Sodium-, chloride-, and mibefradil-sensitive calcium channels in intestinal pacing in wild-type and W/WV mice

2006 ◽  
Vol 84 (6) ◽  
pp. 589-599 ◽  
Author(s):  
Geoffrey Boddy ◽  
A. Willis ◽  
G. Galante ◽  
E.E. Daniel
Keyword(s):  
Sodium Chloride ◽  
Interstitial Cells Of Cajal ◽  
Disulfonic Acid ◽  
Krebs Solution ◽  
Wild Type ◽  
Low Sodium ◽  
Intestinal Pacing ◽  
Uniform Contraction ◽  
Cells Of Cajal ◽  
Channel Currents

Pacing of intestinal smooth muscle is driven by a network of cells found in the myenteric plexus called the interstitial cells of Cajal (ICC-MP), which produce a rhythmic pacemaker current. Using intact segments of circular (CM) and longitudinal (LM) muscle from wild-type and W/WV mice, we found that sodium-, chloride-, and mibefradil-sensitive ion channel currents are required for normal pacing to occur. Application of 30 µmol/L and 300 µmol/L lidocaine, 1 mmol/L 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS), 50 nmol/L and 500 nmol/L mibefradil, or low sodium Krebs significantly reduced pacing frequency in LM and CM. However, simultaneously applying DIDS and lidocaine or low sodium Krebs solution did not completely block pacing nor did it have an additive effect. Lidocaine and low sodium Krebs solution also abolished the gradient of pacing frequencies (higher proximally) found throughout the intestine, resulting in a uniform contraction frequency of 30–40/min. In W/WV mice, which lack ICC-MP, application of DIDS and lidocaine had no effect on the robust pacing in LM segments. In conclusion we found that sodium-, chloride-, and mibefradil-sensitive channel activities were required for normal pacing and to maintain the pacing gradient found throughout the intestines in wild-type but not W/WV mice.

Role of l-Ca2+ channels in intestinal pacing in wild-type and W/WV mice

2005 ◽  
Vol 288 (3) ◽  
pp. G439-G446 ◽  
Author(s):  
Geoffrey Boddy ◽  
E. E. Daniel
Keyword(s):  
Smooth Muscle ◽  
Bay K 8644 ◽  
Wild Type ◽  
Uniform Contraction ◽  
Mouse Intestine ◽  
Cells Of Cajal ◽  
Channel Currents ◽  
Ca2 Channels ◽  
Frequency Gradient

Rhythmic contractions generating transit in the digestive tract are paced by a network of cells called interstitial cells of Cajal (ICC) found in the myenteric plexus (MP). ICC generate cyclic depolarizations termed “slow waves” that are passively transmitted to the smooth muscle to initiate contractions. The opening of l-Ca2+ channels are believed to be primarily responsible for the influx of calcium generating a contraction in smooth muscle. However, l-Ca2+ channels are not thought to be important in generating the pacing current found in ICC. Using intact segments of circular (CM) and longitudinal (LM) muscle from wild-type mice and mice lacking c-kit kinase (W/WV), we found that l-Ca2+ channel currents are required for pacing at normal frequencies to occur. Application of 1 μM nicardipine caused a significant decrease in contraction amplitude and frequency in LM and CM that was successfully blocked with BAY K 8644. Nicardipine also abolished the pacing gradient found throughout the intestines, resulting in a uniform contraction frequency of 30–40/minute. Stimulating l-Ca2+ channels with BAY K 8644 neither removed nor recovered the pacing gradient. W/WV mice, which lack ICC-MP, also exhibited a pacing gradient in LM. Application of nicardipine to LM segments of W/WV mouse intestine did not reduce pacing frequency, and in jejunum, resulted in a slight increase. BAY K 8644 did not affect pacing frequency in W/WV tissue. In conclusion, we found that l-Ca2+ channel activity was required for normal pacing frequencies and to maintain the pacing frequency gradient found throughout the intestines in wild-type but not in W/WV mouse intestine.

scholarly journals Comparison of mechanical and electrical activity and interstitial cells of Cajal in urinary bladders from wild-type andW/Wvmice

2009 ◽  
Vol 156 (2) ◽  
pp. 273-283 ◽  
Author(s):  
KD McCloskey ◽  
UA Anderson ◽  
RA Davidson ◽  
YR Bayguinov ◽  
KM Sanders ◽  
...  
Keyword(s):  
Electrical Activity ◽  
Interstitial Cells Of Cajal ◽  
Interstitial Cells ◽  
Wild Type ◽  
Cells Of Cajal

scholarly journals Classification of gastrointestinal stromal tumor syndromes

2018 ◽  
Vol 25 (2) ◽  
pp. R49-R58 ◽  
Author(s):  
Priya Gopie ◽  
Lin Mei ◽  
Anthony C Faber ◽  
Steven R Grossman ◽  
Steven C Smith ◽  
...  
Keyword(s):  
Interstitial Cells Of Cajal ◽  
Clinical Manifestations ◽  
Incidence Rates ◽  
Wild Type ◽  
Mesenchymal Tumors ◽  
Therapeutic Implications ◽  
The Past ◽  
High Incidence ◽  
Cells Of Cajal

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, thought to derive from neoplastic outgrowth of the interstitial cells of Cajal. Building on recent advances in recognition, classification and diagnosis, the past two decades have seen a changing paradigm with molecular diagnostics and targeted therapies.KITandPDGFRAmutations account for 85–90% of GIST carcinogenesis. However, the remaining 10–15% of GISTs, which until recently were calledKIT/PDGFRAwild-type GISTs, have been found to have one of the several mutations, including in theSDHA,B,C,D,BRAFandNF1genes. Though most of such GISTs are sporadic, a number of families with high incidence rates of GISTs and other associated clinical manifestations have been reported and found to harbor germline mutations inKIT,PDGFRA,SDHsubunits andNF1. The goal of this review is to describe the mutations, clinical manifestations and therapeutic implications of syndromic and inherited GISTs in light of recent studies of their clinicopathologic range and pathogenesis.

Interstitial cells of Cajal and adaptive relaxation in the mouse stomach

2006 ◽  
Vol 291 (6) ◽  
pp. G1129-G1136 ◽  
Author(s):  
Devika Dixit ◽  
Natalia Zarate ◽  
Louis W. C. Liu ◽  
Douglas R. Boreham ◽  
Jan D. Huizinga
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Interstitial Cells Of Cajal ◽  
Interstitial Cells ◽  
Myogenic Tone ◽  
Wild Type ◽  
Pressure Development ◽  
Organ Level ◽  
Cells Of Cajal ◽  
Oxide Synthase

Interstitial cells of Cajal (ICC) are proposed to play a role in stretch activation of nerves and are under intense investigation for potential roles in enteric innervation. Most data to support such roles come from in vitro studies with muscle strips whereas data at the whole organ level are scarce. To obtain insight into the role of ICC in distention-induced motor patterns developing at the organ level, we studied distension-induced adaptive relaxation in the isolated whole stomach of wild-type and W/Wv mice. A method was developed to assess gastric adaptive relaxation that gave quantitative information on rates of pressure development and maximal adaptive relaxation. Pressure development was monitored throughout infusion of 1 ml of solution over a 10-min period. The final intraluminal pressure was sensitive to blockade of nitric oxide synthase, in wild-type and W/Wv mice to a similar extent, indicating NO-mediated relaxation in W/Wv mice. Adaptive relaxation occurred between 0.2 and 0.5 ml of solution infusion; this reflex was abolished by TTX, was not sensitive to blockade of nitric oxide synthase, but was abolished by apamin, suggesting that ATP and not nitric oxide is the neurotransmitter responsible for this intrinsic reflex. Despite the absence of intramuscular ICC (ICC-IM), normal gastric adaptive relaxation occurred in the W/Wv stomach. Because pressure development was significantly lower in W/Wv mice compared with wild type in all the conditions studied, including in the presence of TTX, ICC-IM may play a role in development of myogenic tone. In conclusion, a mouse model was developed to assess the intrinsic component of gastric accommodation. This showed that ICC-IM are not essential for activation of intrinsic sensory nerves nor ATP-driven adaptive relaxation nor NO-mediated relaxation in the present model. ICC-IM may be involved in regulation of (distention-induced) myogenic tone.

Interstitial cells of Cajal and electrical activity in ganglionic and aganglionic colons of mice

2002 ◽  
Vol 283 (2) ◽  
pp. G445-G456 ◽  
Author(s):  
Sean M. Ward ◽  
Michael D. Gershon ◽  
Kathleen Keef ◽  
Yulia R. Bayguinov ◽  
Cheryl Nelson ◽  
...  
Keyword(s):  
Electrical Activity ◽  
Interstitial Cells Of Cajal ◽  
Circular Muscle ◽  
Interstitial Cells ◽  
Proximal Colon ◽  
Neural Responses ◽  
Wild Type ◽  
Circular Layer ◽  
Excitatory Junction Potentials ◽  
Cells Of Cajal

An antibody directed against Kit protein was used to investigate the distribution of interstitial cells of Cajal (ICC) within the murine colon. The ICC density was greatest in the proximal colon and decreased along its length. The distribution of the different classes of ICC in the aganglionic colons of lethal spotted ( ls/ls) mice was found to be similar in age-matched wild-type controls. There were marked differences in the electrical activities of the colons from ls/ls mutants compared with wild-type controls. In ls/ls aganglionic colons, the circular muscle was electrically quiescent compared with the spontaneous spiking electrical activity of wild-type tissues. In ls/ls aganglionic colons, postjunctional neural responses were greatly affected. Inhibitory junction potentials were absent or excitatory junction potentials inhibited by atropine were observed. In conclusion, the distribution of ICC in the ganglionic and aganglionic regions of the colons from ls/ls mutants appeared similar to that of wild-type controls. The electrical activity and neural responses of the circular layer are significantly different in aganglionic segments of ls/ls mutants.

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.

Excitability of canine colon circular muscle disconnected from the network of interstitial cells of Cajal

1992 ◽  
Vol 70 (2) ◽  
pp. 289-295 ◽  
Author(s):  
Louis W. C. Liu ◽  
Edwin E. Daniel ◽  
Jan D. Huizinga
Keyword(s):  
Slow Wave ◽  
Interstitial Cells Of Cajal ◽  
Potassium Conductance ◽  
Circular Muscle ◽  
Interstitial Cells ◽  
Slow Waves ◽  
Oscillatory Activity ◽  
Krebs Solution ◽  
Ionic Mechanisms ◽  
Cells Of Cajal

The 6 cpm omnipresent slow waves recorded in the circular muscle (CM) layer of canine colon are generated at the submucosal surface of the CM layer. After removal of the submucosal network of interstitial cells of Cajal (ICC), 66% of the CM preparations (25 of 38) were quiescent in Krebs solution. In the presence of carbachol, seven of nine of these spontaneously quiescent CM preparations demonstrated slow wave-like activity with mean frequency, duration and amplitude of 5.9 ± 0.4 cpm, 2.8 ± 0.5 s, and 0.8 ± 0.2 mV, respectively. Similar slow wave-like activities were induced by TEA (seven out of eight quiescent CM preparations) with frequency, duration and amplitude of 6.1 ± 0.2 cpm, 2.7 ± 0.5 s, and 1.0 ± 0.2 mV, respectively, and by BaCl2 (eight of eight quiescent CM preparations) with frequency, duration, and amplitude of 6.3 ± 0.3 cpm, 1.8 ± 0.2 s, and 0.5 ± 0.1 mV, respectively. All the induced activities were abolished in the presence of 1 μM D600. CM preparations with the submucosal ICC network intact (ICC–CM) showed slow wave activity in Krebs solution at a frequency of 6.2 ± 0.2 cpm, a duration of 3.6 ± 0.2 s, and an amplitude of 1.0 ± 0.1 mV (n = 22). When ICC–CM preparations were stimulated by BaCl2, carbachol, or TEA, the slow wave frequency did not change significantly, but the duration increased as well as the amplitude. In the presence of D600, the upstroke of slow waves remained and the frequency was not affected. The ability to generate slow wave-like activity after potassium conductance blockade in spontaneously quiescent CM disconnected from the ICC network suggested that circular muscle cells have ionic mechanisms for intrinsic oscillatory activity and are capable of actively participating in the conduction and generation of slow waves.Key words: colon, smooth muscle, interstitial cells of Cajal, canine, slow waves, excitability.

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