastric smooth muscle exerting site-specific effects.

Regulation of myosin light chain phosphatase (MLCP) via protein kinase C (PKC) and the 17 kDa PKC-potentiated inhibitor of myosin light chain phosphatase (CPI-17) has been reported as a Ca(2+) sensitization signaling pathway in smooth muscle (SM), and thus may be involved in tonic vs. phasic contractions. This study examined the protein expression and spatial-temporal distribution of PKCα and CPI-17 in intact SM tissues. KCl or carbachol (CCh) stimulation of tonic stomach fundus SM generates a sustained contraction while the phasic stomach antrum generates a transient contraction. In addition, the tonic fundus generates greater relative force than phasic antrum with 1 µM phorbol 12, 13-dibutyrate (PDBu) stimulation which is reported to activate the PKCα - CPI-17 pathway. Western blot analyses demonstrated that this contractile difference was not caused by a difference in the protein expression of PKCα or CPI-17 between these two tissues. Immunohistochemical results show that the distribution of PKCα in the longitudinal and circular layers of the fundus and antrum do not differ, being predominantly localized near the SM cell plasma membrane. Stimulation of either tissue with 1 µM PDBu or 1 µM CCh does not alter this peripheral PKCα distribution. There are no differences between these two tissues for the CPI-17 distribution, but unlike the PKCα distribution, CPI-17 appears to be diffusely distributed throughout the cytoplasm under relaxed tissue conditions but shifts to a primarily peripheral distribution at the plasma membrane with stimulation of the tissues with 1 µM PDBu or 1 µM CCh. Results from double labeling show that neither PKCα nor CPI-17 co-localize at the adherens junction (vinculin/talin) at the membrane but they do co-localize with each other and with caveoli (caveolin) at the membrane. This lack of difference suggests that the PKCα - CPI-17 pathway is not responsible for the tonic vs. phasic contractions observed in stomach fundus and antrum.

Previous studies have identified differences in the expression of proteins that regulate myosin light chain phosphorylation and contraction in tonic and phasic smooth muscle. cGMP plays a critical role in smooth muscle relaxation and is important for optimal function of phasic and tonic smooth muscle. The intracellular cGMP levels are regulated by its hydrolysis via phosphodiesterase 5 (PDE5) and efflux via novel multidrug resistance protein 5 (MRP5). In the present study we tested the hypothesis that the differences in the phasic and tonic behavior of smooth muscles may be related to differences in mechanisms that terminate cGMP signaling. Expression of PDE5 and MRP5 was significantly (more than 2-fold) higher in fundus compared with antrum. The NO donor S-nitrosoglutathione (GSNO) caused an increase in PDE5 activity and intra- and extracellular cGMP levels in both fundus and antrum. Stimulation of PDE5 activity and increase in extracellular cGMP were significantly higher in fundus, whereas increase in intracellular cGMP was significantly higher in antrum. GSNO-induced increase in extracellular cGMP was blocked in dispersed cells by the cyclic nucleotide export blocker probenecid and in cultured muscle cells by depletion of ATP or suppression of MRP5 by siRNA, providing evidence that cGMP efflux was mediated by ATP-dependent export via MRP5. Consistent with the higher expression and activity levels of PDE5 and MRP5, GSNO-induced PKG activity and muscle relaxation were significantly lower in muscle cells from fundus compared with antrum. Thus higher expression of PDE5 and MRP5 in muscle cells from fundus correlates with tonic phenotype of muscle.

The aim of this work was to compare the preventing capacity of quercetin with Cu/Zn superoxide dismutase (Cu/Zn SOD), ascorbic acid and glutathione on nitric oxide (NO)-induced relaxation in mouse gastric fundus. Furthermore, the effects of the quercetin on the tissue level of total oxidant and antioxidant was investigated. Nitrergic stimulation (4Hz, 25V, 0.1 ms, 10s-train) and exogenous NO (10 μM) induced relaxation. Pyrogallol (10 μM), hydroquinone (100 μM) and LY83583 (6-Anilino-quinolin-5,8-quinone, 5 μM) inhibited nitrergic relaxations. The inhibition observed with pyrogallol, hydroquinone and LY83583 was prevented by quercetin (0.1 μM). Also, ascorbic acid (500 μM), glutathione (100 μM) and Cu/Zn SOD (100 U/ml) prevented the inhibitory effect of superoxide anion generators on the relaxation to nitrergic stimulation and NO. Diethyldithiocarbamic acid (DETCA; 8mM) inhibited nitrergic relaxations. DETCA-induced inhibition on nitrergic stimulation and NO-induced relaxation was prevented by quercetin, ascorbic acid, glutathione or Cu/Zn SOD. DETCA plus pyrogallol, hydroquinone or LY83583 strengthened the inhibition on the relaxations. Also, pre-treatment with quercetin, ascorbic acid and glutathione prevented the inhibitory effect of DETCA plus LY-83583 on the relaxation to nitrergic stimulation and NO but Cu/Zn SOD did not prevent this inhibition. Also, quercetin increased tissue total antioxidant capacity and decreased tissue oxidant level and oxidative stress index in DETCA-treatment group. These results indicate that quercetin has antioxidant effect and protects NO from endogenous superoxide anion-driven inactivation and enhances its biological activity, suggesting that quercetin may scavenge superoxide anion in a Cu/Zn SOD, glutathione or ascorbic acid-inhibitable manner., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The present work aimed at evaluating the radiolysis effect upon a set of peptides, most of them involved in physiological functions. To generate reactive radical species, a Co(60) source (up to 15 kGy) was used for controlled gamma irradiation of some peptide solutions including derivatives attaching the stable free radical Toac (2,2,6,6-tetramethypiperidine-1-oxyl-4-amino-4-carboxylic acid). Regardless of the peptide sequence, a nonlinear and progressive degradation of a total of nine peptides was detected. The results were interpreted in the light of the half-life dose (D(1/2)) parameter which represents the dose necessary for 50% peptide structure degradation. The vasoactive angiotensin II (AngII)'s analogue Ang-(1-7) showed greater stability towards gamma ray radiation than bradykinin (BK), Toac(0)-BK, Pro(4)-BK (D(1/2) around 4 and 2 kGy, respectively) which decreased to about 0.5-1.0 kGy in the case of acetyl-α-melanocyte-stimulating hormone (Ac-α-MSH) and substance P (SP). In terms of peptide structural modifications, the data acquired from different analytical methods suggested a Phe to Tyr (or its ortho and/or meta isomers) transformation as a consequence of the hydroxyl moiety insertion. Noteworthy, this effect seemed to be position-dependent as only Phe located at or near the C-terminal portion seemed to display this transformation. In contrast, Met is comparatively more easily oxidized, thus allowing to conclude that gamma irradiation may induce a complex position and/or sequence-dependent effect on peptides. As previously applied for BK, some irradiated peptides were submitted to their by-products purification, indeed a complementary target of the present approach for development of uncommon analogues for further structure-function investigation.

BAY 41-2272 is a heme-dependent nitric oxide-independent soluble guanylate cyclase (sGC) stimulator, but its relaxant effect in vascular, respiratory and urogenital tissue is only partially dependent on sGC activation. As its mechanism of action has not been studied in the gastrointestinal tract, it was investigated in mouse gastric fundus and colon. Circular smooth muscle strips were mounted in organ baths under non-adrenergic non-cholinergic (NANC) conditions for isometric force recording and cGMP levels were determined using an enzyme immunoassay kit. BAY 41-2272 induced concentration-dependent relaxation in both tissues and increased cGMP levels. The sGC inhibitor ODQ totally inhibited this BAY 41-2272-induced increase of cGMP, but only partially reduced the corresponding relaxation. The PDE-5 inhibitor sildenafil had no effect on BAY 41-2272-induced responses. The NO synthase inhibitor L-NAME caused a significant decrease in BAY 41-2272-induced responses in colonic strips. Electrical field stimulation in the presence of BAY 41-2272 induced increased NANC relaxation in fundus, while in colon, rebound contraction at the end of the stimulation train was no longer visible. This suggests synergy with endogenously released NO. Responses to BAY 41-2272 were not significantly influenced by apamin, charybdotoxin or ouabain, excluding interaction with small, intermediate and large conductance Ca(2+)-activated K(+) channels and with Na(+)-K(+)-ATPase. Under depletion of intracellular calcium, CaCl(2)-induced contractions were significantly reduced by BAY 41-2272 in an ODQ-insensitive way. The present study demonstrates that BAY 41-2272 exerts its relaxing effect in mouse gastric fundus and colon partially through a cGMP-dependent mechanism and at least one additional cGMP-independent mechanism involving Ca(2+)-entry blockade., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background and Aim: Low-dose aspirin (LDA), and Helicobacter pylori (HP) infection are considered the two primary causes of peptic ulceration. The interaction between HP infection and non-steroidal anti-inflammatory drugs is, however, a matter of considerable discussion and controversy. In this study, we investigated possible synergistic or negative interactions between HP infection and LDA in gastric mucosal lesions, according to lesion site., Methods: The subjects were 120 patients attending the Cardiology Outpatients Department (average age, 67.1 ± 8.9 years; male : female ratio 2.9:1). Endoscopic findings were graded using the Modified Lanza score. Lesions were scored for the antral, body and fundal regions. Ulcers were defined as mucosal defects ≥ 5 mm in size., Results: There were 55 HP-positive and 65 HP-negative subjects, and 91 subjects on LDA therapy. The gastric antral Lanza scores were HP(-) LDA(-): 0.2 ± 1.6, HP(-) LDA(+): 1.8 ± 1.5, HP(+) LDA(-): 0.3 ± 0.7, and HP(+) LDA(+): 0.5 ± 1.0. The gastric body and fundal Lanza scores were 0.0 ± 0.0, 0.8 ± 0.9, 0.4 ± 1.1, and 1.0 ± 1.5, respectively, and 0.1 ± 0.3, 0.5 ± 0.9, 0.1 ± 0.3, and 0.1 ± 0.3, respectively. Variance analysis of the correlation between HP infection and LDA by regional Lanza scores identified both HP infection and LDA use as factors that significantly influence the antral Lanza score. However, LDA was an aggressive factor, and HP infection a protective factor. In the gastric body, LDA was a non-significant, and HP infection a significant, aggressive factor. In the gastric fundus, neither HP infection nor LDA was a significant factor (LDA was an aggressive factor, and HP infection a protective factor)., Conclusions:   LDA had aggressive effects in all gastric lesions; on the other hand, HP infection had protective effects in the antrum and fundus in the stomach, and aggressive effects in the body in the stomach., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

We report two cases of a massive fundic gland polyposis associated with protracted proton pump inhibitor (PPI) therapy. Both patients were females aged 51. On repeated endoscopy, the number of fundic gland polyps was increasing steeply, and they resulted in a passage disorder. In the first case, the enormous number of polyps made endoscopic removal impossible, so the patient was treated by total gastrectomy. Although our case is the second one reported in the world, we would like to draw the attention to this rare complication of long lasting PPI therapy.

Voltage-dependent type 7 K+ (KV7) channels play important physiological roles in neurons and muscle cells. The aims of the present study were to investigate the motor effects of KV7 channel modulators in the rat gastric fundus and the expression of KV7 channels in this tissue. Muscle tone and electrical field stimulation (EFS)-evoked relaxations of precontracted longitudinal muscle strips of the rat gastric fundus were investigated under nonadrenergic noncholinergic conditions by organ bath studies. Gene expression was studied by real-time PCR and tissue localization of channels was investigated by immunohistochemistry. The KV7 channel blocker XE-991 induced concentration-dependent contractions, with mean pD2 and Emax of 5.4 and 48% of the maximal U46619-induced contraction, respectively. The KV7 channel activators retigabine and flupirtine concentration-dependently relaxed U46619-precontracted strips, with pD2s of 4.7 and 4.4 and Emax of 93% and 91% of the maximal relaxation induced by papaverine, respectively. XE-991 concentration-dependently inhibited retigabine-induced relaxation with a pIC50 of 6.2. XE-991 and DMP-543, another KV7 channel blocker, increased by 13-25% or reduced by 11-21% the relaxations evoked by low- or high-frequency EFS, respectively. XE-991 also reduced the relaxation induced by vasoactive intestinal polypeptide (VIP) by 33% of controls. Transcripts encoded by all KV7 genes were detected in the fundus, with 7.4 and 7.5 showing the highest expression levels. KV7.4 and 7.5 channels were visualized by confocal immunofluorescence in both circular and longitudinal muscle layers. In conclusion, in the rat proximal stomach, KV7 channels appear to contribute to the resting muscle tone and to VIP- and high-frequency EFS-induced relaxation. KV7 channel activators could be useful relaxant agents of the gastric smooth muscle., (Copyright © 2011 Elsevier Ltd. All rights reserved.)