The relationship between gastric pH and the emptying of solid, semisolid and liquid meals

The effect of three different meal constituents, solid, semisolid and liquid, on gastric pH, recorded in the proximal and distal stomach, was evaluated in a prospective study of 20 normal volunteers. The solid and liquid were ingested together as one meal and the semisolid as another. Simultaneous recordings of the rate of gastric emptying of the isotopically labelled meal constituents and the gastric pH were made. The rate of gastric emptying was more rapid for the liquid and semisolid constituents (t_1/2= 35.6, range 9.8–103.3 min and 47.4, range 33.5–120 min, respectively) than for the solid meal constituent (t_1/2= 72.0, range 45.0–103.8 min), P < 0.01. Both the combined meal of solid and liquid and the semisolid meal produced a higher pH response in the proximal stomach than in the distal stomach (5.2, range 2.4–6.1 vs 2.9, range 0.8–5.3 and 5.9, range 4.3–6.6 vs 4.3, range 1.1–5.9), P < 0.01. There were significant correlations between the rate of gastric emptying of all three meal constituents and the decline phase in the gastric pH recorded at both the proximal and distal probes, P < 0.01 (Pearson's correlation). The strongest correlations were found between the rate of gastric emptying and the gastric pH recorded in the proximal stomach. The decline phase of gastric pH followed the emptying of semisolid more closely than the emptying of either solid or liquid.     

Involvement of NO in gastric emptying of semi-solid meal in conscious pigs

The influence of non-selective nitric oxide synthase (NOS) inhibition on gastric emptying of a semi-solid meal was studied in conscious pigs. Antroduodenal motility and fundic compliance were also assessed to evaluate the mechanisms at the origin of potential alteration in gastric emptying pattern. N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg kg(-1) i.v.) delayed gastric emptying (half-emptying time of 128.98 +/- 16.86 min vs 73.74 +/- 7.73 min after saline, P < 0.05, n = 6) as a result of decreased proximal gastric emptying. No changes were observed for distal gastric emptying as a result of unchanged antral motility. Similarly, no changes were noted on duodenal motor patterns either in the fasted or in the fed state. L-NAME decreased fundic compliance in fasted state (49 +/- 11 mL mmHg(-1) vs 118 +/- 15 mL mmHg(-1) after saline, P < 0.05, n = 6). As this phenomenon is expected to increase emptying rate, the gastroparesis induced by NOS inhibition is thus likely to originate from distal resistive forces. It is concluded that NO positively modulates gastric emptying.     

The involvement of nitric oxide synthase neurons in enteric neuropathies

Nitric oxide (NO), produced by the neural nitric oxide synthase enzyme (nNOS) is a transmitter of inhibitory neurons supplying the muscle of the gastrointestinal tract. Transmission from these neurons is necessary for sphincter relaxation that allows the passage of gut contents, and also for relaxation of muscle during propulsive activity in the colon. There are deficiencies of transmission from NOS neurons to the lower esophageal sphincter in esophageal achalasia, to the pyloric sphincter in hypertrophic pyloric stenosis and to the internal anal sphincter in colonic achalasia. Deficits in NOS neurons are observed in two disorders in which colonic propulsion fails, Hirschsprung's disease and Chagas' disease. In addition, damage to NOS neurons occurs when there is stress to cells, in diabetes, resulting in gastroparesis, and following ischemia and reperfusion. A number of factors may contribute to the propensity of NOS neurons to be involved in enteric neuropathies. One of these is the failure of the neurons to maintain Ca(2+) homeostasis. In neurons in general, stress can increase cytoplasmic Ca(2+), causing a Ca(2+) toxicity. NOS neurons face the additional problem that NOS is activated by Ca(2+). This is hypothesized to produce an excess of NO, whose free radical properties can cause cell damage, which is exacerbated by peroxynitrite formed when NO reacts with oxygen free radicals.     

Acid challenge delays gastric pressure adaptation, blocks gastric emptying and stimulates gastric fluid secretion in the rat

Functional dyspepsia can be associated with impaired gastric relaxation in response to food intake and delayed gastric emptying. In this study, we investigated whether luminal hydrochloric acid (HCl) may reproduce these motor alterations in phenobarbital-anaesthetized rats via activation of extrinsic neural pathways. Intragastric pressure (IGP) changes induced by a 2-mL fluid bolus were recorded with an oesophageal catheter, and gastric emptying was determined via the fluid volume recovered from the stomach 30-min post-bolus. Experiments involving acute nerve transections or pharmacological blockade of nitric oxide synthesis revealed that the initial increase of IGP after a 0.35 mol L(-1) HCl bolus is dampened by duodenogastric and gastrogastric relaxation reflexes depending on vagal and splanchnic pathways as well as nitric oxide. Compared with saline, HCl (0.15-0.5 mol L(-1)) delayed the subsequent decrease (adaptation) of IGP, inhibited gastric emptying and stimulated gastric fluid secretion as seen in stomachs with ligated pylorus. The acid-evoked delay in IGP adaptation and inhibition of gastric emptying involved duodenogastric and duodenopyloric extrinsic nerve reflexes, whereas the gastric fluid secretion was independent of the extrinsic innervation. It is proposed that the gastropyloric motor changes induced by luminal acid challenge have a bearing on the motor disturbances underlying functional dyspepsia.     

Comparative evaluation of DQ-2511, a novel gastroprokinetic agent,with cisapride in ameliorative action on experimentally induced delayed gastric emptying

We compared the main pharmacological effect of DQ-2511 (3-[[[2-(3,4-dimethoxyphenyl)-ethyl]carbamoyl]methyl]amino -N- methylbenzamide), a novel gastroprokinetic agent, with that of cisapride. Single oral administration of DQ-2511 (3–10 mg kg^?1) caused similar significant improvements to delays in gastric emptying of semi-solid meals evoked by chole-cystokinin-octapeptide (CCK₈: 5 μ kg^?1, i.v.) in monkeys, to that with cisapride (3 mg kg^?1). A 2-week oral treatment of unilaterally vagotomized rats with DQ-2511 (1–10 mg kg^?1) lessened delays in gastric emptying, whereas cisapride (0.3–10 mg kg^?1) had no effect under the same experimental protocols. In anesthetized rats, bolus intravenous injection of either compound (60 μg kg^?1) enhanced gastric motility determined by means of strain gauge force transducers. Electrophysiological investigations revealed that bolus injection of DQ-2511 (6–60 μ kg^?1) depressed the afferent discharge rate of the ventral gastric branch of the vagus nerve, while cisapride showed no effect. These results suggest that the mechanism of ameliorative action of DQ-2511 on delayed gastric emptying may differ from that of cisapride.     

Intestinal electrical stimulation improves delayed gastric emptying and vomiting induced by duodenal distension in dogs.

The aim of this study was to investigate the effects of short-pulse intestinal electrical stimulation (IES) on duodenal distention-induced delayed gastric emptying and vomiting in dogs and its possible mechanisms. The study was performed in 12 dogs with jejunal electrodes and a duodenal cannula in three separate experiments to investigate the effects of IES on duodenal distension (DD)-induced delayed gastric emptying and discomfort signs, vagal efferent activity, and jejunal tone. We found that: (i) IES significantly accelerated gastric emptying of liquid delayed by distension (18.05 +/- 4.06%vs. 7.18 +/- 1.99%, P = 0.036 at 60 min). (ii) IES significantly reduced vomiting and discomfort/pain induced by distension. The average signs score was 15.33 +/- 1.37 during distension which decreased to 6.50 +/- 0.91 (P = 0.0002) with IES. (iii) IES did not change vagal afferent activity, which was assessed by the spectral analysis of the heart rate variability. (iv) IES decreased jejunal tone. In conclusion, IES with parameters commonly used in gastric electrical stimulation for nausea and vomiting associated with gastroparesis improves DD-induced delayed gastric emptying and prevents DD-induced vomiting and discomfort signs. Further studies are warranted to investigate the therapeutic potential of IES for gastrointestinal symptoms associated with disturbances in motility and sensory function in small intestine.     

Effect of NG-nitro-L-arginine methyl ester a nitric oxide synthase inhibitor on neurotransmitter receptor systems in aged rats

In order to examine the effect of age and nitric oxide synthase inhibitor N^G-nitro-L-arginine methl ester (l -NAME) we studied the changes on major neurotransmitter receptor systems in 6 (adult and 24-month-old (aged) Fischer male rats using receptor autoradiography. l -name was administrated intraperitoneally in aged rats once a day for 4 weeks. [³H]QNB (quinuclidinyl benzilate) ³HC (hemicholinium-3) [³H] muscimol ³H] SCH 23390 ([N-methyl-³H] N-methyl-³H]R[+]-8-chloro-2 3 4 5-tetrahydro-3-methyl-5-phenyl-7-il-benzazepine) ³H] mazindol were used as markers of muscarinic acetylcholine receptors high-high-affinity choline uptake sites GABA_A (γ-aminobutyric acid (SP2)_A) receptors dopamine D₁ receptors dopamine D₂ receptors and dopamine uptake sites respectively. The age-related change in ³H muscimol binding in the brain was more pronounced than that in [³H] QNB ³H]HC ³H]SCH 23390 ³H] nemonapride and ³H] nemonapride and ³H] mazindol binding.Chronic treatment (4 weeks) with l -NAME caused no significant changes in [sp1)³H] muscimol ³H SCH 23390 and [³H] nemonapride binding in most areas of aged rat brain as compared with vehicle-treated aged animals. However chronic treatment with l -NAME caused a significant reduction in ³H] HC and ³H] mazindol binding in any brain regions of aged rats in comparison with the vehicle-treated aged animals. These results demonstrate that the GABAergic system is more susceptible to aging processes than cholinergic and dopaminergic systems in teh brain. Furthermore our findings suggest that nitric oxide may play some role in the regulation of choline uptake and dopamine uptake systems during aging processes.     

Sleep and nitric: oxide: effects of 7-nitro indazole, inhibitor of brain nitric oxide synthase

We examined the effect of 7-nitro indazole (7-NI, 2.5–50 mg/kg, i.p.), an inhibitor of central nitric oxide (NO) synthesis, on general behaviour and sleep. The results show that 7-NI induces ptosis, a loss of the righting reflex and decrease of the EEG amplitudes. Furthermore, a duration of slow wave sleep (SWS) and REM sleep decreased, while the latencies of SWS and REM sleep increased. The effects of 7-NI on general behaviour and sleep were partially antagonized by intraventricular administration of the NO precursor,l-arginine (600 μg). These findings indicate that 7-NI induces a state of prominent central depression associated with motor deficit and decrease in sleep stages and wakefulness. It further suggests that NO exerts a significant excitatory effect on the neuronal structure involved in the regulation of locomotion and vigilance.     

Measurements of gastric emptying of low- and high-nutrient liquids using 3D ultrasonography and scintigraphy in healthy subjects

Scintigraphy represents the 'gold standard' for the measurement of gastric emptying. Recent studies suggest that three-dimensional (3D) ultrasonography may allow a precise measure of gastric emptying, given the capacity for accurate volume calculations of the stomach. The aim of this study was to compare measurements of gastric emptying of both low- and high-nutrient drinks by 3D ultrasonography with scintigraphy. Ten healthy young subjects (6M, 4F, age 23.5 +/- 1.5 years) were studied on 2 days. Concurrent measurements of gastric emptying by scintigraphy and 3D ultrasonography were performed after ingestion of 500 mL beef soup (12 kcal) or 300 ml dextrose (25% w/v) (314 kcal) labelled with 20 MBq (99m)Tc-sulphur colloid. There was no significant difference between scintigraphic and ultrasonographic 50% emptying times (T50s) (soup: 27.7 +/- 4.8 min vs 23.8. +/- 4.8 min; dextrose: 122.2 +/- 13.3 min vs 131.9 +/- 10.2 min). There was a close correlation between scintigraphic and ultrasonographic T50s for both soup (r = 0.92, P = 0.0005) and dextrose (r = 0.88, P = 0.0007). For the T50s, the limits of agreement were -15.2 min and +8.1 min for the soup (mean difference -3.6 min) and -35.3 min and +47.6 min for dextrose (mean difference +6.2 min). 3D ultrasonography provides a valid measure of gastric emptying of liquid meals in healthy subjects.     

神经型一氧化氮合酶参与脂多糖诱导的大鼠脑微出血的相关性研究

目的改进并稳定脂多糖(LPS)诱导脑微出血(CMBS)动物模型的建立方法,为进一步研究提供稳定成熟的技术手段;探讨神经型一氧化氮合酶(nNOS)在CMBS过程中的作用。方法 40只SD大鼠,随机分成LPS给药组(n=20)和生理盐水对照组(n=20),分别于0 h、12 h和24 h腹腔注射1 mg/ml、3 mg/kg LPS或相同剂量的生理盐水,48 h后行头部MRI扫描,SWI序列显示出血灶;免疫荧光染色显示小胶质细胞标记分子Iba的表达;蛋白印迹法分析nNOS和ZO-1(血脑屏障标记分子)的表达情况。结果 3 mg/kg LPS给药后,MRI显示散在SWI序列点状低信号影,蛋白印迹法及免疫荧光结果显示ZO-1明显减少,Iba及nNOS表达显著增多。结论 LPS可能通过增加全身炎症反应,促进脑内小胶质细胞增殖,增加nNOS的表达,对中枢神经系统血脑屏障产生破坏作用,从而导致微出血的产生。     

NG-nitro-L-arginine,a nitric oxide synthase inhibitor,and seizure susceptibility in four seizure models in mice

Summary Nitric oxide may be involved in seizure phenomena even though data often seem to be contradictory. This prompted us to study the influence of nitric oxide upon electrically and chemically induced seizures. The effects of nitric oxide synthase inhibitor, N^G-nitro-L-arginine (NNA), on pentylenetetrazol-, aminooxyacetic acid-, aminophylline-induced seizures or electroconvulsive shock were evaluated. NNA was applied at 1, 10 and 40 mg/kg 0.5 and 2.0 h before chemical seizures and at 1 and 40 mg/kg 0.5 and 2.0 h prior to electroconvulsions. The nitric oxide synthase inhibitor (up to 40 mg/kg) did not affect the susceptibility of mice to pentylenetetrazol, aminooxyacetic acid or electroconvulsions. However, NNA significantly enhanced the convulsive properties of aminophylline when applied at 40 mg/kg, 0.5 h before the test. The CD₅₀ value for aminophylline-induced clonus and tonus/mortality was decreased from 233 to 191 and from 242 to 212 mg/kg, respectively. However, this pretreatment also led to a significant increase in the plasma levels of theophylline. Our results suggest that differential effects of NNA on chemically-induced convulsions might in some cases be associated with a pharmacokinetic interaction.     

首发偏执型精神分裂症血清NO/NOS水平的研究

目的探讨首发偏执型精神分裂症血清一氧化氮/一氧化氮合成酶（NO/NOS）水平及与精神症状的关系。方法共收集首发偏执型精神分裂症患者26例（研究组）,健康对照者30例（对照组）,采用阳性与阴性症状量表（PANSS）评定患者的精神症状,同时检测血清NO/NOS水平。结果首发偏执型精神分裂症血清NO/NOS水平均显著高于健康对照组（t=2.08,P〈0.05;t=2.72,P〈0.05）,血清NO/NOS水平与精神症状无显著相关性（P〉0.05）;血清NO水平与血清NOS水平两者存在显著正相关（r=0.41,P〈0.05）。结论首发偏执型精神分裂症患者存在血清NO/NOS水平病理性增高。     

Nitric oxide released by gastric mechanoreceptors modulates nicotinic activation of coeliac plexus neurons in the rabbit

The effects on the nicotinic activation of the coeliac plexus neurons of nitric oxide (NO) released within the coeliac plexus by gastric mechanoreceptors, in particular during gastroduodenal inhibitory reflex, were assessed. This study was performed in the rabbit on an in vitro preparation of the coeliac plexus connected to the stomach and the duodenum. The electrical activity of ganglionic neurons was recorded with intracellular recording techniques. Water-filled balloons were used for gastric distensions and recording of duodenal motility. When a 10-s train of pulses (20-40Hz) of supramaximal intensity was applied to the splanchnic nerves, gradual depression of nicotinic activation occurred. Gastric distension (50 mL, 7.5 min) modulated this depression phenomenon by inhibiting or facilitating the nicotinic activation. In the neurons impaled during the recording of duodenal motility, gastric distension triggered an inhibition of nicotinic activation concomitantly with a gastroduodenal inhibitory reflex organized by the coeliac plexus. If the gastric distensions were performed while the coeliac plexus was superfused by a NO scavenger, the nicotinic activation was unaffected and the gastroduodenal inhibitory reflex was abolished. Moreover, when the coeliac plexus was superfused with an inhibitor of nitric oxide synthase, gastric distensions were without effect on the nicotinic activation. These results demonstrate that NO released within the coeliac plexus by gastric mechanoreceptors, in particular during the gastroduodenal inhibitory reflex, modulates the central nicotinic activation of coeliac plexus neurons, so NO released within a prevertebral ganglion by gastric afferent fibres, in particular during the organization by this ganglion of a reflex regulating the gastrointestinal tract motility, also exerts a gating of the central inputs to the ganglionic neurons.     

The 13C-octanoic acid breath test: validation of a new noninvasive method of measuring gastric emptying in rats

Abstract Currently available rat models for measuring gastric emptying are hampered by the necessity to kill the animals at the end of each experiment, which makes repetitive testing impossible. We have developed and validated a noninvasive test model, adapted from the¹³C‐octanoic breath test in humans, for repetitive measurements of gastric emptying in rats. Male Wistar rats were trained on a fixed protocol to eat a piece of pancake doped with 1 μg¹³C‐octanoic acid after 12 h fasting, and to stay thereafter in cylindrical glass cages. Breath tests were performed by a fully automated system of computer‐guided switching valves, which collected consecutive breath samples. All breath samples were analysed by gas chromatography and isotope mass spectrometry. The area under the curve (AUC) from the cumulative¹³CO₂excretion from 0 to 6 h was determined by the trapezium method to calculate the gastric half‐emptying times (t½). Inter‐day variability was determined. The effect of subcutaneous or intraperitoneal injection of saline was studied. The test was further validated for pharmacological interventions by oral administration of cisapride and parenteral administration of atropine, to induce, respectively. acceleration and delay of gastric emptying. Mean gastric emptying times ± SD of 24 rats were 119.3 ± 28.2 min, 138.7 ± 26.0 min, and 124.5 ± 30.9 min on three different test days. The mean coefficient of variation of three repeated measurements in the same 24 rats was 17.5%. No significant differences were observed after subcutaneous or intraperitoneal injection of saline. In a second test series of eight rats, cisapride significantly accelerated gastric emptying (mean t½ 112.7 ± 33.1 min, P < 0.05), while atropine caused a significant delay (mean t½ 205.9 ± 24.9 min, P < 0.05) when compared to control test results (mean t½ 140.7 ± 16.7 min) in the same rats. We validated the¹³C‐octanoic breath test to study gastric emptying in rats. This test method obviates the necessity to kill laboratory animals and allows repetitive measurements of gastric emptying to study its physiology or pathophysiology as well as the effect of pharmacological agents.     

Neural mechanisms involved in the delay of gastric emptying of liquid elicited by acute blood volume expansion in awake rats

We have previously reported that acute blood volume expansion in awake rats delays the gastric emptying of a liquid meal, using the phenol red method. In this study we attempted to investigate the neural mechanisms involved in this phenomenon. Blood volume expansion, due to Ringer-bicarbonate infusion up to a volume equivalent to 5% of body weight, decreased the gastric emptying of a liquid meal by half (38.2 +/- 1.8 vs 18.7 +/- 3.2%, P < 0.05). The blood volume expansion effect on gastric emptying of liquid was prevented by separate pretreatments, consisting of subdiaphragmatic vagotomy or i.v. injection of hexamethonium (20 mg kg-1) or yohimbine (3 mg kg-1). Intravenous injection of atropine (0.5 mg kg-1), guanethidine (10 mg kg-1), L-NAME (3 mg kg-1), prazosin (1 mg kg-1) or propranolol (2 mg kg-1) did not prevent the blood volume expansion effect on gastric emptying. Bilateral adrenalectomy or coeliac ganglionectomy were also ineffective. The results indicate that blood volume expansion decreases gastric emptying of liquid through vagal-dependent pathways, sensitive to hexamethonium and yohimbine. Evidence for the participation of the peripheral sympathetic nervous system was not found.     

The effect of gastric secretion on gastric physiology and emptying in the fasted and fed state assessed by magnetic resonance imaging

Abstract Conventional measurement of gastric secretion is invasive and cannot assess the intra‐gastric distribution of gastric contents or the effects of secretion on gastric function. This study assessed the effect of gastric secretion on gastric volume responses and emptying (GE) using a validated fast T₁ mapping magnetic resonance imaging (MRI) technique. Twelve healthy participants were studied in the fasted state and after 200 kcal Gadolinium‐DOTA labelled glucose meal during intravenous infusion of pentagastrin or placebo in double‐blind, randomized order. Total gastric volume (TGV) and gastric content volume (GCV) was assessed by MRI volume scans and secretion by fast T₁ mapping. Data was described by the κ‐coefficient (volume change after meal ingestion), by GE half time (T₅₀) and maximal GE rate (GER_max) derived all from a GE model. Pentagastrin increased GCV and TGV compared to placebo [κ(GCV):1.6 ± 0.1 vs 0.6 ± 0.1; κ(TGV): 1.6 ± 0.1 vs 0.7 ± 0.1; P < 0.001]. T₁ maps revealed a secretion layer above the meal, the volume of which was associated with κ (R² = 83%, P < 0.001). TGV and GCV change were similar in both conditions (κ; P = ns). T₅₀ was higher for pentagastrin than for placebo (84 ± 7 vs 56 ± 4min, P < 0.001); however, GER_max was similar (5.9 ± 0.6 vs 4.9 ± 0.4 mL min^?1, P = ns). This study shows volume and distribution of gastric secretion can be quantified in‐vivo by non‐invasive MRI T₁ mapping. Increased GCV drove TGV accommodation without evidence of a direct effect of pentagastrin or excess acid on gastric function. Secretion increases GCV thus prolongs GE as assessed by T₅₀; however, GE rate is unchanged.