Prostaglandin regulation of gastric slow waves and peristalsis

Gastric emptying depends on functional coupling of slow waves between the corpus and antrum, to allow slow waves initiated in the gastric corpus to propagate to the pyloric sphincter and generate gastric peristalsis. Functional coupling depends on a frequency gradient where slow waves are generated at higher frequency in the corpus and drive the activity of distal pacemakers. Simultaneous intracellular recording from corpus and antrum was used to characterize the effects of PGE2 on slow waves in the murine stomach. PGE2 increased slow-wave frequency, and this effect was mimicked by EP3, but not by EP2, receptor agonists. Chronotropic effects were due to EP3 receptors expressed by intramuscular interstitial cells of Cajal because these effects were not observed in W/W V mice. Although the integrated chronotropic effects of EP3 receptor agonists were deduced from electrophysiological experiments, no clear evidence of functional uncoupling was observed with two-point electrical recording. Gastric peristalsis was also monitored by video imaging and spatiotemporal maps to study the impact of chronotropic agonists on propagating contractions. EP3 receptor agonists increased the frequency of peristaltic contractions and caused ectopic sites of origin and collisions of peristaltic waves. The impact of selective regional application of chronotropic agonists was investigated by use of a partitioned bath. Antral slow waves followed enhanced frequencies induced by stimulation of the corpus, and corpus slow waves followed when slow-wave frequency was elevated in the antrum. This demonstrated reversal of slow-wave propagation with selective antral chronotropic stimulation. These studies demonstrate the impact of chronotropic agonists on regional intrinsic pacemaker frequency and integrated gastric peristalsis.

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Neural regulation of slow-wave frequency in the murine gastric antrum

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00349.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. G486-G495 ◽

Cited By ~ 36

Author(s):

Abigail S. Forrest ◽

Tamás Ördög ◽

Kenton M. Sanders

Keyword(s):

Motor Neurons ◽

Slow Wave ◽

Electrical Field Stimulation ◽

Slow Waves ◽

Wave Frequency ◽

Field Stimulation ◽

Neural Regulation ◽

Electrical Field ◽

Chronotropic Response ◽

Chronotropic Effects

Gastric peristaltic contractions are driven by electrical slow waves modulated by neural and humoral inputs. Excitatory neural input comes primarily from cholinergic motor neurons, but ACh causes depolarization and chronotropic effects that might disrupt the normal proximal-to-distal spread of gastric slow waves. We used intracellular electrical recording techniques to study cholinergic responses in stomach tissues from wild-type and W/W V mice. Electrical field stimulation (5 Hz) enhanced slow-wave frequency. These effects were abolished by atropine and the muscarinic M3-receptor antagonist 4-diphenylacetoxy- N-methylpiperidine methiodide. ACh released from nerves did not depolarize antral muscles. At higher rates of stimulation (10 Hz), chronotropic effects were mediated by ACh and a noncholinergic transmitter and blocked by muscarinic antagonists and neurokinin (NK1 and NK2)-receptor antagonists. Neostigmine enhanced slow-wave frequency, suggesting that the frequency of antral pacemakers is kept low by efficient metabolism of ACh. Neostigmine had no effect on slow-wave frequency in muscles of W/W v mice, which lack intramuscular interstitial cells of Cajal (ICC-IM). These muscles also showed no significant chronotropic response to 5-Hz electrical field stimulation or the cholinergic agonist carbachol. The data suggest that the chronotropic effects of cholinergic nerve stimulation occur via ICC-IM in the murine stomach. The capacity of gastric muscles to metabolize ACh released from enteric motor neurons contributes to the maintenance of the proximal-to-distal slow-wave frequency gradient in the murine stomach. ICC-IM play a critical role in neural regulation of gastric motility, and ICC-IM become the dominant pacemaker cells during sustained cholinergic drive.

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Effect of secretin on electrical activity of small intestine

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1975.229.2.484 ◽

1975 ◽

Vol 229 (2) ◽

pp. 484-488 ◽

Cited By ~ 27

Author(s):

AK Mukhopadhyay ◽

LR Johnson ◽

EM Copeland ◽

NW Weisbrodt

Keyword(s):

Small Intestine ◽

Small Bowel ◽

Electrical Activity ◽

Slow Wave ◽

Intravenous Infusion ◽

Action Potentials ◽

Slow Waves ◽

Wave Frequency ◽

Conscious Dogs ◽

Total Percentage

The effect of intravenously administered secretin (0.5, 2.0, 6.0 U/kg-h) and intraduodenal acidification (13.2 meq/h HCl) on the electrical activity of the small bowel of three conscious dogs with gastric and duodenal cannulas was observed. Electrical activity was recorded in fasted as well as fed conditions through silver wire electrodes implanted along the entire length of the small bowel. Intravenous infusion of secretin in all dosages and in all dogs delayed the onset of the interdigestive myoelectric complex and reduced the total percentage of slow waves with superimposed spike potentials. Intraduodenal acidification also inhibited the interdigestive myoelectric complex, which developed incompletely with fewer action potentials on slow waves. Secretin did not produce any alteration in the fed pattern of activity, slow-wave frequency, or the caudal migration of the interdigestive myoelectric complex. The present study indicates that the nuerohumoral mechanisms responsible for initiation of the interdigestive myoelectric complex may be different from those responsible for its caudal migration.

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Voltage sensitivity of slow wave frequency in isolated circular muscle strips from guinea pig gastric antrum

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1999.276.2.g518 ◽

1999 ◽

Vol 276 (2) ◽

pp. G518-G528 ◽

Cited By ~ 7

Author(s):

S.-M. Huang ◽

S. Nakayama ◽

S. Iino ◽

T. Tomita

Keyword(s):

Smooth Muscle ◽

Guinea Pig ◽

Slow Wave ◽

Circular Muscle ◽

Gastric Antrum ◽

Slow Waves ◽

Wave Frequency ◽

Voltage Sensitivity ◽

Dependent Manner ◽

Circular Smooth Muscle

In circular muscle preparations isolated from the guinea pig gastric antrum, regular spontaneous electrical activity (slow waves) was recorded. Under normal conditions (6 mM K+), the frequency and shape of the slow waves were similar to those observed in ordinary stomach smooth muscle preparations. When the resting membrane potential was hyperpolarized and depolarized by changing the extracellular K+ concentration (2–18 mM), the frequency of slow waves decreased and increased, respectively. Application of cromakalim hyperpolarized the cell membrane and reduced the frequency of slow waves in a dose-dependent manner. Cromakalim (3 μM) hyperpolarized the membrane, and slow waves ceased in most preparations. In the presence of cromakalim, subsequent increases in the extracellular K+ concentration restored the frequency of slow waves accompanied by depolarization. Also, glibenclamide completely antagonized this effect of cromakalim. In smooth muscle strips containing both circular and longitudinal muscle layers, such changes in the slow wave frequency were not observed. It was concluded that the maneuver of isolating circular smooth muscle altered the voltage dependence of the slow wave frequency.

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Selective lesioning of interstitial cells of Cajal by methylene blue and light leads to loss of slow waves

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1994.266.3.g485 ◽

1994 ◽

Vol 266 (3) ◽

pp. G485-G496 ◽

Cited By ~ 15

Author(s):

L. W. Liu ◽

L. Thuneberg ◽

J. D. Huizinga

Keyword(s):

Methylene Blue ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Electrical Activity ◽

Slow Wave ◽

Interstitial Cells Of Cajal ◽

Wave Activity ◽

Slow Waves ◽

Slow Wave Activity ◽

Cells Of Cajal

Incubation with 50 microM methylene blue (MB) and subsequent intense illumination resulted in abolition of the slow-wave activity in the submuscular interstitial cells of Cajal-circular muscle (ICC-CM) preparations of canine colon. This was often accompanied by a decrease in resting membrane potential. Repolarization of cells back to -70 mV did not restore the slow-wave activity, indicating that MB plus light directly interrupted the generation mechanism of slow waves. After MB incubation, a 2-min illumination consistently changed the mitochondrial conformation in ICCs from very condensed to orthodox, without inducing any obvious changes in smooth muscle cells. After 4- to 10-min illumination, ICCs became progressively more damaged with swollen and ruptured mitochondria, loss of cytoplasmic contrast and detail, loss of caveolae, and rupture of the plasma membrane. No damage was seen in smooth muscle cells or nerves. Gap junctional ultrastructure was preserved. Intense illumination without preincubation with MB left the slow waves and the ultrastructure of ICC-CM preparations unaffected. In CM preparations, without the submuscular ICC-smooth-muscle network, MB plus light induced no changes in electrical activity. We conclude that the correlation between selective damage to the submuscular ICCs (relative to smooth muscle) and selective loss of the slow-wave activity (relative to other electrical activity of the CM) strongly indicates that the ICCs play an essential role in the generation of slow waves.

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Quantitative cellular description of gastric slow wave activity

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00528.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. G989-G995 ◽

Cited By ~ 49

Author(s):

Alberto Corrias ◽

Martin L. Buist

Keyword(s):

Slow Wave ◽

Interstitial Cells Of Cajal ◽

Quantitative Description ◽

Wave Activity ◽

Slow Waves ◽

Slow Wave Activity ◽

Good Correspondence ◽

Gastric Slow Wave ◽

Intracellular Ca ◽

Cells Of Cajal

Interstitial cells of Cajal (ICC) are responsible for the spontaneous and omnipresent electrical activity in the stomach. A quantitative description of the intracellular processes whose coordinated activity is believed to generate electrical slow waves has been developed and is presented here. In line with recent experimental evidence, the model describes how the interplay between the mitochondria and the endoplasmic reticulum in cycling intracellular Ca2+ provides the primary regulatory signal for the initiation of the slow wave. The major ion channels that have been identified as influencing slow wave activity have been modeled according to data obtained from isolated ICC. The model has been validated by comparing the simulated profile of the slow waves with experimental recordings and shows good correspondence in terms of frequency, amplitude, and shape in both control and pharmacologically altered conditions.

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Conditional genetic deletion of Ano1 in interstitial cells of Cajal impairs Ca2+ transients and slow waves in adult mouse small intestine

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00363.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. G228-G245 ◽

Cited By ~ 36

Author(s):

John Malysz ◽

Simon J. Gibbons ◽

Siva A. Saravanaperumal ◽

Peng Du ◽

Seth T. Eisenman ◽

...

Keyword(s):

Small Intestine ◽

Slow Wave ◽

Interstitial Cells Of Cajal ◽

Adult Mouse ◽

Rank Order ◽

Interstitial Cells ◽

Slow Waves ◽

Functional Reserve ◽

Mouse Small Intestine ◽

Cells Of Cajal

Myenteric plexus interstitial cells of Cajal (ICC-MY) in the small intestine are Kit+ electrical pacemakers that express the Ano1/TMEM16A Ca2+-activated Cl– channel, whose functions in the gastrointestinal tract remain incompletely understood. In this study, an inducible Cre-LoxP-based approach was used to advance the understanding of Ano1 in ICC-MY of adult mouse small intestine. KitCreERT2/+;Ano1Fl/Fl mice were treated with tamoxifen or vehicle, and small intestines (mucosa free) were examined. Quantitative RT-PCR demonstrated ~50% reduction in Ano1 mRNA in intestines of conditional knockouts (cKOs) compared with vehicle-treated controls. Whole mount immunohistochemistry showed a mosaic/patchy pattern loss of Ano1 protein in ICC networks. Ca2+ transients in ICC-MY network of cKOs displayed reduced duration compared with highly synchronized controls and showed synchronized and desynchronized profiles. When matched, the rank order for Ano1 expression in Ca2+ signal imaged fields of view was as follows: vehicle controls>>>cKO(synchronized)>cKO(desynchronized). Maintenance of Ca2+ transients’ synchronicity despite high loss of Ano1 indicates a large functional reserve of Ano1 in the ICC-MY network. Slow waves in cKOs displayed reduced duration and increased inter-slow-wave interval and occurred in regular- and irregular-amplitude oscillating patterns. The latter activity suggested ongoing interaction by independent interacting oscillators. Lack of slow waves and depolarization, previously reported for neonatal constitutive knockouts, were also seen. In summary, Ano1 in adults regulates gastrointestinal function by determining Ca2+ transients and electrical activity depending on the level of Ano1 expression. Partial Ano1 loss results in Ca2+ transients and slow waves displaying reduced duration, while complete and widespread absence of Ano1 in ICC-MY causes lack of slow wave and desynchronized Ca2+ transients. NEW & NOTEWORTHY The Ca2+-activated Cl− channel, Ano1, in interstitial cells of Cajal (ICC) is necessary for normal gastrointestinal motility. We knocked out Ano1 to varying degrees in ICC of adult mice. Partial knockout of Ano1 shortened the widths of electrical slow waves and Ca2+ transients in myenteric ICC but Ca2+ transient synchronicity was preserved. Near-complete knockout was necessary for transient desynchronization and loss of slow waves, indicating a large functional reserve of Ano1 in ICC. View this article's corresponding video summary at https://youtu.be/cyPtDP0KLY4 .

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Migrating spike complex in the small intestine of the fasting cat

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1993.265.4.g619 ◽

1993 ◽

Vol 265 (4) ◽

pp. G619-G627

Author(s):

W. C. De Vos

Keyword(s):

Small Intestine ◽

Action Potential ◽

Electrical Activity ◽

Slow Wave ◽

Close Association ◽

Slow Waves ◽

Wave Frequency ◽

Laboratory Animals ◽

Variable Frequency ◽

Implanted Electrodes

This study characterizes the migrating spike complex (MSC) in the small intestine of the awake fasting cat and compares the MSC with interdigestive activity in the small intestine of other species. Electrical activity in each of 12 cats with implanted electrodes showed MSCs, bands of spike potentials which attenuated slow-wave frequency and amplitude as the MSCs progressed distally. MSCs occurred at variable frequency with intervals ranging from < 1 min to > 5 h and averaged 51.2 +/- 2.8 (SE) min. MSCs migrated at 1-8 mm/s, accelerating distally; the duration decreased distally such that the length of the bowel in a burst (2-3 cm proximally) was conserved. The MSC was associated with an intense prolonged contraction of duration similar to that of the MSC. Sometimes the MSCs occurred in close association, and when an MSC period was < 5.7 min, the second MSC propagated at a slower rate than the first. Frequently, a brief series of slow wave-associated spikes preceded an MSC. MSCs were not associated with slow waves. The MSC differs in several respects from the migrating myoelectric complex of other laboratory animals and is more appropriately classified in a category that includes giant migrating spikes, prolonged propagated contractions, power contractions, and migrating action potential complexes.

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Na+-K+-Cl− cotransporter (NKCC) maintains the chloride gradient to sustain pacemaker activity in interstitial cells of Cajal

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00277.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. G1037-G1046 ◽

Cited By ~ 10

Author(s):

Mei Hong Zhu ◽

Tae Sik Sung ◽

Masaaki Kurahashi ◽

Lauren E. O'Kane ◽

Kate O'Driscoll ◽

...

Keyword(s):

Slow Wave ◽

Interstitial Cells Of Cajal ◽

High Current Density ◽

Reversal Potential ◽

Interstitial Cells ◽

Slow Waves ◽

Hek293 Cells ◽

Pacemaker Activity ◽

Inward Currents ◽

Cells Of Cajal

Interstitial cells of Cajal (ICC) generate electrical slow waves by coordinated openings of ANO1 channels, a Ca2+-activated Cl− (CaCC) conductance. Efflux of Cl− during slow waves must be significant, as there is high current density during slow-wave currents and slow waves are of sufficient magnitude to depolarize the syncytium of smooth muscle cells and PDGFRα+ cells to which they are electrically coupled. We investigated how the driving force for Cl− current is maintained in ICC. We found robust expression of Slc12a2 (which encodes an Na+-K+-Cl− cotransporter, NKCC1) and immunohistochemical confirmation that NKCC1 is expressed in ICC. With the use of the gramicidin permeabilized-patch technique, which is reported to not disturb [Cl−]i, the reversal potential for spontaneous transient inward currents ( ESTICs) was −10.5 mV. This value corresponds to the peak of slow waves when they are recorded directly from ICC in situ. Inhibition of NKCC1 with bumetanide shifted ESTICs to more negative potentials within a few minutes and reduced pacemaker activity. Bumetanide had no direct effects on ANO1 or CaV3.2 channels expressed in HEK293 cells or L-type Ca2+ currents. Reducing extracellular Cl− to 10 mM shifted ESTICs to positive potentials as predicted by the Nernst equation. The relatively rapid shift in ESTICs when NKCC1 was blocked suggests that significant changes in the transmembrane Cl− gradient occur during the slow-wave cycle, possibly within microdomains formed between endoplasmic reticulum and the plasma membrane in ICC. Recovery of Cl− via NKCC1 might have additional consequences on shaping the waveforms of slow waves via Na+ entry into microdomains.

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Effects of alterations in calcium levels on cat small intestinal slow waves

AJP Cell Physiology ◽

10.1152/ajpcell.1982.243.1.c7 ◽

1982 ◽

Vol 243 (1) ◽

pp. C7-C13 ◽

Cited By ~ 20

Author(s):

A. W. Mangel ◽

J. A. Connor ◽

C. L. Prosser

Keyword(s):

Intracellular Calcium ◽

Slow Wave ◽

Calcium Concentration ◽

Longitudinal Muscle ◽

Slow Waves ◽

Wave Frequency ◽

Intracellular Calcium Concentration ◽

Magnesium Concentration ◽

Reduced Frequency ◽

Intestinal Slow Waves

Intact segments of cat intestinal muscle and strips of isolated longitudinal muscle were treated with agents that reduce intracellular calcium concentration: incubation in 0-calcium saline, treatment with calcium conductance blockers, elevated extracellular magnesium concentration, or alkalinization with NH4Cl. These treatments reduced amplitude and frequency of slow waves in intact segments but only reduced frequency in isolated longitudinal muscle. The reduction in frequency was characterized by prolongation of the hyperpolarized phase of the slow waves. Treatments that would moderately increase intracellular calcium concentration, i.e., increasing external calcium to four times normal levels or lowering pH by CO2, increased slow-wave frequency. Increased frequency was associated with reduced amplitude and shortening of the hyperpolarized phase of the slow waves. Greater than four times normal calcium levels and intense spiking reduced slow-wave frequency. Chlorotetracycline fluorescence, an indicator of intracellular calcium concentration, showed fluctuations synchronous with slow waves. It is concluded that the reactions that pace the generation of slow waves are dependent on the level of intracellular calcium.

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Effect of bethanechol, gastrin I, or cholecystokinin on myoelectrical activity.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1979.236.4.e458 ◽

1979 ◽

Vol 236 (4) ◽

pp. E458

Author(s):

W J Snape ◽

S Cohen

Keyword(s):

Smooth Muscle ◽

Slow Wave ◽

Spike Activity ◽

Control Period ◽

Threshold Concentration ◽

Slow Waves ◽

Wave Frequency ◽

Myoelectrical Activity ◽

Dose Dependent Increase ◽

Dose Dependent

The purpose of this study was to determine the effect of bethanechol, gastrin I, or the octapeptide of cholecystokinin (CCK-OP) on the smooth muscle of the isolated cat colon. Myoelectrical activity was recorded with monopolar glass-pore electrodes. Slow-wave frequency was 5.9 +/- 0.2 cycles/min during the basal period. Slow waves were generally coupled during the control period and the apparent propagation velocity was predominantly aborad at a velocity of 3.8 +/- 0.4 mm/s. Spike activity was superimposed on 11.9 +/- 1.5% of the slow waves during the control period. Bethanechol stimulated a dose-dependent increase in colonic spike activity, with a threshold concentration of 10(-7) M. Bethanechol did not alter the congruence of the colonic slow-wave frequency at any concentration. Gastrin I or CCK-OP increased colonic spike activity. The threshold concentrations for gastrin I and CCK-OP were 2 X 10(-11) M and 4 x 10(-11) M, respectively. Unlike bethanechol, gastrin I (2 X 10(-9) M - 2 X 10(-8) M) and CCK-OP (4 X 10(-9) - 4 X 10(-8) M) altered slow-wave frequency and decreased slow-wave congruence. These studies suggest that 1) bethanechol, gastrin I, or CCK-OP increases colonic spike activity, and 2) only gastrin I or CCK-OP alters the slow-wave frequency of colonic muscle. Thus neurohumoral substances may act independently on colonic spike activity and colonic slow-wave frequency.

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