The pacemaker activity of interstitial cells of Cajal and gastric electrical activity

Interstitial cells of Cajal (ICC) are the pacemaker cells in the gut. They have special properties that make them unique in their ability to generate and propagate slow waves in gastrointestinal muscles. The electrical slow wave activity determines the characteristic frequency of phasic contractions of the stomach, intestine and colon. Slow waves also determine the direction and velocity of propagation of peristaltic activity, in concert with the enteric nervous system. Characterization of receptors and ion channels in the ICC membrane is under way, and manipulation of slow wave activity markedly alters the movement of contents through the gut. Gastric myoelectrical slow wave activity produced by pacemaker cells (ICC) can be reflected by electrogastrography (EGG). Electrogastrography is a perspective non-invasive method that can detect gastric dysrhythmias associated with symptoms of nausea or delayed gastric emptying.     

胃多导电刺激及胃液体排空犬动物模型的建立

目的建立胃浆膜多导联电刺激和胃排空动物模型。方法在12条英国比格犬的胃大弯浆膜层包埋四对心内起搏电极,距幽门40cm空肠近端行一造瘘口。结果①造瘘管收集食糜的方法简单易行,通过其排空量,能了解不同的电刺激和不同的电刺激参数对胃动力的作用。②胃浆膜多导联电极记录的胃体、胃窦慢波电信号清晰、稳定,能准确地记录不同时间和不同实验的胃慢波变化。③单导联和多导长脉冲电刺激均能控制胃慢波。结论胃浆膜多导联电极是研究胃电生理、胃电起搏及胃电起搏对胃排空的影响较理想的方法。英国比格犬是此模型的理想材料。     

Abnormal gastric slow waves in patients with functional dyspepsia assessed by multichannel electrogastrography

The aim of this study was to utilize multichannel electrogastrography to investigate whether patients with functional dyspepsia had impaired propagation or coordination of gastric slow waves in the fasting state compared with healthy controls. The study was performed in 10 patients with functional dyspepsia and 11 healthy subjects. Gastric myoelectrical activity was measured by using surface electrogastrography with a specially designed four-channel device. The study was performed for 30 min or more in the fasting state. Special computer programs were developed for the computation of the propagation and coupling of the gastric slow wave. It was found that, compared with the healthy controls, the patients showed a significantly lower percentage of slow wave propagation (58.0 +/- 8.9 vs. 89.9 +/- 2.6%, P < 0.002) and a significantly lower percentage of slow wave coupling (46.9 +/- 4.4 vs. 61.5 +/- 6.9%, P < 0.04). In addition, the patients showed inconsistencies in the frequency and regularity of the gastric slow wave among the four-channel electrogastrograms (EGGs). It was concluded that patients with functional dyspepsia have impaired slow wave propagation and coupling. Multichannel EGG has more information than single-channel EGG for the detection of gastric myoelectrical abnormalities.     

大鼠蓝斑核对迷走-迷走抑胃反射的加强作用

本文研究了蓝斑核对迷走-迷走抑胃反射的影响。实验结果表明,单独刺激迷走神经中枢端抑制胃电和胃运动,胃电慢波的振幅和胃内压分别下降到对照值的60.9％和45.7％,与对照值相比有明显的统计学意义(P<0.05)。刺激迷走神经中枢端的同时,以弱刺激刺激蓝斑核时,胃电慢渡的振幅和胃内压分别下降到对照值的42.1％和34.1％,与单独刺激迷走神经的效果相比较有非常显著的差异(P<0.01)。本文结果提示:蓝斑核的兴奋加强迷走-迷走抑胃反射。     

Engaging biological oscillators through second messenger pathways permits emergence of a robust gastric slow-wave during peristalsis

Peristalsis, the coordinated contraction—relaxation of the muscles of the stomach is important for normal gastric motility and is impaired in motility disorders. Coordinated electrical depolarizations that originate and propagate within a network of interconnected layers of interstitial cells of Cajal (ICC) and smooth muscle (SM) cells of the stomach wall as a slow-wave, underly peristalsis. Normally, the gastric slow-wave oscillates with a single period and uniform rostrocaudal lag, exhibiting network entrainment. Understanding of the integrative role of neurotransmission and intercellular coupling in the propagation of an entrained gastric slow-wave, important for understanding motility disorders, however, remains incomplete. Using a computational framework constituted of a novel gastric motility network (GMN) model we address the hypothesis that engaging biological oscillators (i.e., ICCs) by constitutive gap junction coupling mechanisms and enteric neural innervation activated signals can confer a robust entrained gastric slow-wave. We demonstrate that while a decreasing enteric neural innervation gradient that modulates the intracellular IP₃ concentration in the ICCs can guide the aboral slow-wave propagation essential for peristalsis, engaging ICCs by recruiting the exchange of second messengers (inositol trisphosphate (IP₃) and Ca²⁺) ensures a robust entrained longitudinal slow-wave, even in the presence of biological variability in electrical coupling strengths. Our GMN with the distinct intercellular coupling in conjunction with the intracellular feedback pathways and a rostrocaudal enteric neural innervation gradient allows gastric slow waves to oscillate with a moderate range of frequencies and to propagate with a broad range of velocities, thus preventing decoupling observed in motility disorders. Overall, the findings provide a mechanistic explanation for the emergence of decoupled slow waves associated with motility impairments of the stomach, offer directions for future experiments and theoretical work, and can potentially aid in the design of new interventional pharmacological and neuromodulation device treatments for addressing gastric motility disorders.     

Action potentials in gastrointestinal smooth muscle.

Recent investigation of the ultrastructure and electrophysiology of gastrointestinal smooth muscle layers has revealed a fascinating heterogeneity in cell type, cell structure, intercellular communication, and generated electrical activities. Networks of interstitial cells of Cajal (ICC) have been identified in many muscle layers and evidence is accumulating for a role of these networks in gut pacemaking activity. Synchronized motility in the organs of the gut result from interaction between ICC, neural-tissue, and smooth muscle cells. Regulation of cell to cell communication between the different cell types will be an important area for further research. Progress has been made in the elucidation of the ionic basis of the slow wave type action potentials and the spike-like action potentials. The mechanism underlying smooth muscle autorhythmicity seems different from that encountered in cardiac tissue, and evidence exists for metabolic regulation of the frequency of slow wave type action potentials.     

莫沙必利对糖尿病胃轻瘫大鼠胃窦Cajal间质细胞的影响

目的:研究莫沙必利对糖尿病胃轻瘫大鼠胃窦Cajal间质细胞(ICC)的影响。方法:将48只SD雄性大鼠随机分为正常组、模型组、莫沙必利组,各组分别16只。模型组、莫沙必利组大鼠给予一次性腹腔注射链脲佐菌素后建立糖尿病胃轻瘫模型,建模第10天起,莫沙必利组大鼠给予莫沙必利注灌胃治疗。建模30周后,检测各组大鼠的血糖水平、胃残留率,通过采用电生理学方法检测各组大鼠胃动力,并采用免疫组化染色方法检测各组胃窦ICC的相对数量。结果:模型组大鼠胃残留率明显高于正常组大鼠(P0.05),而给予莫沙必利后胃残留率显著降低(P0.05);模型组大鼠胃电图波幅和频率均明显低于正常组大鼠(P0.05),而给予莫沙必利后胃电图波幅和频率明显增加(P0.05);模型组大鼠胃窦ICC明显低于正常组大鼠(P0.05),而给予莫沙必利后胃窦ICC有所增加(P0.05)。结论:莫沙必利可显著改善糖尿病胃轻瘫大鼠的胃动力,可能与其增加胃窦Cajal间质细胞有关。     

Recording of data and immediate interpretation of myoelectric activity of the stomach--electrogastrography]

Unlike other electrophysiological measurements such as electrocardiography (ECG) and electroencephalography (EEG), the cutaneous measurement of the electrical activity of the stomach (electrogastrography, EGG) is not an established clinical diagnostic procedure. To overcome common problems in acquiring very-low-frequency signals in the presence of large and unstable voltages we developed a real time data acquisition and analysis system based on linear-phase digital signal processing instead of analog filtering. FFT's computed on line from highly overlapping time sets are displayed as pseudo-3D or grey-scale graphic plots.     

P物质尾核微量注射抑制小鼠胃肌电活动和胃运动

本文观察了小鼠尾核微量注射Ｐ物质或乙酰胆碱对胃肌电和胃运动的ｍ影响;并初步探讨了两者作用的关系。用双极康铜导线引导胃窦部肌电;用水囊连接压力换能器记录胃窦部运动。上述信息经生物电放大器和载波放大器放大后,由四道记录仪描记曲线,同时输入微机进行采集、贮存和处理。计算出注药前后每分钟胃肌电快波、慢波和胃运动波的频率和总幅度的变化百分数。结果如下：尾核注射ＳＰ或ＡＣｈ胃电快波和胃运动呈明显的抑制效应。用     

Effect of ghrelin on gastric myoelectric activity and gastric emptying in rats

Ghrelin is a recently discovered peptide in the endocrine cells of the stomach, which may stimulate gastric motility via the vagal nerve pathway. However, the mechanism of ghrelin-induced changes in gastrointestinal motility has not been clearly defined. The purpose of this study was to investigate the pharmacological effects of ghrelin on gastric myoelectrical activity and gastric emptying in rats, and to investigate whether cholinergic activity is involved in the effects of ghrelin. The study was performed on Sprague-Dawley rats implanted with serosal electrodes for electrogastrographic recording. Gastric slow waves were recorded from fasting rats at baseline and after injection of saline, ghrelin, atropine, or atropine+ghrelin. Gastric emptying of non-caloric liquid was measured by the spectrophotometric method in conscious rats. Intravenous administration of rat ghrelin (20 microg/kg) increased not only dominant frequency, dominant power and regularity of the gastric slow wave but also the gastric emptying rate when compared with the control rats (P<0.01, P<0.05, P<0.05, P<0.001 respectively). These stimulatory actions of ghrelin on both gastric myoelectrical activity and gastric emptying were not fully eliminated by pretreatment with atropine sulphate. These results taken together suggest that ghrelin may play a physiological role in the enteric neurotransmission controlling gastric contractions in rats.     

Noninvasive assessment of the effects of glucagon on the gastric slow wave

Hyperglycemic effects on the gastric slow wave are not well understood, and no studies have examined the effects that hyperglycemia has on gastric slow wave magnetic fields. We recorded multichannel magnetogastrograms (MGGs) before and after intravenous administration of glucagon and subsequent modest hyperglycemia in 20 normal volunteers. Normal slow waves were evident in baseline MGG recordings from all 20 subjects, but within 15 min after glucagon had been given, we noted significant effects on MGG signals. In addition to an overall decrease in the slow wave frequency from 2.9 +/- 0.5 cycles per min (cpm) to 2.2 +/- 0.1 cpm (P < 0.05), we observed significant changes in the number and range of spectral peaks recorded. Furthermore, the propagation velocity determined from surface current density maps computed from the multichannel MGG decreased significantly (7.1 +/- 0.8 mm/s to 5.0 +/- 0.3 mm/s, P < 0.05). This is the first study of biomagnetic effects of hyperglycemia in normal subjects. Our results suggest that the analysis of the MGG provides parameter quantification for gastric electrical activity specific to and characteristic of slow wave abnormalities associated with increased serum glucose by injection of glucagon.     

Electrophysiological characterization of tomato hypocotyl putative action potentials induced by cotyledon heating

Young tomato plants ( Lycopersico n esculentum , 8 days old) were given a heat-wound to a cotyledon. The resulting electrical activity at the hypocotyl level was monitored with intracellular microelectrodes. We observed an original pattern of slow wave potentials (SWPs), consisting of 2–3 slow waves, with associated spikes. The electrophysiological study of the SWPs confirms previous conclusions that the SWPs are due to the inhibition of an active component of the membrane potential. The electrophysiological study of the spikes shows that they fit particularities of putative action potentials (APs). They seem to be triggered by the depolarization accompanying the SWPs and thus can appear late during the SWP. An ionic characterization of the spikes by using different extracellular ionic concentrations and channel blockers suggests that anionic channels might be involved, carrying SO₄^2– ions. The channels activity might be down regulated by the calcium released by the vacuole during the SWPs and APs. A better characterization of the nature of these APs could permit the understanding of the information transmission mechanisms in higher plants.     

十二指肠内胆盐对胃肌电和运动的影响及其神经...

Changes of gastric myoelectric fast wave, slow wave and gastric motility were studied after intraduodenal infusion of sodium taurocholate (ST) in an attempt to search the concerned neuromechanism. Frequency and total amplitude of the fast wave and slow wave of gastric myoelectric activity and of gastric contractile wave were recorded every five minutes before and after intraduodenal infusion of ST under the background action of various drugs. The frequency and amplitude were expressed in percentage change of the respective premedication value. After intraduodenal infusion of ST (n = 10) the frequency and the amplitude of fast wave and gastric contractile wave were suppressed. Blocking anesthesia of celiac plexus, reserpinization and intravenous infusion of carbachol could eliminate the inhibition induced by ST, which could be partly eliminated by intravenous infusion of propranolol but not affected by phentolamine at all. The results demonstrate that intraduodenal infusion of bile salt suppresses the fast wave of gastric myoelectric activity and gastric motility, most probably controlled by efferent sympathetic adrenergic fibres through beta-receptor.     

Modelling gastrointestinal bioelectric activity

The development of an anatomically realistic biophysically based model of the human gastrointestinal (GI) tract is presented. A major objective of this work is to develop a modelling framework that can be used to integrate the physiological, anatomical and medical knowledge of the GI system. The anatomical model was developed by fitting derivative continuous meshes to digitised data taken from images of the visible man. Structural information, including fibre distributions of the smooth muscle layers and the arrangement of the networks of interstitial cells of Cajal, were incorporated using published information. A continuum modelling framework was used to simulate electrical activity from the single cell to the whole organ and body. Also computed was the external magnetic field generated from the GI electrical activity.

The set of governing equations were solved using a combination of numerical techniques. Activity at the (continuum) cell level was solved using a high-resolution trilinear finite element procedure that had been defined from the previously fitted C¹ continuous anatomical mesh. Multiple dipolar sources were created from the excitation waves which were embedded within a coupled C¹ continuous torso model to produce both the cutaneous electrical field and the external magnetic field.

Initial simulations were performed using a simplified geometry to test the implementation of the numerical solution procedure. The numerical procedures were shown to rapidly converge with mesh refinement. In the process of this testing, errors in a long standing analytic solution were identified and are corrected in Appendix B.

Results of single cell activity were compared to published results illustrating that the key features of the slow wave activity were successfully replicated. Simulations using a two-dimensional slice through the gastric wall produced slow wave activity that agreed with the known frequency and propagation characteristics. Three-dimensional simulations were also performed using the full stomach mesh and results illustrated the slow wave propagation throughout the stomach musculature.     

The effects of cholecystokinin-octapeptide and pentagastrin on electrical and motor activities of canine colonic circular muscle

The effects of cholecystokinin-octapeptide (CCK-OP) and pentagastrin on electrical and motor activities of circular muscle of the canine colon were studied with the sucrose gap technique. Additional organ bath experiments were performed to further characterize the motor response to the peptides and to elucidate their site of action. The electrical activity consisted of slow waves having an initial potential followed by a plateau potential, at a regular frequency of 4.5 cycles/min. Both peptides prolonged the duration and increased the amplitude of the plateau phase of the slow waves. Concomitantly, the slow wave frequency was reduced. In addition, CCK-OP increased spiking activity. Both spiking activity and the prolonged plateau potential generated contractile activity, prolonged phasic contraction occurring with slow waves with a prolonged plateau. In organ bath experiments, both CCK-OP and pentagastrin increased the basal tone of the muscle strips and prolonged the duration of the phasic contractions. The prolongation of the duration of the contractions was not antagonized by tetrodotoxin (TTX) and atropine. CCK-OP but not pentagastrin increased the force of contractions, this action was not affected by atropine but was reduced in the presence of TTX, suggesting that the increase in force may be partially mediated by noncholinergic excitatory nerves. The increase in basal tension by the peptides was enhanced in the presence of TTX indicating that myenteric inhibitory neurones were tonically active under our experimental conditions. The results provide the electrophysiological basis for CCK-OP and pentagastrin induced changes in colonic motility.     

Ameliorating Effects of Auricular Electroacupuncture on Rectal Distention-Induced Gastric Dysrhythmias in Rats

Gastric slow waves (GSW) are known to regulate gastric motility and are impaired with rectal distention (RD). Electroacupuncture (EA) at body acupoints, such as ST 36, has been shown to improve gastric dysrhythmias; however, little is known about the possible effects of auricular electroacupuncture (AEA) on GSW. To study effects and possible mechanisms of AEA on RD-induced gastric dysrhythmias in rats, ten male Sprague-Dawley (SD) rats implanted with gastric serosal electrodes were studied in two different experiments in fed state. Four sessions were performed in experiment 1 as follows: control (RD, no stimulation), RD+AEA, RD+EA at body points and RD+sham AEA. Two sessions were included in experiment 2 to study mechanisms of AEA: RD + atropine and RD + atropine + AEA. It was found that 1) RD significantly decreased the percentage of normal GSW from 89.8±3.5% to 76.0±3.3% (P<0.05); 2) AEA increased the percentage of normal GSW during RD to 94.0±2.1% (P<0.05 vs. RD) via a reduction in the percentages of tachygastria and arrhythmia (P<0.05 vs. RD); 3) atropine blocked the ameliorating effect of AEA on RD-induced gastric dysrhythmias. Our results demonstrated that RD induces gastric dysrhythmias in fed state in rats. AEA improves RD-induced gastric dysrhythmias via the vagal pathway. AEA may have a therapeutic potential in treating gastric dysrhythmias.     

Spatial and temporal coupling between slow waves and pendular contractions

In contrast to the mechanisms of segmental and peristaltic contractions in the small intestine, not much is known about the mechanism of pendular contractions. High-resolution electrical and mechanical recordings were performed from isolated segments of the rabbit ileum during pendular contractions. The electrical activities were recorded with 32 extracellular electrodes while motility was assessed simultaneously by video tracking the displacements of 20-40 serosal markers. The electrical activities consisted of slow waves, followed by spikes, that propagated in either the aboral or oral direction. The mechanical activity always followed the initial electrical activity, describing a contraction phase in one direction followed by a relaxation phase in the opposite direction. Pendular displacements were always in rhythm with the slow wave, whereas the direction of the displacements was dictated by the origin of the slow wave. If the slow wave propagated aborally, then the pendular displacement occurred in the oral direction, whereas if the slow wave propagated in the oral direction, then the displacement occurred in the aboral direction. In the case of more complex propagation patterns, such as in the area of pacemaking or collision, direction of displacements remained always opposite to the direction of the slow wave. In summary, the direction and pattern of propagation of the slow wave determine the rhythm and the direction of the pendular motility. The well-known variability in pendular movements is caused by the variability in the propagation of the underlying slow wave.     

The myogenic component in distention-induced peristalsis in the guinea pig small intestine

In an in vitro model for distention-induced peristalsis in the guinea pig small intestine, the electrical activity, intraluminal pressure, and outflow of contents were studied simultaneously to search for evidence of myogenic control activity. Intraluminal distention induced periods of nifedipine-sensitive slow wave activity with superimposed action potentials, alternating with periods of quiescence. Slow waves and associated high intraluminal pressure transients propagated aborally, causing outflow of content. In the proximal small intestine, a frequency gradient of distention-induced slow waves was observed, with a frequency of 19 cycles/min in the first 1 cm and 11 cycles/min 10 cm distally. Intracellular recording revealed that the guinea pig small intestinal musculature, in response to carbachol, generated slow waves with superimposed action potentials, both sensitive to nifedipine. These slow waves also exhibited a frequency gradient. In addition, distention and cholinergic stimulation induced high-frequency membrane potential oscillations (~55 cycles/min) that were not associated with distention-induced peristalsis. Continuous distention produced excitation of the musculature, in part neurally mediated, that resulted in periodic occurrence of bursts of distally propagating nifedipine-sensitive slow waves with superimposed action potentials associated with propagating intraluminal pressure waves that caused pulsatile outflow of content at the slow wave frequency.     

Spatial localization and properties of pacemaker potentials in the canine rectoanal region

The present study investigated the spatial organization of electrical activity in the canine rectoanal region and its relationship to motility patterns. Contraction and resting membrane potential (E(m)) were measured from strips of circular muscle isolated 0.5-8 cm from the anal verge. Rapid frequency [25 cycles/min (cpm)] E(m) oscillations (MPOs, 12 mV amplitude) were present across the thickness of the internal anal sphincter (IAS; 0.5 cm) and E(m) was constant (-52 mV). Between the IAS and the proximal rectum an 18 mV gradient in E(m) developed across the muscle thickness with the submucosal edge at -70 mV and MPOs were replaced with slow waves (20 mV amplitude, 6 cpm). Slow waves were of greatest amplitude at the submucosal edge. Nifedipine (1 micro M) abolished MPOs but not slow waves. Contractile frequency changes were commensurate with the changes in pacemaker frequency. Our results suggest that changing motility patterns in the rectoanal region are associated with differences in the characteristics of pacemaker potentials as well as differences in the sites from which these potentials emanate.