Disturbed gastrointestinal motility and decreased interstitial cells of Cajal in diabetic <i>db/db</i> mice

Yamamoto, Takahiro; Watabe, Kenji; Nakahara, Masanori; Ogiyama, Hideharu; Kiyohara, Tatsuya; Tsutsui, Shusaku; Tamura, Shinji; Shinomura, Yasuhisa; Hayashi, Norio

doi:10.1111/j.1440-1746.2008.05326.x

Cited by 73 publications

(62 citation statements)

References 32 publications

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“…The purpose of that study was to correlate the expected decrease in slow wave propagation with the reported decrease in the census of ICC-MY in the small intestine (8,10,20,30). To our initial surprise, we did not measure a significant decrease in slow wave propagation although there was a reduction in the number of ICC-MY by ϳ50% (10).…”

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confidence: 86%

Functional reentry and circus movement arrhythmias in the small intestine of normal and diabetic rats

Lammers¹,

Stephen²,

Karam

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Lammers WJ, Stephen B, Karam SM. Functional reentry and circus movement arrhythmias in the small intestine of normal and diabetic rats. Am J Physiol Gastrointest Liver Physiol 302: G684 -G689, 2012. First published December 29, 2011; doi:10.1152/ajpgi.00332.2011.-In a few recent studies, the presence of arrhythmias based on reentry and circus movement of the slow wave have been shown to occur in normal and diseased stomachs. To date, however, reentry has not been demonstrated before in any other part of the gastrointestinal system. No animals had to be killed for this study. Use was made of materials obtained during the course of another study in which 11 rats were treated with streptozotocin and housed with age-matched controls. After 3 and 7 mo, segments of duodenum, jejunum, and ileum were isolated and positioned in a tissue bath. Slow wave propagation was recorded with 121 extracellular electrodes. After the experiment, the propagation of the slow waves was reconstructed. In 10 of a total of 66 intestinal segments (15%), a circus movement of the slow wave was detected. These reentries were seen in control (n ϭ 2) as well as in 3-mo (n ϭ 2) and 7-mo (n ϭ 6) diabetic rats. Local conduction velocities and beat-to-beat intervals during the reentries were measured (0.42 Ϯ 0.15 and 3.03 Ϯ 0.67 cm/s, respectively) leading to a wavelength of 1.3 Ϯ 0.5 cm and a circuit diameter of 4.1 Ϯ 1.5 mm. This is the first demonstration of a reentrant arrhythmia in the small intestine of control and diabetic rats. Calculations of the size of the circuits indicate that they are small enough to fit inside the intestinal wall. Extrapolation based on measured velocities and rates indicate that reentrant arrhythmias are also possible in the distal small intestine of larger animals including humans. slow wave; diabetes; wavelength THE SMOOTH MUSCLE LAYER OF the gastrointestinal (GI) tract generates spontaneous electrical activities that are referred to as "slow waves." These slow waves are dependent on the interstitial cells of Cajal in the myenteric plexus (ICC-MY) and are important for maintaining normal GI motility (8, 9).In a recent study, we investigated the propagation of slow waves in a streptozotocin (STZ) model of diabetes in rats. The purpose of that study was to correlate the expected decrease in slow wave propagation with the reported decrease in the census of ICC-MY in the small intestine (8,10,20,30). To our initial surprise, we did not measure a significant decrease in slow wave propagation although there was a reduction in the number of ICC-MY by ϳ50% (10). We concluded from that study that the reduction of ICC-MY was not enough to block slow wave propagation.Further analysis of the propagation in both control and in 3-and 7-mo diabetic rats, however, revealed another unexpected result. In ϳ15% of the segments, slow wave propagation did not originate from one or a few foci (10, 11). Instead, the slow wave was seen to propagate in a circular fashion for relatively long periods of time, whereby the impulse could rotate ...

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confidence: 86%

Functional reentry and circus movement arrhythmias in the small intestine of normal and diabetic rats

Lammers¹,

Stephen²,

Karam

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…7,11 Kit mRNA and KIT protein levels decline in the colons of patients with slow-transit constipation. 12,13 In addition, stem cell factors and KIT protein activity is closely related to the development and sustenance of ICCs, and their expression levels decrease with age in the rat ascending colon (AC). [14][15][16] Neuronal degeneration in the enteric nervous system is an important mechanism of age-related functional changes in the guts of older animals.…”

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confidence: 99%

Comparison of Changes in the Interstitial Cells of Cajal and Neuronal Nitric Oxide Synthase-positive Neuronal Cells With Aging Between the Ascending and Descending Colon of F344 Rats

Lee

Kim

et al. 2017

J Neurogastroenterol Motil

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Background/AimsNeuronal degeneration and changes in interstitial cells of Cajal (ICCs) are important mechanisms of age-related constipation. This study aims to compare the distribution of ICCs and neuronal nitric oxide synthase (nNOS) with regard to age-related changes between the ascending colon (AC) and descending colon (DC) in 6-, 31-, and 74-week old and 2-year old male Fischer-344 rats. MethodsThe amount of fecal pellet and the bead expulsion times were measured. Fat proportion in the muscle layer of the colon was analyzed by hematoxylin and eosin staining. Proto-oncogene receptor tyrosine kinase (KIT) and neuronal nitric oxide synthase (nNOS) expression were analyzed with Western blotting and immunohistochemistry. Isovolumetric contractile measurements and electrical field stimulation were used to assess smooth muscle contractility. ResultsColon transit and bead expulsion slowed with senescence. Fat in the muscle layer accumulated with age in the AC, but not in the DC. The proportion of KIT-immunoreactive ICCs in the submucosal and myenteric plexus was higher in the DC than in the AC, and it declined with age, especially in the AC. In contrast, the proportion of NOS-immunoreactive neurons in the myenteric plexus was higher in the AC than in the DC, and both decreased in older rats. Nitric oxide levels declined with age in the DC. Muscle strip experiments showed that the inhibitory response mediated by nitric oxide in the circular direction of the DC was reduced in 2-year old rats. ConclusionThe AC and DC differ in their distribution of ICCs and nNOS, and age-related loss of nitrergic neurons more severely affects the DC than the AC.

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“…It is well known that ICC express protooncogene c-kit (6,47). The stem cell factor (SCF) is a natural ligand of Kit (50) and involves the development and maintenance of ICC (35). It has been known that the expression of c-kit mRNA and c-Kit protein significantly decreased in the colon of patients with slow-transit constipation and mice with diabetes mellitus (44,50).…”

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confidence: 99%

“…The stem cell factor (SCF) is a natural ligand of Kit (50) and involves the development and maintenance of ICC (35). It has been known that the expression of c-kit mRNA and c-Kit protein significantly decreased in the colon of patients with slow-transit constipation and mice with diabetes mellitus (44,50). In addition, there was a study on the number and volume of ICC networks in the normal human stomach and colon, which declined with aging (15).…”

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confidence: 99%

Fat deposition in the tunica muscularis and decrease of interstitial cells of Cajal and nNOS-positive neuronal cells in the aged rat colon

Jo¹,

Kim

Nam³

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Little is known about the time course of aging on interstitial cells of Cajal (ICC) of colon. The aim of this study was to investigate the change of morphology, ICC, and neuronal nitric oxide synthase (nNOS)-immunoreactive cells in the aged rat. The proximal colon of 344 Fischer rats at four different ages (6, 31, 74 wk, and 2 yr) were studied. The immunoreactivity of c-Kit, nNOS, anti-protein gene product 9.5, and synaptophysin were counted after immunohistochemistry. The c-kit, stem cell factor (ligand of Kit), and nNOS mRNA were measured by real-time PCR. c-Kit and nNOS protein were assessed by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS) were conducted. The area of intramuscular fat deposition significantly increased with age after 31 wk. c-Kit-immunoreactive ICC and nNOS-immunoreactive neurons and nerve fibers significantly declined with age. mRNA and protein expression of c-kit and nNOS decreased with aging. The functional study showed that the spontaneous contractility was decreased in aged rat, whereas EFS responses in the presence of atropine and L-NG-Nitroarginine methyl ester were increased in aged rat. In conclusion, the decrease of proportion of proper smooth muscle, the density of ICC and nNOSimmunoreactive neuronal fibers, and the number of nNOS-immunoreactive neurons during the aging process may explain the agingassociated colonic dysmotility.aging; colon; interstitial cells of Cajal; neuronal nitric oxide synthase; rats; inbred F344 AGING LEADS TO THE IMPAIRMENT of organ function as a result of accumulation of diverse deleterious changes throughout the cells and tissues (16). Constipation is a common problem in the elderly and known to be associated with multiple factors, such as decreased intestinal secretory epithelial function, abnormal colonic motility caused by enteric neurodegeneration, and reduced contractile response of smooth muscle cells with age (3-5).Enteric neurodegeneration involves the loss of enteric neuron, especially excitatory cholinergic neurons (2). In contrast, nitrergic myenteric neurons are known to be selectively spared in the aged (9, 36, 45). However, there was a contrary report that nitrergic neurons decreased in aged rats (43). Nitrergic enteric neurons, which release nitric oxide (NO) generated by catalysis of neuronal NO synthase (nNOS), act as nonadrenergic, noncholinergic inhibitory neuron and induce colonic smooth muscle relaxation (42). This NO is known to enhance transit of the rat colon by mediating descending relaxation, which in turn facilitates propulsion of the colonic contents (32). Nitrergic nerves of colon may be an important component of colonic motility.Interstitial cells of Cajal (ICC) also play important roles in gastrointestinal motility. ICC play as an electrical pacemaker and mediate both inhibitory and excitatory motor neurotransmissions, which manifest as electrical slow waves in smooth muscles. Consequently, ICC contribute to segmenting and peristaltic contractile activity (20,33). ICC have ...

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Disturbed gastrointestinal motility and decreased interstitial cells of Cajal in diabetic db/db mice

Abstract: We demonstrated disturbed gastrointestinal motility in db/db mice with reduced areas of ICC and expression of SCF. Our results suggest the involvement of ICC in the gastroenteropathy of type 2 DM.

Cited by 73 publications

References 32 publications

Functional reentry and circus movement arrhythmias in the small intestine of normal and diabetic rats

Functional reentry and circus movement arrhythmias in the small intestine of normal and diabetic rats

Comparison of Changes in the Interstitial Cells of Cajal and Neuronal Nitric Oxide Synthase-positive Neuronal Cells With Aging Between the Ascending and Descending Colon of F344 Rats

Fat deposition in the tunica muscularis and decrease of interstitial cells of Cajal and nNOS-positive neuronal cells in the aged rat colon

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