GABA(B)-receptor mediation of the inhibitory effect of gamma-hydroxybutyric acid on intestinal motility in mice

The effect of acutely administered gamma-hydroxybutyric acid (GHB) and GHB receptor antagonist, NCS-382, on the propulsive activity in the mouse small intestine was assessed by measuring the transit of an orally administered, non absorbable marker. Both GHB (0, 25, 50, 100, 200 and 300 mg/kg; i.p.) and NCS-382 (0, 25, 50 and 75 mg/kg; i.p.) induced a dose-dependent inhibition (up to 50-60%) of the marker transit. Pretreatment with the GABA(B) receptor antagonist, SCH 50911 (100 mg/kg; i.p.), resulted in the blockade of the inhibiting effect of both GHB and NCS-382. These results suggest that the constipating effect of GHB and NCS-382 are secondary to stimulation of the GABA(B) receptor.     

Gamma-hydroxybutyrate reduces mitogen-activated protein kinase phosphorylation via GABA B receptor activation in mouse frontal cortex and hippocampus

gamma-Hydroxybutyrate (GHB) naturally occurs in the brain, but its exogenous administration induces profound effects on the central nervous system in animals and humans. The intracellular signaling mechanisms underlying its actions remain unclear. In the present study, the effects of GHB on the activation (phosphorylation) of mitogen-activated protein kinases (MAP kinases), extracellular signal-regulated kinase 1 and 2 (ERK1/2), were investigated. Acute administration of GHB (500 mg/kg, intraperitoneal) induced a fast and long lasting inhibition of MAP kinase phosphorylation in both frontal cortex and hippocampus. The reduced MAP kinase phosphorylation was observed in the CA1 and CA3 areas but not in the dentate gyrus. Pretreatment with the specific gamma-aminobutyric acid, type B (GABAB), receptor antagonist CGP56999A (20 mg/kg, intraperitoneal) prevented the action of GHB, and the effect of GHB was mimicked by baclofen, a selective GABAB receptor agonist, whereas the high affinity GHB receptor antagonist NCS-382 (200 mg/kg, intraperitoneal) had no effect on GHB-inhibited MAP kinase phosphorylation. Moreover, the GHB dehydrogenase inhibitor valproate (500 mg/kg, intraperitoneal), which inhibits the conversion of GHB into GABA, failed to block the effect of GHB on MAP kinase phosphorylation. Altogether, these data suggest that GHB, administered in vivo, reduces MAP kinase phosphorylation via a direct activation of GABAB receptors by GHB. In contrast, GHB (10 mm for 15 min) was found ineffective on MAP kinase phosphorylation in brain slices, indicating important differences in the conditions required for the second messenger activating action of GHB.     

PYY immunoneutralization does not alter lipid-induced inhibition of gastric emptying in rats

PYY is released from the distal ileum by fat and may be involved in mediating lipid-induced inhibition of gastric acid secretion and intestinal motility. The role of PYY in intestinal lipid-induced inhibition of gastric emptying in awake rats was investigated using a specific polyclonal antibody raised against PYY. METHODS: Gastric emptying of liquids was measured in awake rats fitted with a Thomas gastric cannula. Intralipid (total dose 50 or 100 mg) was perfused for 10 min (0.05 ml/min) into a duodenal (n = 11) or mid-intestinal cannula (60 cm from Ligament of Treitz; n = 8), and gastric emptying was measured over the 5-10 min period. Gastric emptying was measured 15 min after IP injection of PYY (1 nmol/rat). PYY antibody (20 mg) or a control antibody (anti-KLH; keyhole limpet hemocyanin) was injected ip 8-12 h before experiments. RESULTS: Exogenous PYY (1 nmol) inhibited gastric emptying and administration of PYY antibody blocked this response. Perfusion of lipid (50 and 100 mg) into the proximal intestine produced a 46% and 66% inhibition of gastric emptying respectively. Inhibition of gastric emptying in response to 50 mg lipid in the proximal small intestine was unaffected by administration of PYY antibody but was abolished by administration of the CCK A receptor antagonist devazepide (0.1 mg/kg ip). Perfusion of lipid into the distal intestine (50 and 100 mg) inhibited gastric emptying by 10% and 32% respectively. Inhibition of gastric emptying in response to 100 mg lipid in the distal intestine was unaffected by PYY antibody. CONCLUSIONS: Lipid perfused into either the proximal or distal intestine inhibits gastric emptying via a PYY-independent mechanism. CCK is involved in proximal lipid induced inhibition of gastric emptying.     

Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat

A novel peptide called ghrelin or motilin-related-peptide (MTLRP) was found in the stomach of various mammals. We studied its effect on the motor function of the rat gastrointestinal tract. In normal, conscious unoperated animals, ghrelin/MTLRP (5 or 20 microg/kg iv) significantly accelerated the gastric emptying of a methylcellulose liquid solution (gastric residue after 15 min: 57 +/- 7, 42 +/- 11, 17 +/- 4, and 9 +/- 3% of the ingested meal with doses of 0, 1, 5, and 20 microg/kg iv, respectively) Transit of the methylcellulose liquid solution was also accelerated by ghrelin/MTLRP in the small intestine but not in the colon. Des-[Gln(14)]ghrelin, also found in the mammalian stomach, was as potent as ghrelin in emptying the stomach (gastric residue after 15 min: 12 +/- 3% at a dose of 20 microg/kg iv). In rats in which postoperative gastrointestinal ileus had been experimentally induced, ghrelin/MTLRP (20 microg/kg iv) reversed the delayed gastric evacuation (gastric residue after 15 min: 28 +/- 7% of the ingested meal vs. 82 +/- 9% with saline). In comparison, the gastric ileus was not modified by high doses of motilin (77 +/- 7%) or erythromycin (82 +/- 6%) and was only partially improved by calcitonin gene-related peptide (CGRP) 8-37 antagonist (59 +/- 7%). Ghrelin/MTLRP, therefore, accelerates the gastric emptying and small intestinal transit of a liquid meal and is a strong prokinetic agent capable of reversing the postoperative gastric ileus in rat.     

Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid

Two gamma-hydroxybutyric acid (GHB) analogues, trans-gamma-hydroxycrotonic acid (t-HCA) and gamma-(p-methoxybenzyl)-gamma-hydroxybutyric acid (NCS-435) displaced [3H]GHB from GHB receptors with the same affinity as GHB but, unlike GHB, failed to displace [3H]baclofen from GABAB receptors. The effect of the GHB analogues, GHB and baclofen, on G protein activity and hippocampal extracellular glutamate levels was compared. While GHB and baclofen stimulated 5'-O-(3-[35S]thiotriphospate) [35S]GTPgammaS binding both in cortex homogenate and cortical slices, t-HCA and NCS-435 were ineffective up to 1 mm concentration. GHB and baclofen effect was suppressed by the GABAB antagonist CGP 35348 but not by the GHB receptor antagonist NCS-382. Perfused into rat hippocampus, 500 nm and 1 mm GHB increased and decreased extracellular glutamate levels, respectively. GHB stimulation was suppressed by NCS-382, while GHB inhibition by CGP 35348. t-HCA and NCS-435 (0.1-1000 microm) locally perfused into hippocampus increased extracellular glutamate; this effect was inhibited by NCS-382 (10 microm) but not by CGP 35348 (500 microm). The results indicate that GHB-induced G protein activation and reduction of glutamate levels are GABAB-mediated effects, while the increase of glutamate levels is a GHB-mediated effect. Neither t-HCA nor NCS-435 reproduced GHB sedative/hypnotic effect in mice, confirming that this effect is GABAB-mediated. The GHB analogues constitute important tools for understanding the physiological role of endogenous GHB and its receptor.     

Acetaminophen distribution in the rat central nervous system

Based on the evidence that the antinociceptive effects of acetaminophen could be mediated centrally, tissue distribution of the drug after systemic administration was determined in rat anterior and posterior cortex, striatum, hippocampus, hypothalamus, brain stem, ventral and dorsal spinal cord. In a first study, rats were treated with acetaminophen at 100, 200 or 400 mg/kg per os (p.o.), and drug levels were determined at 15, 45, 120, 240 min by high performance liquid chromatography (HPLC) coupled with electrochemical detection (ED). In a second study, 45 min after i.v. administration of [3H]acetaminophen (43 microCi/rat; 0.65 microg/kg), radioactivity was counted in the same structures, plus the septum, the anterior raphe area and the cerebellum. Both methods showed a homogeneous distribution of acetaminophen in all structures studied. Using the HPLC-ED method, maximal distribution appeared at 45 min. Tissue concentrations of acetaminophen then decreased rapidly except at the dose of 400 mg/kg where levels were still high 240 min after administration, probably because of the saturation of clearance mechanisms. Tissue levels increased with the dose up to 200 mg/kg and then leveled off up to 400 mg/kg. Using the radioactive method, it was found that the tissue/blood ratio was remarkably constant throughout the CNS, ranking from 0.39 in the dorsal spinal cord to 0.46 in the cerebellum. These results, indicative of a massive impregnation of all brain regions, are consistent with a central antinociceptive action of acetaminophen.     

Peripheral urocortin inhibits gastric emptying and food intake in mice: differential role of CRF receptor 2

Intraperitoneal urocortin inhibits gastric emptying and food intake in mice. We investigated corticotropin-releasing factor receptor (CRF-R) subtypes involved in intraperitoneal urocortin actions using selective CRF-R antagonists. Gastric emptying was measured 2 h after a chow meal, and food intake was measured hourly after an 18-h fast in mice. Urocortin (3 microg/kg ip) inhibited gastric emptying by 88%. The CRF-R1/CRF-R2 antagonist astressin B (30 microg/kg ip) and the selective CRF-R2 antagonist antisauvagine-30 (100 microg/kg ip) completely antagonized urocortin action, whereas the selective CRF-R1 antagonist CP-154,526 (10 mg/kg ip) had no effect. Urocortin (1-10 microg/kg ip) dose dependently decreased the 2-h cumulative food intake by 30-62%. Urocortin (3 microg/kg)-induced hypophagia was completely antagonized by astressin B (30 microg/kg ip) and partially (35 and 31%) by antisauvagine-30 (100 or 200 microg/kg ip). The CRF-R1 antagonists CP-154,526 or DMP904 (10 mg/kg ip) had no effect. Capsaicin did not alter urocortin-inhibitory actions while blocking the satiety effect of intraperitoneal CCK. These data indicate that intraperitoneal urocortin-induced decrease in feeding is only partly mediated by CRF-R2, whereas urocortin action to delay gastric emptying of a meal involves primarily CRF-R2.     

Leptin inhibits gastric emptying in rats: role of CCK receptors and vagal afferent fibers

Leptin regulates energy homeostasis and body weight by balancing energy intake and expenditure. It was recently reported that leptin, released into the gut lumen during the cephalic phase of gastric secretion, is capable of initiating intestinal nutrient absorption. Vagal afferent neurons also express receptors for both CCK and leptin, which are believed to interact in controlling food intake. The present study was undertaken to investigate the central and peripheral effects of leptin on gastric emptying rate. Under anesthesia, male Sprague-Dawley rats (250-300 g) were fitted with gastric Gregory cannulas (n=12) and some had additional cerebroventricular cannulas inserted into their right lateral ventricles. Following recovery, the rate of gastric emptying of saline (300 mOsm/kg H(2)O) was determined after instillation into the gastric fistula (3 ml, 37 degrees C, containing phenol red, 60 mg/l as a non-absorbable dilution marker). Gastric emptying rate was determined from the volume and phenol red concentrations recovered after 5 min. Leptin, injected intraperitoneally (i.p.; 10, 30, 60, 100 microg/kg) or intracerebroventricularly (i.c.v.; 5, 15 microg/rat) 15 min before the emptying, delayed gastric emptying rate of saline at the dose of 30 microg/kg or 15 microg/rat (p<0.001). When CCK(1) receptor blocker L-364,718 (1 mg/kg, i.p.), CCK(2) receptor blocker L-365,260 (1 mg/kg, ip) or adrenergic ganglion blocker bretylium tosylate (15 mg/kg, i.p.) was administered 15 min before ip leptin (30 microg/kg) injections, leptin-induced delay in gastric emptying was abolished only by the CCK(1) receptor blocker (p<0.001). However, the inhibitory effect of central leptin on gastric emptying was reversed by adrenergic blockade, but not by either CCK antagonists. Our results demonstrated that leptin delays gastric emptying. The peripheral effect of leptin on gastric motility appears to be mediated by CCK(1) receptors, suggesting the release of CCK and the involvement of vagal afferent fibers. On the other hand, the central effect of leptin on gastric emptying is likely to be mediated by adrenergic neurons. These results indicate the existence of a functional interaction between leptin and CCK receptors leading to inhibition of gastric emptying and short-term suppression of food intake, providing an additional feedback control in producing satiety.     

Complement plays an important role in gastric mucosal damage induced by ischemia-reperfusion in rats.

Ischemia-reperfusion (I/R) of stomach causes gastric mucosal injury. Complement can also cause tissue damage, however its role in gastric I/R injury has not been thoroughly investigated. We evaluated the effect of complement suppression in reducing damage to the gastric epithelium caused by local I/R. Local gastric ischemia was induced by clamping the left gastric artery. The blood-to-lumen clearance of 51Cr-labeled EDTA (51Cr-EDTA) served as an index of epithelial damage. 51Cr-EDTA clearance increased shortly after reperfusion with peak values at 10 min. Intraperitoneal administration of cobra venom factor (CVF; 50 units) prior to I/R, which reduced the serum complement value (CH50) to an undetectable level, remarkably suppressed the 51Cr-EDTA clearance following reperfusion. A monocarboxylic acid derivative of K-76 (K-76 COOH) reduced the CH50 by more than 30% (100 mg/kg) and 60% (200 mg/kg). Rats pretreated with K-76 significantly attenuated the increase in 51Cr-EDTA clearance produced by I/R. These results suggest that complement inhibitor could be used to protect gastric mucosal injury induced by local I/R stress.     

Capsaicin-sensitive vagal fibres and 5-HT3-, gastrin releasing peptide- and cholecystokinin A-receptors are involved in distension-induced inhibition of gastric emptying in the rat.

The present study was undertaken to investigate how the activation of gastric mechanoreceptors by distension of the stomach in conscious gastric fistula rats influences gastric emptying; and the roles of capsaicin sensitive vagal afferent fibres and the 5-HT3, GRP and CCK-A receptors involved in mediating these responses. To activate mechanoreceptors by non-nutrient dependent pathways, methylcellulose in saline was used to distend the stomach (5 cm H2O) and the subsequent emptying of saline was examined immediately, and at 3, 5 and 10 min following distension. Prior distension delayed the subsequent emptying of saline instilled into the stomach compared with non-distended controls (2.28+/-0.09 ml/5 min; P < 0.001). Topical application of capsaicin, completely abolished the distension-induced inhibition of gastric emptying when compared with vehicle treated rats (2.82+/-0.09 vs. 2.38+/-0.04 ml/5 min; P < 0.001). Peripheral administration of a GRP antagonist (2258 U89UJ, 1 mg/kg), and a 5-HT3 antagonist (BRL4369UA, 50 microg/kg) significantly reversed (2.56+/-0.14 ml/5 min; P < 0.05 and 2.61+/-0.07 ml/5 min; P < 0.01; respectively) the delay in gastric emptying induced by distension. When the rats were treated with the CCK-A antagonist, gastric emptying of saline following distension was also significantly facilitated (2.56+/-0.07 ml/5 min; P < 0.001). In contrast, the CCK-B/gastrin receptor antagonist had no significant effect on the distension induced delay in gastric emptying (1.95+/-0.12 ml/5 min). The present results suggest that gastric distension in conscious gastric fistula rats delays gastric emptying by activating capsaicin-sensitive extrinsic afferent nerve fibres. Moreover, the results also indicate that distension-induced mechanisms involve GRP, 5-HT3 and CCK-A receptors, but not CCK-B receptors.     

Downregulation of nNOS and synthesis of PGs associated with endotoxin-induced delay in gastric emptying

A single intraperitoneal injection of endotoxin (40 microg/kg) significantly delayed gastric emptying of a solid nutrient meal. Blockade of nitric oxide synthase (NOS) with 30 mg/kg ip N(G)-nitro-L-arginine methyl ester or 20 mg/kg ip 7-nitroindazole [neuronal NOS (nNOS) inhibitor] significantly delayed gastric emptying in control animals but failed to modify gastric emptying in endotoxin-treated rats. Administration of 2.5, 5, and 10 mg/kg ip N(6)-iminoethyl-L-lysine [inducible NOS (iNOS) inhibitor] had no effect in either experimental group. Indomethacin (5 mg/kg sc), NS-398 (cyclooxygenase-2 inhibitor; 10 mg/kg ip), and dexamethasone (10 mg/kg sc) but not quinacrine (20 mg/kg ip) significantly prevented delay in gastric emptying induced by endotoxin but failed to modify gastric emptying in vehicle-treated animals. Ca(2+)-dependent NOS activity in the antrum pylorus of the stomach was diminished by endotoxin, whereas Ca(2+)-independent NOS activity was not changed. In addition, decreased nNOS mRNA and protein were observed in the antrum pylorus of endotoxin-treated rats. Our results suggest that downregulation of nNOS in the antrum pylorus of the stomach and synthesis of prostaglandins mediate the delay in gastric emptying of a solid nutrient meal induced by endotoxin.     

Gamma-hydroxybutyrate increases tryptophan availability and potentiates serotonin turnover in rat brain

Gamma-hydroxybutyrate (GHB) is both a therapeutic agent and a recreative drug. It has sedative, anxiolytic and euphoric effects. These effects are believed to be due to GHB-induced potentiation of cerebral GABAergic and dopaminergic activities, but the serotonergic system might also be involved. In this study, we examine the effects of pharmacological doses of GHB on the serotonergic activity in rat brain. Administration of 4.0 mmol/kg i.p. GHB to rats induces an accumulation of tryptophan and 5-HIAA (5-hydroxyindole acetic acid) in the frontal cortex, striatum and hippocampus without causing significant change in the tissue serotonin content. In the extracellular space, GHB induced a slight decrease in serotonin release. The tryptophan and 5-HIAA accumulation induced by GHB is mimicked by the GHB receptor agonist para-chlorophenyl-transhydroxycrotonate (NCS-356) and blocked by NCS-382 (6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5-ol-4-ylidene acetic acid) a selective GHB receptor antagonist. GHB induces the accumulation of either a derivative of or [3H]-tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood-brain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. Some of the effect of GHB could be reproduced by baclofen and reduced by the GABAB antagonist CGP 35348. Taken together, these results indicate that the GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration.     

Exogenous melatonin delays gastric emptying rate in rats: role of CCK2 and 5-HT3 receptors.

Pineal hormone melatonin is proposed as a potential treatment for severe sleep disturbances, and various gastrointestinal disorders. It was shown that melatonin increases intestinal motility and influences the activity of myoelectric complexes of the gut. The aim of the study was to evaluate the mechanisms of the effect of exogenous melatonin on gastric emptying rate. Male Sprague-Dawley rats were fitted with gastric cannulas under anesthesia. The rate of gastric emptying of saline was determined after instillation into the gastric fistula, from the volume and phenol red concentrations recovered after 5 min. Melatonin injected intraperitoneally (ip; 0.001-100 mg/kg) delayed gastric emptying rate of saline at 3 and 10 mg/kg doses. When administered ip 15 min before melatonin (10 mg/kg) injections, CCK2 (L-365,260, 1 mg/kg) or 5-HT3 receptor (ramosetrone, 50 microg/kg) blockers abolished melatonin-induced delay in gastric emptying rate, while the blockade of sympathetic ganglia (bretylium tosylate, 15 mg/kg) significantly reduced the delay in gastric emptying rate. CCK1 receptor blocker (L-364,718, 1 mg/kg) had no significant effect on the delaying action of melatonin. Our results indicate that pharmacological doses of melatonin delay gastric emptying via mechanisms that involve CCK2 and 5-HT3 receptors. Moreover, it appears that exogenous melatonin inhibits gastric motility in part by activating sympathetic neurons.     

Two new peptides to improve post-operative gastric ileus in dog

Peptides can influence gastrointestinal motility, and from data obtained earlier in rats, we hypothesized that MTL-RP/Ghrelin, as well as CGRP receptor antagonist 8-37, could improve gastric post-operative ileus in dog. Dogs submitted to laparotomy were perfused with or saline or CGRP 8-37 or MTL-RP/Ghrelin on days 1-4 post-operatively while gastric emptying was estimated by measuring the postprandial increase in plasma acetaminophen ingested with a meal. As expected, in saline-treated animals the gastric emptying function was impaired post-operatively. The total amount of acetaminophen emptied (AUC over 150 min) on post-operative days 1-4 reached respectively 31+/-5%, 65+/-8%, 60+/-8% and 62+/-8% of the normal emptying capacity. CGRP antagonist increased the total emptying of acetaminophen to 52+/-5% on day 1, 95+/-2% on day 2 and 103+/-3% (P<0.05) on day 3. The delayed emptying of acetaminophen seen post-operatively in saline-treated animals could be completely reversed by MTL-RP/Ghrelin (P<0.01) whether it was given at 100 microg/kg on day 2 (102+/-7% of the normal emptying capacity), 4 microg/kg on day 3 (106+/-7%) or 20 microg/kg on day 4 (132+/-8%). As found earlier in rodents, CGRP receptor antagonist 8-37 as well as MTL-RP/Ghrelin are potent prokinetics to improve post-operative gastric ileus in dog.     

Influence of enkephalinase inhibitors on gastric emptying in mice depends on the nature of the meal

The effects of two enkephalinase inhibitors (thiorphan and acétorphan) and DALAMIDE on gastric emptying of fat or non-fat meals were evaluated in mice. When administered intraperitonally at low doses (0.1 and 0.2 mg/kg) 30 min prior to a fatty (milk) meal, both thiorphan and acetorphan increased significantly (P less than 0.01) gastric emptying; these effects were maximal for 0.2 and 0.1 mg/kg respectively and decreased progressively to be not significant for doses higher than 5 mg/kg for thiorphan and 0.5 mg/kg for acetorphan. Similarly DALAMIDE given IP increased significantly (P less than 0.05) gastric emptying at doses of 0.5 and 1 mg/kg while a slowing of gastric emptying was obtained for 10 times higher doses. The effects of thiorphan (0.2 mg/kg) and DALAMIDE (0.5 mg/kg) were blocked by previous administration of naloxone (0.3 mg/kg) and methyl-naloxone (0.5 mg/kg) while only naloxone (0.3 mg/kg) blocked the slowing effect of high dose of DALAMIDE. Administered prior to a non-fat meal, thiorphan (1 mg/kg) stimulated gastric emptying and inhibited it at higher dosage (10 mg/kg). Neither acetorphan nor DALAMIDE at similar dosages affected the gastric emptying of a non-fat meal and the effects of thiorphan (1 and 0.1 mg/kg) were not blocked by naloxone (0.3 mg/kg). It is concluded that enkephalinase inhibitors (thiorphan and acetorphan) administered systemically stimulate the gastric emptying of a fat meal by increasing enkephalin levels in peripheral tissues, while thiorphan exhibits non-opiate effects on gastric emptying of a non-fat meal.     

Preproghrelin-derived peptide, obestatin, fails to influence food intake in lean or obese rodents

Objectives: Obestatin has been initially characterized as a new peptide derived from the ghrelin precursor, which suppresses food intake and inhibits the orexigenic and prokinetic actions of ghrelin when injected peripherally or centrally in lean mice. However, reproducing these data remains controversial. Reasons for the disparity may be the use of different doses, routes, and animal models. We aimed to investigate the effects of peripheral and intracisternal (IC) injection of obestatin on feeding, gastric motility, and blood glucose in rats as well as in diet‐induced obese (DIO) mice. Research Methods and Procedures: Food intake and gastric emptying of a semi‐liquid caloric meal were measured after intraperitoneal (IP) injection of obestatin in rats and DIO mice. Gastric phasic motility and blood glucose were monitored in urethane‐anesthetized rats after IC or intravenous (IV) injection of obestatin. Results: Obestatin injected intraperitoneally at doses ranging from 0.1 to 3 mg/kg influenced neither acute food intake nor gastric emptying in rats. Obestatin injected intravenously at 0.3 or 3 mg/kg and IC at 7.5 or 30 µg/rat modified neither fasted gastric phasic motility nor blood glucose levels, while ghrelin (30 µg/kg, IV) increased and vagotomy suppressed gastric motility, and an oligosomatostatin analog (3 µg/rat, IC) decreased blood glucose. Obestatin, injected intraperitoneally (0.3 mg/kg) in DIO mice, did not alter feeding response to a fast, while urocortin 1 (10 µg/kg, IP) induced a 73.3% inhibition at 2 hours. Discussion: Our data demonstrate that peripheral administration of obestatin did not modify food intake in rats or obese mice or gastric motor function in rats.     

Oral administration of Tyr-MIF-1 stimulates gastric emptying and gastrointestinal motility in rodents.

The effects of orally administered Tyr-MIF-1, an agonist of an endogenous antiopiate system, were examined on gastric emptying in mice and gastrointestinal myoelectric activity in rats. Tyr-MIF-1 (5 mg/kg in mice, 20 mg/kg in rats) accelerated gastric emptying of a methylcellulose test meal, increased the frequency of antral spike bursts, and disrupted intestinal migrating myoelectric complexes. These effects were reproduced by a subcutaneous administration of Tyr-MIF-1 at the same dosage. They were blocked by naloxone (1 mg/kg) but not by the kappa receptor subtype antagonist MR 2266 (1 mg/kg). The GABAA antagonist bicuculline (0.5 mg/kg), but not the GABAB antagonist 2-hydroxysaclofen (4 mg/kg), also antagonized the effects of Tyr-MIF-1. These data demonstrate that oral Tyr-MIF-1 stimulates gastric emptying and gastrointestinal motility through a systemic or central action that involves opioid and GABA systems.     

Alkaline elution of DNA from stomach pyloric mucosa of rats treated with glyoxal

DNA damage in the pyloric mucosa of the stomach of male F344 rats was determined by the alkaline elution method after administration of glyoxal, a direct-acting mutagen present in various heated foods, by gastric intubation. Glyoxal at doses of 50-550 mg/kg body weight induced DNA damage in the pyloric mucosa of rat stomach, detected by a 5- to 12-fold increase in the elution rate constant 2 h after its administration. N-Methyl-N'-nitro-N-nitrosoguanidine, a glandular stomach carcinogen, used as a positive control at doses of 1-100 mg/kg body weight induced a 11- to 24-fold increase in the elution rate constant, while 2-acetylaminofluorene, which is not a gastric carcinogen, given as a negative control at doses of 200-400 mg/kg body weight did not increase the elution rate constant. Thus glyoxal, which was previously suggested to induce unscheduled DNA synthesis in the pyloric mucosa of rat stomach, was confirmed to be genotoxic in this region.     

Anti-Helicobacter pylori effects of IgY from egg york of immunized hens

Effects of egg york containing IgY specific for Helicobacter pylori on the bacterial growth and intragastric infection were investigated in comparison with a proton-pump inhibitor pantoprazole. For in vitro anti-bacterial activity test, H. pylori (1×10(8) CFU/mL) was incubated with a serially diluted IgY for 3 days. As a result, IgY fully inhibited the bacterial growth at 16 mg/mL, which was determined to a minimal inhibitory concentration. In vivo elimination study, male C57BL/6 mice were infected with the bacteria by intragastric inoculation (1×10(8) CFU/mouse) 3 times at 2-day intervals, and 2 weeks later, orally treated twice a day with 50, 100, 200 or 500 mg/kg IgY for 18 days. After the final administration, biopsy sample of the gastric mucosa was assayed for the bacterial identification via urease, oxidase, catalase, nitrate reduction and H(2)S tests in addition to microscopic examination for mucosal inflammation. In CLO kit test, 75, 50, 12.5 and 12.5% of the animals revealed positive reaction following treatment with 50, 100, 200 and 500 mg/kg IgY, respectively, resulting in a superior efficacy at 200 mg/kg than 30 mg/kg pantoprazole that displayed 75% elimination. The CLO test results were confirmed by bacterial identification. Microscopic examination revealed that H. pylori infection caused severe gastric mucosal inflammation, which were not observed in the CLO-negative mice following treatment with IgY or pantoprazole. Taken together, IgY inhibited the growth of H. pylori, and improved gastritis and villi injuries by eliminating the bacteria from the stomach. The results indicate that IgY could be a good candidate overcoming tolerance of antibiotics for the treatment of H. pylori-mediated gastric ulcers.     

枸橼酸莫沙必利对老年功能性消化不良患者胃功能的影响

目的:探讨枸橼酸莫沙必利分散片对老年功能性消化不良(FD)患者胃功能的影响。方法:将2012年3月~2014年3月我院79例老年FD患者(FD组)给予口服枸缘酸莫沙必利分散片,并随机抽取同一时期120例我院健康体检者为对照组,检测并比较两组的胃底气体的评分、延迟排空相、近端胃容积以及近端胃液体半排空时间。结果:FD组治疗前延迟排空相大于对照组,近端胃液体半排空时间小于对照组,差异有统计学意义(P0.05),两组的胃底气体的评分差异无统计学意义(P0.05);FD组治疗后延迟排空相小于治疗前,近端胃液体半排空时间大于治疗前,差异有统计学意义(P0.05);FD组治疗前0 min、5 min、15 min、30min、60 min的近端胃容积均小于对照组,差异均有统计学意义(P0.05);FD组治疗后各时刻近端胃容积大于治疗前,差异均有统计学意义(P0.05)。结论:老年FD患者采用枸缘酸莫沙必利分散片治疗可明显改善患者的胃功能,促进胃排空的速度,值得临床推广。