Therapeutic potential of synchronized gastric electrical stimulation for gastroparesis: enhanced gastric motility in dogs

The aim of this study was to determine the effects and mechanism of synchronized gastric electrical stimulation (SGES) on gastric contractions and gastric emptying. The first experiment was designed to study the effects of SGES on antral contractions in four randomized sessions. Sessions 1 (control) and 2 (atropine) were performed in the fasting state, composed of three 30-min periods (baseline, stimulation, and recovery). Sessions 3 (control) and 4 (SGES performed during 2nd 20-min period) were performed in the fed state, consisting of two 20-min periods; glucagon was injected after the first 20-min recording. The second experiment was designed to study the effect of SGES on gastric emptying and consisted of two sessions (control and SGES). SGES was delivered with train duration of 0.5-0.8s, pulse frequency of 40 Hz, width of 2 ms, and amplitude of 4 mA. We found that 1) SGES induced gastric antral contractions in the fasting state. The motility index was 1.3 +/- 0.5 at baseline and 6.1 +/- 0.7 (P = 0.001) during SGES. This excitatory effect was completely blocked by atropine. 2) SGES enhanced postprandial antral contractions impaired by glucagon. 3) SGES significantly accelerated glucagon-induced delayed gastric emptying. Gastric emptying was 25.5 +/- 11.3% without SGES and 38.3 +/- 10.7% with SGES (P = 0.006 vs. control). This novel method of SGES induces gastric antral contractions in the fasting state, enhances glucagon-induced antral hypomotility in the fed state, and accelerates glucagon-induced delayed gastric emptying. The effect of SGES on antral contractions is mediated via the cholinergic pathway.     

Inhibitory effects and mechanisms of intestinal electrical stimulation on gastric tone, antral contractions, pyloric tone, and gastric emptying in dogs

The aim of this study was to investigate the effects and mechanisms of intestinal electrical stimulation (IES) on gastric tone, antral and pyloric contractions, and gastric emptying in dogs. Female hound dogs were equipped with a duodenal or gastric cannula, and one pair of serosal electrodes was implanted in the small intestine. The study consisted of five different experiments. Liquid gastric emptying was assessed by collection of chyme from the duodenal cannula in a number of sessions with and without IES and with and without N-nitro-l-arginine (l-NNA). Postprandial antral and pyloric contractions were measured with and without IES and in the absence and presence of l-NNA or phentolamine by placement of a manometric catheter into the antrum and pylorus via the duodenal cannula. Gastric tone was assessed by measurement of gastric volume at a constant pressure. Gastric emptying was substantially and significantly delayed by IES or l-NNA compared with the control session. IES-induced delay of gastric emptying became normal with addition of l-NNA. IES reduced gastric tone, which was blocked by l-NNA. IES also inhibited antral contractions (frequency and amplitude), and this inhibitory effect was not blocked by l-NNA but was blocked by phentolamine. IES alone did not affect pyloric tone or resistance, but IES + l-NNA decreased pyloric tone. In conclusion, IES reduces gastric tone via the nitrergic pathway, inhibits antral contractions via the adrenergic pathway, does not affect pyloric tone, and delays liquid gastric emptying. IES-induced delay of gastric emptying is attributed to its inhibitory effects on gastric motility.     

Central effects of growth hormone-releasing factor (GRF) on intestinal motility in dogs: involvement of dopaminergic receptors

The effects of intracerebroventricular (ICV) and intravenous (IV) administration of human pancreatic growth hormone-releasing factor (hpGRF) on gastro-intestinal motility were examined in fasted and fed conscious dogs equipped with chronically implanted strain-gauges on the antrum and the jejunum. During the fasted state, hpGRF injected ICV at 0.1 micrograms . kg-1 or IV at 0.5 micrograms . kg-1 did not affect the cyclic occurrence of the migrating motor complex (MMC). This pattern was normally disrupted for 8-10 hours by a daily standard meal. Injected ventricularly (0.1 micrograms . kg-1) but not intravenously (0.5 micrograms . kg-1) 10-15 min after the daily meal, hpGRF significantly reduced (p less than 0.01) the duration of the jejunal fed pattern (2.0 +/- 1.4 vs. 8.4 +/- 1.1 hours for control) but not that of the stomach. This effect persisted when hpGRF (0.1 micrograms . kg-1 ICV) was administered after indomethacin (2 mg . kg-1 IM), naltrexone (0.1 mg . kg-1 IV) or domperidone (1 mg . kg-1 IV) but was abolished by a previous IV injection of metoclopramide (1 mg . kg-1). It was concluded that hpGRF is able to act centrally to control the pattern of jejunal motility in fed but not in fasted dog, its effect being probably mediated through dopaminergic pathways.     

Transmural potential and a profile of intestinal motility in dogs]

Relationships between motor patterns of the jejunum and transmural potential changes were studied in the dog chronically fitted with transparietal electrodes and with an intraluminal catheter. The transmural potential increases above 13 mV at the beginning of the irregular spiking activity of a myoelectric complex and reaches 6 mV at the end of a phase of regular spiking activity. Oscillations of 3 mV are recorded during the phases of irregular spiking activity. A sustained increase of the potential occurred after feeding : 10 mV for a diet rich in protides and fat, 25 mV when glucides are predominant.     

Cross-talk along gastrointestinal tract during electrical stimulation: effects and mechanisms of gastric/colonic stimulation on rectal tone in dogs

Gastric electrical stimulation (GES) has been shown to alter motor and sensory functions of the stomach. However, its effects on other organs of the gut have rarely been investigated. The study was performed in 12 dogs implanted with two pairs of electrodes, one on the serosa of the stomach and the other on the colon. The study was composed of two experiments. Experiment 1 was designed to study the effects of GES on rectal tone and compliance in nine dogs compared with colonic electrical stimulation (CES). Rectal tone and compliance were assessed before and after GES or CES. Experiment 2 was performed to study the involvement of sympathetic pathway in 8 of the 12 dogs. The rectal tone was recorded for 30-40 min at baseline and 20 min after intravenous guanethidine. GES or CES was given for 20 min 20 min after the initiation of the infusion. It was found that both GES and CES reduced rectal tone with comparable potency. Rectal compliance was altered neither with GES, nor with CES. The inhibitory effect of GES but not CES on rectal tone was abolished by an adrenergic blockade, guanethidine. GES inhibited rectal tone with a comparable potency with CES but did not alter rectal compliance. The inhibitory effect of GES on rectal tone is mediated by the sympathetic pathway. It should be noted that electrical stimulation of one organ of the gut may have a beneficial or adverse effect on another organ of the gut.     

Enhancement of antral contractions and vagal afferent signaling with synchronized electrical stimulation

Gastric filling activates vagal afferents involved in peripheral signaling to the central nervous system (CNS) for food intake. It is not known whether these afferents linearly encode increasing contractions of the antrum during antral distension (AD). The aim of this study was to investigate effects of AD and electrically enhanced antral contractions on responses of vagal afferents innervating the antrum. Single-fiber recordings were made from the vagal afferents in anesthetized male Long-Evans rats. Antral contractions were measured with a solid-state probe placed in the antrum. A nonexcitatory electrical stimulation (NES) inducing no smooth muscle contractions was applied during the ascending phase of antral contractions to enhance subsequent antral contractions. Fifty-six fibers identified during AD (1 ml for 30 s) were studied through different types of mechanical stimuli. Under normal conditions, one group of fibers exhibited rhythmic firing in phase with antral contractions. Another group of fibers had nonrhythmic spontaneous firing. Responses of 15 fibers were tested with NES during multiple-step distension (MSD). NES produced a mean increase in antral contraction amplitude (177.1 +/- 35.3%) and vagal afferent firing (21.6 +/- 2.6%). Results show that both passive distension and enhanced antral contractions activate distension-sensitive vagal afferents. Responses of these fibers increase linearly to enhanced antral contraction induced by NES or MSD up to a distending volume of 0.6 ml. However, responses reached a plateau at a distending volume >0.8 ml. We concluded that enhanced contraction of the antrum can activate vagal afferents signaling to the CNS.     

甘草对大鼠小肠动力功能影响的实验研究

目的:初步探讨甘草对大鼠小肠动力的作用,及其作用与胃肠激素的相关性.方法:观察甘草组与空白组移行性综肌电(MMC)周期持续时间、Ⅲ相持续时间、Ⅲ相每分钟快波数(FM)和每簇的快波数(FC)的变化;采用免疫组织化学法结合显微图像定量分析扫描系统检测十二指肠、空肠嗜铬细胞及其肌间神经丛中5-羟色胺(5-HT)、P-物质(SP)、血管活性肠肽(VIP)的相对含量.结果:①甘草组与空白组比较MMCⅢ相FM和FC明显减少,MMC周期明显延长,Ⅲ相持续时间明显缩短,统计有显著性差异(P＜0.05).②甘草组十二指肠、空肠粘膜及肌间神经丛内5-HT表达明显较空白组减少,比较有显著性差异,小肠粘膜无明显SP、VIP阳性免疫反映物表达,但小肠肌间神经丛内SP含量明显减少、VIP含量明显增加,组间比较有显著性差异(P＜0.05,P＜0.01).结论:甘草对大鼠小肠动力有抑制作用,这种抑制作用与5-HT、SP、VIP分泌失调密切相关.     

Inhibitory effects of intestinal electrical stimulation on food intake, weight loss and gastric emptying in rats

The aim was to investigate the effects of intestinal electrical stimulation (IES) on food intake, body weight, and gastric emptying in rats. An experiment on food intake and weight change was performed in 22 rats on a control diet and 10 diet-induced obese (DIO) rats for 4 wk with IES or sham IES. The effect of IES on gastric emptying was performed in another 20 rats in the control group. We found that 1) in control rats, 4-wk IES resulted in a reduction of 18.2% in the total amount of food intake compared with sham-IES (P = 0.02); the rats treated with IES had a weight change of -1 +/- 7.8g (P = 0.03), which was equivalent to a weight loss of 6.2% due to IES when adjusted for normal growing. 2) Acute IES delayed gastric emptying by 20% in the control rats (P < 0.01). 3) In the DIO rats, 1-wk IES with the same parameters as those used in the control rats resulted in a significant reduction in the total amount of food intake (126.6 +/- 6.3 g vs. 116.9 +/- 3.2 g, P < 0.01). More reduction in food intake was noted, and a significant weight change was also observed when stimulation energy was increased. 4) No adverse events were observed in any of the experiments. In conclusion, IES delays gastric emptying, reduces food intake, and decreases weight gain in control growing rats. These data suggest that it is worthy to explore therapeutic potentials of IES for obesity.     

Chronic tachygastrial electrical stimulation reduces food intake in dogs

Objective: Tachygastria is known to be associated with gastric hypomotility. This study investigated the effect of tachygastrial electrical stimulation (TES) on food intake and its effects on gastric motility. Research Methods and Procedures: Five experiments were performed to study the effects of TES on gastric slow waves, gastric tone, accommodation, and antral contractions, gastric emptying, acute food intake, and chronic food intake in dogs. Results: TES at tachygastrial frequencies induced tachygastria and reduced normal slow waves. TES significantly reduced gastric tone or induced gastric distention, impaired gastric accommodation, and inhibited antral contractions. TES significantly delayed gastric emptying. Acute TES reduced food intake but did not induce any noticeable symptoms. Chronic TES resulted in a 20% reduction in food intake, and the effect of TES was found to be related to specific parameters. Discussion: TES at the distal antrum results in a significant reduction in food intake in dogs, and this inhibitory effect is probably attributed to TES‐induced reduction in proximal gastric tone, gastric accommodation, antral contractility, and gastric emptying. These data suggest a therapeutic potential of the specific method of TES for obesity.     

Central muscarinic control of the pattern of small intestinal motility in rats

The effects of central and peripheral administration of muscarinic agonists and antagonists on small intestinal motility were examined in conscious rats chronically fitted with electrodes implanted in the duodeno-jejunal wall and a cannula in a cerebral lateral ventricle. Intracerebroventricular (i.c.v.) administration of either atropine or pirenzepine at doses from 1 to 10 micrograms, 15 min before a 3 and 6 g lab chow meal significantly reduced the duration of the postprandial disruption of the migrating myoelectric complexes (MMC). The reduction was significantly greater for atropine, a mixed M1 and M2 muscarinic receptor antagonist, than for pirenzepine, an antagonist with a high affinity for M1 receptors. At a higher dose (10 micrograms) intra peritoneal (i.p.) administration of atropine or pirenzepine did not modify the postprandial disruption of MMC. Oxotremorine (10 ng) a M2 agonist, but not McNeil A343 (5 micrograms), a selective M1 agonist, given i.c.v. in fasted rats disrupted for 1.5 h the MMC pattern. At the same doses given i.p. oxotremorine and McNeil A343 disrupted the MMC for 15 and 45 min respectively. We conclude that the postprandial changes in the small intestinal motility involve muscarinic receptors, mainly of M2 subtype, at the level of the central nervous system.     

Effect of temperature changes of the intestinal wall on the digestive motility in wakeful dogs]

The effect of intestinal wall temperature variations on the digestive motility has been studied in the non anaesthetized dog. The results show the presence of a linear relation between the basic electrical rythm frequency and the intestinal wall temperature; the frequence of spikes potentials emission is an exponentiel function of intestinal wall temperature.     

Role of 5-hydroxytryptamine mechanisms in mediating the effects of small intestinal glucose on blood pressure and antropyloroduodenal motility in older subjects

Postprandial hypotension is an important clinical problem, particularly in the elderly. 5-Hydroxytryptamine3 (5-HT3) mechanisms may be important in the regulation of splanchnic blood flow and blood pressure (BP), and in mediating the effects of small intestinal nutrients on gastrointestinal motility. The aims of this study were to evaluate the effects of the 5-HT3 antagonist granisetron on the BP, heart rate (HR), and antropyloroduodenal (APD) motility responses to intraduodenal glucose in healthy older subjects. Ten subjects (5 male, 5 female, aged 65-76 yr) received an intraduodenal glucose infusion (3 kcal/min) for 60 min (t = 0-60 min), followed by intraduodenal saline for a further 60 min (t = 60-120 min) on 2 days. Granisetron (10 microg/kg) or control (saline) was given intravenously at t = -25 min. BP (systolic and diastolic), HR, and APD pressures were measured. Pressure waves in the duodenal channel closest ("local") to the infusion site were quantified separately. During intraduodenal glucose, there were falls in systolic and diastolic BP and a rise in HR (P < 0.0001 for all); granisetron had no effect on these responses. Granisetron suppressed the number and amplitude (P < 0.05 for both) of local duodenal pressures during intraduodenal glucose. Otherwise, the effects of intraduodenal glucose on APD motility did not differ between study days. We conclude that in healthy older subjects, 5-HT3 mechanisms modulate the local duodenal motor effects of, but not the cardiovascular responses to, small intestinal glucose.     

Interdigestive intestinal motility in dogs with chronic exclusion of bile from the digestive tract

To elucidate the role of bile delivery into the duodenum on the regulation of plasma motilin and on the interdigestive migrating complex, three dogs were operated upon to ligate the main bile duct and divert the biliary flow into the urinary bladder via a Foley catheter. After the operation, despite the chronic diversion of bile from the digestive tract, all animals maintained an excellent health status and exhibited recurrent periods of phase III motor activity migrating from the duodenum to the ileum, which were associated with cyclic increases in plasma motilin. Following the infusion of pooled dog bile (1 mL/min for 10 min) into the duodenum, a premature phase III and a concomitant rise in plasma motilin were observed. These results suggest, that although bile delivery into the duodenum can induce motilin increase in plasma and period of phase III activity in the gut, this phenomenon does not constitute an essential stimulus for the release of motilin and for the induction of the phase III of the interdigestive migrating complex.     

Spatiotemporal electrical and motility mapping of distension-induced propagating oscillations in the murine small intestine

Since the development of knockout animals, the mouse has become an important model to study gastrointestinal motility. However, little information is available on the electrical and contractile activities induced by distension in the murine small intestine. Spatiotemporal electrical mapping and mechanical recordings were made from isolated intestinal segments from different regions of the murine small intestine during distension. The electrical activity was recorded with 16 extracellular electrodes while motility was assessed simultaneously by tracking the border movements with a digital camera. Distension induced propagating oscillatory contractions in isolated intestinal segments. These propagating contractions were dictated by the underlying propagating slow wave with superimposed spikes. The frequencies, velocities, and direction of the propagating oscillations strongly correlated with the frequencies (r = 0.86), velocities (r = 0.84), and direction (r = 1) of the electrical slow waves. N(omega)-nitro-L-arginine methyl ester decreased the maximal diameter of the segment and reduced the peak contraction amplitude of the propagating oscillatory contractions, whereas atropine and verapamil blocked the propagating oscillations. Tetrodotoxin had little effect on the maximal diameter and peak contraction amplitude. In conclusion, distension in the murine small intestine does not initiate peristaltic reflexes but induces a propagating oscillatory motor pattern that is determined by propagating slow waves with superimposed spikes. These spikes are cholinergic and calcium dependent.