Stimulus‐induced pacemaker activity in interstitial cells of Cajal associated with the deep muscular plexus of the small intestine

Zhu, Yong Fang; Wang, X.‐Y.; Parsons, Sean P.; Huizinga, Jan D.

doi:10.1111/nmo.12808

Cited by 11 publications

(10 citation statements)

References 43 publications

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“…In addition, mathematical modeling suggested that ICC-DMP might be involved in generation of the minute rhythm of peristaltic contractions (Huizinga et al, 2015). Furthermore, we proved the concept of ICC-DMP being stimulus-dependent pacemaker cells when we established that Substance P changed non-synchronized high frequency intracellular calcium flickering or quiescence in ICC-DMP into strong rhythmic calcium transients that were synchronized within the network and associated with rhythmic transient depolarizations (Zhu et al, 2016). The cluster-associated depolarizations were facilitated by ICC-DMP and not by the ICC-MP, since ICC-MP driven contractions remained after clusters were abolished; furthermore, the distention-induced minute rhythm is prominent in WWv mice that lack ICC-MP (Huizinga et al, 1998).…”

Section: Icc-dmp As Stimulus-dependent Pacemaker Cellssupporting

confidence: 54%

Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP

Parsons

Huizinga

2021

Front. Neurosci.

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Nitrergic nerves have been proposed to play a critical role in the orchestration of peristaltic activities throughout the gastrointestinal tract. In the present study, we investigated the role of nitric oxide, using spatiotemporal mapping, in peristaltic activity of the whole ex vivo mouse intestine. We identified a propulsive motor pattern in the form of propagating myogenic contractions, that are clustered by the enteric nervous system into a minute rhythm that is dependent on nitric oxide. The cluster formation was abolished by TTX, lidocaine and nitric oxide synthesis inhibition, whereas the myogenic contractions, occurring at the ICC-MP initiated slow wave frequency, remained undisturbed. Cluster formation, inhibited by block of nitric oxide synthesis, was fully restored in a highly regular rhythmic fashion by a constant level of nitric oxide generated by sodium nitroprusside; but the action of sodium nitroprusside was inhibited by lidocaine indicating that it was relying on neural activity, but not rhythmic nitrergic nerve activity. Hence, distention-induced activity of cholinergic nerves and/or a co-factor within nitrergic nerves such as ATP is also a requirement for the minute rhythm. Cluster formation was dependent on distention but was not evoked by a distention reflex. Block of gap junction conductance by carbenoxolone, dose dependently inhibited, and eventually abolished clusters and contraction waves, likely associated, not with inhibition of nitrergic innervation, but by abolishing ICC network synchronization. An intriguing feature of the clusters was the presence of bands of rhythmic inhibitions at 4–8 cycles/min; these inhibitory patches occurred in the presence of tetrodotoxin or lidocaine and hence were not dependent on nitrergic nerves. We propose that the minute rhythm is generated by nitric oxide-induced rhythmic depolarization of the musculature via ICC-DMP.

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Section: Icc-dmp As Stimulus-dependent Pacemaker Cellssupporting

confidence: 54%

Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP

Parsons

Huizinga

2021

Front. Neurosci.

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“…; Zhu et al . , ). In physiological conditions, a stimulus is most likely to be experienced locally and not to be uniform along the entire intestine.…”

Section: Resultsmentioning

confidence: 99%

“…; Zhu et al . , ). Here, we show that locally increasing slow‐wave frequency has marked effects on motor patterns but does not necessarily increase propulsive activity.…”

Section: Discussionmentioning

confidence: 99%

Network properties of interstitial cells of Cajal affect intestinal pacemaker activity and motor patterns, according to a mathematical model of weakly coupled oscillators

Wei

Parsons

Huizinga

2017

Experimental Physiology

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What is the central question of this study? What are the effects of interstitial cells of Cajal (ICC) network perturbations on intestinal pacemaker activity and motor patterns? What is the main finding and its importance? Two-dimensional modelling of the ICC pacemaker activity according to a phase model of weakly coupled oscillators showed that network properties (coupling strength between oscillators, frequency gradient and frequency noise) strongly influence pacemaker network activity and subsequent motor patterns. The model explains motor patterns observed in physiological conditions and provides predictions and testable hypotheses for effects of ICC loss and frequency modulation on the motor patterns. Interstitial cells of Cajal (ICC) are the pacemaker cells of gut motility and are associated with motility disorders. Interstitial cells of Cajal form a network, but the contributions of its network properties to gut physiology and dysfunction are poorly understood. We modelled an ICC network as a two-dimensional network of weakly coupled oscillators with a frequency gradient and showed changes over time in video and graphical formats. Model parameters were obtained from slow-wave-driven contraction patterns in the mouse intestine and pacemaker slow-wave activities from the cat intestine. Marked changes in propagating oscillation patterns (including changes from propagation to non-propagating) were observed by changing network parameters (coupling strength between oscillators, the frequency gradient and frequency noise), which affected synchronization, propagation velocity and occurrence of dislocations (termination of an oscillation). Complete uncoupling of a circumferential ring of oscillators caused the proximal and distal section to desynchronize, but complete synchronization was maintained with only a single oscillator connecting the sections with high enough coupling. The network of oscillators could withstand loss; even with 40% of oscillators lost randomly within the network, significant synchronization and anterograde propagation remained. A local increase in pacemaker frequency diminished anterograde propagation; the effects were strongly dependent on location, frequency gradient and coupling strength. In summary, the model puts forth the hypothesis that fundamental changes in oscillation patterns (ICC slow-wave activity or circular muscle contractions) can occur through physiological modulation of network properties. Strong evidence is provided to accept the ICC network as a system of coupled oscillators.

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“…We have shown that substance P can evoke the ICC-DMP pacemaker. 43 Potential stimuli are not limited to neurotransmitters; fatty acids such as butyrate and decanoic acid can also evoke the low frequency pacemaker activity, 34 and so can distention. 44 Siegle and Ehrlein's observation that neurotensin can evoke segmentation can be explained by the induction of ICC-DMP pacemaker activity.…”

Section: Discussionmentioning

confidence: 99%

Neurotensin Changes Propulsive Activity into a Segmental Motor Pattern in the Rat Colon

Chen

Yang

et al. 2016

J Neurogastroenterol Motil

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Background/AimsNeurotensin is a gut-brain peptide with both inhibitory and excitatory actions on the colonic musculature; our objective was to understand the implications of this for motor patterns occurring in the intact colon of the rat. MethodsThe effects of neurotensin with concentrations ranging from 0.1-100 nM were studied in the intact rat colon in vitro, by investigating spatio-temporal maps created from video recordings of colonic motility before and after neurotensin. ResultsLow concentration of neurotensin (0.1-1 nM) inhibited propagating long distance contractions and rhythmic propagating motor complexes; in its place a slow propagating rhythmic segmental motor pattern developed. The neurotensin receptor 1 antagonist SR-48692 prevented the development of the segmental motor pattern. Higher concentrations of neurotensin (10 nM and 100 nM) were capable of restoring long distance contraction activity and inhibiting the segmental activity. The slow propagating segmental contraction showed a rhythmic contraction --relaxation cycle at the slow wave frequency originating from the interstitial cells of Cajal associated with the myenteric plexus pacemaker. High concentrations given without prior additions of low concentrations did not evoke the segmental motor pattern. These actions occurred when neurotensin was given in the bath solution or intraluminally. The segmental motor pattern evoked by neurotensin was inhibited by the neural conduction blocker lidocaine. ConclusionsNeurotensin (0.1-1 nM) inhibits the dominant propulsive motor patterns of the colon and a distinct motor pattern of rhythmic slow propagating segmental contractions develops. This motor pattern has the hallmarks of haustral boundary contractions. (J Neurogastroenterol Motil 2016;22:517-528)

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Stimulus‐induced pacemaker activity in interstitial cells of Cajal associated with the deep muscular plexus of the small intestine

Cited by 11 publications

References 43 publications

Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP

Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP

Network properties of interstitial cells of Cajal affect intestinal pacemaker activity and motor patterns, according to a mathematical model of weakly coupled oscillators

Neurotensin Changes Propulsive Activity into a Segmental Motor Pattern in the Rat Colon

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