Interstitial cells of Cajal in the urethra are cGMP-mediated targets of nitrergic neurotransmission

2008 ◽  
Vol 295 (4) ◽  
pp. F971-F983 ◽  
Author(s):  
Ángeles García-Pascual ◽  
María Sancho ◽  
Gonzalo Costa ◽  
Domingo Triguero
Keyword(s):  
Interstitial Cells Of Cajal ◽  
Electrical Field Stimulation ◽  
Muscle Layer ◽  
Interstitial Cells ◽  
No Synthase ◽  
Nerve Terminals ◽  
Electrical Field ◽  
No Donors ◽  
Cells Of Cajal ◽  
Nitrergic Nerves

While interstitial cells of Cajal (ICC) in the urethra respond to nitric oxide (NO) donors by increasing cGMP, it remains unclear whether urethral ICC are functionally innervated by nitrergic nerves. We have addressed this issue in the rat and sheep urethra, where cGMP production and relaxation were compared in preparations subjected to electrical field stimulation (EFS; 2 Hz, 4 min) of nitrergic nerves or to exogenous S-nitroso-l-cysteine (SNC; 0.1 mM, 4 min). Upon EFS, cGMP immunoreactivity (cGMP-ir) was observed in both smooth muscle cells (SMC) and in spindle-shaped cells that contained c-kit and vimentin, features of ICC. Similarly, cGMP-ir was preferentially, but inconsistently, found in ICC of the outer muscle layer on exposure to SNC. We found separate functional groups of ICC within the urethra. Thus only ICC present in the muscle layers (ICC-M) but not those in the serosa (ICC-SR) and lamina propia (ICC-LP) seem to be specifically influenced by activation of neuronal NO synthase (nNOS). Thus the increase in cGMP-ir in the ICC-M induced by EFS was prevented by Nω-nitro-l-arginine and ODQ. Urethral ICC did not express nNOS, although they were closely associated with nitrergic nerves. cGMP-ir was also present in the urothelium (in the rat but not in the sheep) and the vascular endothelium but not in neural structures, such as the nerve trunks and nerve terminals. Together, these results suggest a model of parallel innervation in which both SMC and ICC-M are effectors of nerve-released NO in the urethra.

Do gap junctions play a role in nerve transmissions as well as pacing in mouse intestine?

2007 ◽  
Vol 292 (3) ◽  
pp. G734-G745 ◽  
Author(s):  
E. E. Daniel ◽  
Ahmed El Yazbi ◽  
Marco Mannarino ◽  
Gary Galante ◽  
Geoffrey Boddy ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Interstitial Cells Of Cajal ◽  
Circular Muscle ◽  
Electrical Field Stimulation ◽  
Cell Types ◽  
Interstitial Cells ◽  
Glycyrrhetinic Acid ◽  
Mouse Intestine ◽  
Cells Of Cajal

Varicosities of nitrergic and other nerves end on deep muscular plexus interstitial cells of Cajal or on CD34-positive, c- kit-negative fibroblast-like cells. Both cell types connect to outer circular muscle by gap junctions, which may transmit nerve messages to muscle. We tested the hypotheses that gap junctions transmit pacing messages from interstitial cells of Cajal of the myenteric plexus. Effects of inhibitors of gap junction conductance were studied on paced contractions and nerve transmissions in small segments of circular muscle of mouse intestine. Using electrical field stimulation parameters (50 V/cm, 5 pps, and 0.5 ms) which evoke near maximal responses to nitrergic, cholinergic, and apamin-sensitive nerve stimulation, we isolated inhibitory responses to nitrergic nerves, inhibitory responses to apamin-sensitive nerves and excitatory responses to cholinergic nerves. 18β-Glycyrrhetinic acid (10, 30, and 100 μM), octanol (0.1, 0.3, and 1 mM) and gap peptides (300 μM of40Gap27,43Gap26,37,43Gap27) all failed to abolish neurotransmission. 18β-Glycyrrhetinic acid inhibited frequencies of paced contractions, likely owing to inhibition of l-type Ca2+channels in smooth muscle, but octanol or gap peptides did not. 18β-Glycyrrhetinic acid and octanol, but not gap peptides, reduced the amplitudes of spontaneous and nerve-induced contractions. These reductions paralleled reductions in contractions to exogenous carbachol. Additional experiments with gap peptides in both longitudinal and circular muscle segments after NG-nitro-l-arginine and TTX revealed no effects on pacing frequencies. We conclude that gap junction coupling may not be necessary for pacing or nerve transmission to the circular muscle of the mouse intestine.

Selective accumulation of methylene blue by interstitial cells of Cajal in canine colon

1993 ◽  
Vol 264 (1) ◽  
pp. G64-G73 ◽  
Author(s):  
L. W. Liu ◽  
L. Thuneberg ◽  
E. E. Daniel ◽  
J. D. Huizinga
Keyword(s):  
Methylene Blue ◽  
Interstitial Cells Of Cajal ◽  
Three Dimensional ◽  
Circular Muscle ◽  
Muscle Cells ◽  
Muscle Layer ◽  
Interstitial Cells ◽  
Resting Membrane Potential ◽  
Selective Staining ◽  
Cells Of Cajal

The network of interstitial cells of Cajal (ICC) at the submucosal surface of the canine colon was selectively stained by incubation with 15-50 microM methylene blue for 30-45 min. The network was composed of regularly scattered ICC cell bodies interconnected by long processes. Circular muscle cells were unstained. Staining of neurons was limited to one or two axons within bundles. The ICC network had a thickness of a single cell, since no overlapping of ICC cell bodies was observed. The ICC network connected the circular muscle cells at the submucosal surface across the septa which circumferentially divided the circular muscle into lamellae. Methylene blue at 50 microM slightly decreased the resting membrane potential and increased the duration of slow waves, leading to an increase in the force of phasic contractions, with no significant influence on other slow-wave parameters. Methylene blue produced neither electrophysiological nor mechanical effects on circular muscle preparations from which the submuscular ICC network was removed, indicating that the excitatory effects of methylene blue on the full-thickness circular muscle layer were mediated by ICC. In summary, the three-dimensional aspects of the submuscular ICC network can be visualized after selective staining by methylene blue. This staining does not affect physiological characteristics of smooth muscle cells.

scholarly journals Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal

2017 ◽  
Vol 313 (5) ◽  
pp. G419-G433 ◽  
Author(s):  
Leonie Durnin ◽  
Andrea Lees ◽  
Sheerien Manzoor ◽  
Kent C. Sasse ◽  
Kenton M. Sanders ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Interstitial Cells Of Cajal ◽  
Colonic Motility ◽  
Circular Muscle ◽  
Electrical Field Stimulation ◽  
Interstitial Cells ◽  
Partial Loss ◽  
Purinergic Neurotransmission ◽  
Cells Of Cajal

Regulation of colonic motility depends on the integrity of enteric inhibitory neurotransmission mediated by nitric oxide (NO), purine neurotransmitters, and neuropeptides. Intramuscular interstitial cells of Cajal (ICC-IM) and platelet-derived growth factor receptor-α-positive (PDGFRα+) cells are involved in generating responses to NO and purine neurotransmitters, respectively. Previous studies have suggested a decreased nitrergic and increased purinergic neurotransmission in KitW/KitW-v ( W/Wv) mice that display lesions in ICC-IM along the gastrointestinal tract. However, contributions of NO to these phenotypes have not been evaluated. We used small-chamber superfusion assays and HPLC to measure the spontaneous and electrical field stimulation (EFS)-evoked release of nicotinamide adenine dinucleotide (NAD+)/ADP-ribose, uridine adenosine tetraphosphate (Up4A), adenosine 5′-triphosphate (ATP), and metabolites from the tunica muscularis of human, monkey, and murine colons and circular muscle of monkey colon, and we tested drugs that modulate NO levels or blocked NO receptors. NO inhibited EFS-evoked release of purines in the colon via presynaptic neuromodulation. Colons from W/Wv, Nos1−/−, and Prkg1−/− mice displayed augmented neural release of purines that was likely due to altered nitrergic neuromodulation. Colons from W/Wv mice demonstrated decreased nitrergic and increased purinergic relaxations in response to nerve stimulation. W/Wv mouse colons demonstrated reduced Nos1 expression and reduced NO release. Our results suggest that enhanced purinergic neurotransmission may compensate for the loss of nitrergic neurotransmission in muscles with partial loss of ICC. The interactions between nitrergic and purinergic neurotransmission in the colon provide novel insight into the role of neurotransmitters and effector cells in the neural regulation of gastrointestinal motility. NEW & NOTEWORTHY This is the first study investigating the role of nitric oxide (NO) and intramuscular interstitial cells of Cajal (ICC-IM) in modulating neural release of purines in colon. We found that NO inhibited release of purines in human, monkey, and murine colons and that colons from KitW/KitW-v ( W/Wv) mice, which present with partial loss of ICC-IM, demonstrated augmented neural release of purines. Interactions between nitrergic and purinergic neurotransmission may affect motility in disease conditions with ICC-IM deficiencies.

scholarly journals Abnormalities of digestive tract innervation in rat fetus treated with ethylenethiourea

2012 ◽  
Vol 27 (3) ◽  
pp. 244-250 ◽  
Author(s):  
Sidney Pereira Pinto Lemos ◽  
José Luiz Martins ◽  
Patrícia Veruska Ribeiro Barbosa Lemos ◽  
Silvio Romero Gonçalves e Silva ◽  
Fernando Leandro dos Santos ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Digestive Tract ◽  
Myenteric Plexus ◽  
Interstitial Cells Of Cajal ◽  
Muscle Layer ◽  
Interstitial Cells ◽  
Female Rats ◽  
Nerve Plexus ◽  
Cells Of Cajal ◽  
Experimental Group

PURPOSE: The pathophysiology of abnormalities associated with myenteric plexus lesions remains imperfectly understood. Such abnormalities have been correlated with subocclusive intestinal conditions in children with Hirschsprung's disease, cases of chronic constipation and, postoperatively, in cases of anorectal anomalies. This study evaluated abnormalities of the myenteric plexus in fetus from female rats that received ethylenethiourea. METHODS: Female rats were exposed to ethylenethiourea on the 11th day of pregnancy (experimental group) or to 0.9% physiological solution (control group). Abnormalities were only found in the experimental group. The digestive tract muscle layer was analyzed morphometrically and changes to the frequencies of nerve plexus cells and interstitial cells of Cajal were evaluated, using hematoxylin-eosin, S-100 protein, neuron-specific enolase and C-Kit, respectively. RESULTS: Muscle and skeletal abnormalities were observed in 100%, anorectal anomalies in 86%, absent tail in 71%, short tail in 29%, duodenal atresia in 5%, esophageal atresia in 5% and persistent omphalomesenteric duct in 5%. Histopathological analysis showed a thinner muscle layer associated with lower frequencies of ganglion cells and interstitial cells of Cajal, in all gastrointestinal tract. CONCLUSION: Severe nerve plexus abnormalities associated with muscle layer atrophy were observed throughout the gastrointestinal tract in newborn rats exposed to ethylenethiourea.

Ultrastructure of interstitial cells of Cajal in the canine distal esophagus

1994 ◽  
Vol 72 (9) ◽  
pp. 1049-1059 ◽  
Author(s):  
I. Berezin ◽  
E. E. Daniel ◽  
J. D. Huizinga
Keyword(s):  
Smooth Muscle ◽  
Action Potentials ◽  
Neural Control ◽  
Interstitial Cells Of Cajal ◽  
Three Dimensional ◽  
Muscle Layer ◽  
Interstitial Cells ◽  
Distal Esophagus ◽  
Esophageal Sphincter ◽  
Cells Of Cajal

The ultrastructure of canine distal esophagus was studied focusing on interstitial cells of Cajal (ICC) and their relationships to nerves and muscle. The distal esophagus consisted of two muscle layers composed of intertwining skeletal and smooth muscle bundles. The ICC formed an interconnecting network and were an integral part of these structures. The ICC communicated with one another and with adjacent smooth muscle cells through numerous gap junctions. The morphology of individual ICC resembled that observed in other gut regions. All interstitial cells were densely innervated. The highest density of ICC, just proximal to the lower esophageal sphincter, coincided with the previously reported highest incidence of occurrence of electrical slow wave type action potentials. Examination of a large number of structural associations of ICC led us to conclude that in the distal esophagus, two networks of ICC and nerves exist, one associated with the inner muscle layer, another associated with the outer muscle layer. These networks are not sheet-like structures, such as the network of ICC in the myenteric plexus or deep muscular plexus of the small intestine, but are three dimensional and are interspersed throughout both muscle layers. The networks do not extend into Auerbach's plexus. The main branches of the networks run along the long axis of the esophagus and seem ideally suited to facilitate communication in this direction. These observations suggest that esophageal interstitial cells are structurally organized in such a manner that they may play a role in pacemaking and neural control of esophageal motility.Key words: interstitial cells of Cajal, enteric nervous system, esophagus, ultrastructure, pacemaking.

Neuromuscular structures specific to the submucosal border of the human colonic circular muscle layer

1990 ◽  
Vol 68 (11) ◽  
pp. 1437-1446 ◽  
Author(s):  
M. S. Faussone-Pellegrini ◽  
C. Cortesini ◽  
D. Pantalone
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Interstitial Cells Of Cajal ◽  
Circular Muscle ◽  
Muscle Cells ◽  
Muscle Layer ◽  
Interstitial Cells ◽  
Circular Muscle Layer ◽  
The Right ◽  
Cells Of Cajal

The circular muscle layer of the human caecum and ascending colon is clearly subdivided into two portions: an outer one which includes the bulk of the circular muscle layer, and an inner one made up of only six to eight rows of cells. In the right transverse colon no demarcation can be observed, but a difference exists between the innermost and the outermost cells, since those of the two innermost rows possess some peculiarities with regard to the sarcoplasmic reticulum, glycogen particles, caveolae, and intercellular junctions. In the left part of the colon, the circular muscle layer is also divided into two portions. In fact, the innermost smooth muscle cells still possess peculiar morphologies, progressively increase in number, and become separate from each other making up a superficial muscle network. A fibrous lamella, along and inside which a ganglionated nerve plexus runs, is strictly apposed to the submucosal border of the circular muscle layer of the entire colonic length. A second nerve plexus runs between the two portions of the circular muscle layer. Both these plexuses are accompanied by interstitial cells of Cajal in the right colon only. The peculiar organization of the entire submucosal border of the human colonic circular muscle layer distinguishes it from other parts of the gut and probably represents a structural basis for control of human colonic motility. The presence of putative pacemaker cells (interstitial cells and peculiar smooth muscle cells) indicates that the inner border of human colonic circular muscle layer possesses pacemaking activities. Moreover, the interstitial cell – smooth muscle cell ratio differs depending on the colonic level; two main regions can be identified: the right and the left colon. Consequently, we might expect regional variation in pacemaking.Key words: smooth muscle cells, interstitial cells of Cajal, human colon, ultrastructure.

Distinct roles of nitric oxide synthases and interstitial cells of Cajal in rectoanal relaxation

2005 ◽  
Vol 289 (2) ◽  
pp. G291-G299 ◽  
Author(s):  
Akiko Terauchi ◽  
Daisuke Kobayashi ◽  
Hiroshi Mashimo
Keyword(s):  
Nitric Oxide ◽  
Interstitial Cells Of Cajal ◽  
Electrical Field Stimulation ◽  
Interstitial Cells ◽  
Organ Bath ◽  
Wild Type ◽  
Basal Tone ◽  
Cells Of Cajal

Nitric oxide (NO) relaxes the internal anal sphincter (IAS), but its enzymatic source(s) remains unknown; neuronal (nNOS) and endothelial (eNOS) NO synthase (NOS) isoforms could be involved. Also, interstitial cells of Cajal (ICC) may be involved in IAS relaxation. We studied the relative roles of nNOS, eNOS, and c-Kit-expressing ICC for IAS relaxation using genetic murine models. The basal IAS tone and the rectoanal inhibitory reflex (RAIR) were assessed in vivo by a purpose-built solid-state manometric probe and by using wild-type, nNOS-deficient (nNOS−/−), eNOS-deficient (eNOS−/−), and W/Wv mice (lacking certain c-Kit-expressing ICC) with or without l-arginine or Nω-nitro-l-arginine methyl ester (l-NAME) treatment. Moreover, the basal tone and response to electrical field stimulation (EFS) were studied in organ bath using wild-type and mutant IAS. In vivo, the basal tone of eNOS−/− was higher and W/Wv was lower than wild-type and nNOS−/− mice. l-Arginine administered rectally, but not intravenously, decreased the basal tone in wild-type, nNOS−/−, and W/Wv mice. However, neither l-arginine nor l-NAME affected basal tone in eNOS−/− mice. In vitro, l-arginine decreased basal tone in wild-type and nNOS−/− IAS but not in eNOS−/− or wild-type IAS without mucosa. The in vivo RAIR was intact in wild-type, eNOS−/−, and W/Wv mice but absent in all nNOS−/− mice. EFS-induced IAS relaxation was also reduced in nNOS−/− IAS. Thus the basal IAS tone is largely controlled by eNOS in the mucosa, whereas the RAIR is controlled by nNOS. c-Kit-expressing ICC may not be essential for the RAIR.

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