Mice lacking the dopamine transporter display altered regulation of distal colonic motility

2000 ◽  
Vol 279 (2) ◽  
pp. G311-G318 ◽  
Author(s):  
Julia K. L. Walker ◽  
Raul R. Gainetdinov ◽  
Allen W. Mangel ◽  
Marc G. Caron ◽  
Michael A. Shetzline
Keyword(s):  
Contractile Activity ◽  
Colonic Motility ◽  
Distal Colon ◽  
Wild Type ◽  
Gi Tract ◽  
Inhibitory Effects ◽  
Motility Index ◽  
Organ Tissue ◽  
Altered Regulation ◽  
Species Specific

The mechanisms by which dopamine (DA) influences gastrointestinal (GI) tract motility are incompletely understood and complicated by tissue- and species-specific differences in dopaminergic function. To improve the understanding of DA action on GI motility, we used an organ tissue bath system to characterize motor function of distal colonic smooth muscle segments from wild-type and DA transporter knockout (DAT −/−) mice. In wild-type mice, combined blockade of D1 and D2 receptors resulted in significant increases in tone (62 ± 9%), amplitude of spontaneous phasic contractions (167 ± 24%), and electric field stimulation (EFS)-induced (40 ± 8%) contractions, suggesting that endogenous DA is inhibitory to mouse distal colonic motility. The amplitudes of spontaneous phasic and EFS-induced contractions were lower in DAT −/− mice relative to wild-type mice. These differences were eliminated by combined D1 and D2 receptor blockade, indicating that the inhibitory effects of DA on distal colonic motility are potentiated in DAT −/− mice. Motility index was decreased but spontaneous phasic contraction frequency was enhanced in DAT −/− mice relative to wild-type mice. The fact that spontaneous phasic and EFS-induced contractile activity were altered by the lack of the DA transporter suggests an important role for endogenous DA in modulating motility of mouse distal colon.

Neurohumoral control of colonic motility in the rabbit

1983 ◽  
Vol 245 (4) ◽  
pp. G582-G588 ◽  
Author(s):  
W. J. Snape ◽  
S. Shiff
Keyword(s):  
Contractile Activity ◽  
Control Period ◽  
Colonic Motility ◽  
Distal Colon ◽  
Proximal Colon ◽  
Base Line ◽  
Cholinergic Stimulation ◽  
Bipolar Electrodes ◽  
Neurohumoral Control ◽  
Alpha Adrenergic Agonist

Colonic motility was examined in the proximal (taeniated) and distal (nontaeniated) colon of New Zealand White rabbits. Colonic myoelectric and contractile activities were recorded by bipolar electrodes and extraluminal strain gauges sewn on the antimesenteric serosal surface of the proximal and distal colon. Slow-wave frequency consistently was slower in the proximal colon (13.2 +/- 0.9) compared with the distal colon (15.8 +/- 1.2) (P less than 0.05). During the control period 81.8 +/- 5.2% of slow waves have superimposed spike potentials in the proximal colon. The distal colon had similar amounts of spike activity. The distal colon had increased base-line contractility (P less than 0.02). Atropine inhibited spike and contractile activity on both sides of the colon, but the distal colon still had more contractile activity than the proximal colon (P less than 0.02). The alpha-adrenergic agonist phenylephrine and antagonist phentolamine had no effect on colonic motility. Isoproterenol inhibited colonic smooth muscle spike and contractile activity. This effect was blocked by propranolol. Administration of trimethaphan camsylate caused an increase in spike and contractile activity only in the distal colon. The effect of trimethaphan on the distal colon was inhibited by atropine. These studies show that 1) tonic cholinergic stimulation exists both in the proximal and in the distal colon, 2) circulating catecholamines have minimal effect on base-line colonic motility, and 3) tonic nonadrenergic inhibition of the distal colon modulates the tonic cholinergic stimulation.

Effects of morphine on colonic myoelectric and motor activity in subhuman primates

1990 ◽  
Vol 258 (2) ◽  
pp. G247-G252 ◽  
Author(s):  
C. T. Frantzides ◽  
R. E. Condon ◽  
W. J. Schulte ◽  
V. Cowles
Keyword(s):  
Motor Activity ◽  
Contractile Activity ◽  
Colonic Motility ◽  
Macaca Arctoides ◽  
Motility Index ◽  
Bipolar Electrodes ◽  
Biphasic Effect ◽  
Before And After ◽  
Unanesthetized Animals ◽  
Dose Dependent

We investigated the effects of numerous doses of morphine on colonic myoelectric and motor activity in monkeys. In each of four monkeys (Macaca arctoides), combined strain gauge transducers and bipolar electrodes were chronically implanted at four defined sites in the colon and recordings were made for 3 h in fasted, unanesthetized animals before and after intravenous administration of morphine sulfate (10-1,000 micrograms/kg). The basal fasting pattern of colonic motility was characterized by random contractions, nonmigrating clusters of contractions, and migrating individual contractions. Morphine at very low doses (10-25 micrograms/kg) had no effect on colonic motility at any site. At doses of 50-200 micrograms/kg, clusters and migrating contractions were eliminated, but there was an overall increase in the frequency of random contractions without an alteration in contraction amplitude or duration. At morphine doses of 500 and 1,000 micrograms/kg, contraction clusters and migrating contractions also were not seen, but there was a decrease in the colonic motility index caused entirely by a decreased frequency of random contractions. Both stimulation and inhibition were most marked in the sigmoid colon. Morphine has a dose-dependent biphasic effect on colonic myoelectric and contractile activity and alters colonic motility patterns by inhibiting migrating contractions and clusters of contractions.

Comparison of the effects of leukotrienes B4 and D4 on distal colonic motility in the rabbit in vivo

1989 ◽  
Vol 257 (6) ◽  
pp. G860-G864 ◽  
Author(s):  
R. Burakoff ◽  
E. Nastos ◽  
S. Won ◽  
W. H. Percy
Keyword(s):  
Contractile Activity ◽  
Colonic Motility ◽  
Distal Colon ◽  
Mechanical Activity ◽  
Excitatory Action ◽  
Potential Frequency ◽  
Small And Large Intestine ◽  
Related Increase

Leukotrienes (LTs) have been shown to contract smooth muscle of the small and large intestine in vitro, and an increased mucosal synthesis of leukotrienes has been reported to occur in ulcerative colitis. The purpose of this study was to evaluate the effects of LTs B4 and D4 on the myoelectric and mechanical activity of the rabbit distal colon in vivo and to determine how these effects were modified by indomethacin. LTB4 had a weak excitatory action on both electrical and mechanical activity but this was not statistically significant; LTD4 on the other hand caused a significant dose-related increase in spike potential frequency and contractile activity. Indomethacin alone (1 mg/kg) had no significant effect on the electrical or mechanical activity of the colon but blocked the effects of subsequently administered LTD4. It is concluded from these data that at least part of the excitatory action of LTD4 results from its causing the synthesis and release of excitatory prostaglandins. However, whereas leukotrienes have the potential to play an important role in modulating colonic motility, it seems most likely that this effect would occur after pathological stimulus rather than in the normal healthy colon.

Electroacupuncture at ST-36 accelerates colonic motility and transit in freely moving conscious rats

2006 ◽  
Vol 290 (2) ◽  
pp. G285-G292 ◽  
Author(s):  
Masahiro Iwa ◽  
Megumi Matsushima ◽  
Yukiomi Nakade ◽  
Theodore N. Pappas ◽  
Mineko Fujimiya ◽  
...  
Keyword(s):  
Colonic Motility ◽  
Distal Colon ◽  
Proximal Colon ◽  
Colonic Transit ◽  
Motility Index ◽  
Conscious Rats ◽  
Beneficial Effects ◽  
Efferent Pathway ◽  
Bowel Diseases ◽  
Parasympathetic Pathway

Acupuncture is useful for functional bowel diseases, such as constipation and diarrhea. However, the mechanisms of beneficial effects of acupuncture on colonic function have scarcely ever been investigated. We tested the hypothesis that electroacupuncture (EA) at ST-36 stimulates colonic motility and transit via a parasympathetic pathway in conscious rats. Hook-shaped needles were inserted at bilateral ST-36 (lower limb) or BL-21 (back) and electrically stimulated at 10 Hz for 20 min. We also studied c-Fos expression in response to EA at ST-36 in Barrington's nucleus of the pons. EA at ST-36, but not BL-21, significantly increased the amplitude of motility at the distal colon. The calculated motility index of the distal colon increased to132 ± 9.9% of basal levels ( n = 14, P < 0.05). In contrast, EA at ST-36 had no stimulatory effects in the proximal colon. EA at ST-36 significantly accelerated colonic transit [geometric center (GC) = 6.76 ± 0.42, n = 9, P < 0.001] compared with EA at BL-21 (GC = 5.23 ± 0.39, n = 7). The stimulatory effect of EA at ST-36 on colonic motility and transit was abolished by pretreatment with atropine. EA-induced acceleration of colonic transit was also abolished by extrinsic nerve denervation of the distal colon (GC = 4.69 ± 0.33, n = 6). The number of c-Fos-immunopositive cells at Barrington's nucleus significantly increased in response to EA at ST-36 to 8.1 ± 1.1 cells/section compared with that of controls (2.4 ± 0.5 cells/section, n = 3, P < 0.01). It is concluded that EA at ST-36 stimulates distal colonic motility and accelerates colonic transit via a sacral parasympathetic efferent pathway (pelvic nerve). Barrington's nucleus plays an important role in mediating EA-induced distal colonic motility in conscious rats.

scholarly journals Molecular and functional characterization of Kv7 K+ channel in murine gastrointestinal smooth muscles

2009 ◽  
Vol 297 (1) ◽  
pp. G107-G115 ◽  
Author(s):  
Thomas A. Jepps ◽  
Iain A. Greenwood ◽  
James D. Moffatt ◽  
Kenton M. Sanders ◽  
Susumu Ohya
Keyword(s):  
Contractile Activity ◽  
Functional Characterization ◽  
Smooth Muscles ◽  
Circular Muscle ◽  
Distal Colon ◽  
Muscle Layer ◽  
K Channel ◽  
Neuronal Membrane ◽  
Gi Tract ◽  
Membrane Excitability

Members of the Kv7 voltage-gated K+ channel family are important determinants of cardiac and neuronal membrane excitability. Recently, we and others have shown that Kv7 channels are also crucial regulators of smooth muscle activity. The aim of the present study was to assess the Kv7 expression in different parts of the murine gastrointestinal (GI) tract and to assess their functional roles by use of pharmacological agents. Of KCNQ/Kv7 members, both KCNQ4/Kv7.4 and KCNQ5/Kv7.5 genes and proteins were the most abundantly expressed Kv7 channels in smooth muscles throughout the GI tract. Immunohistochemical staining also revealed that Kv7.4 and Kv7.5 but not Kv7.1 were expressed in the circular muscle layer of the colon. In segments of distal colon circular muscle exhibiting spontaneous phasic contractions, the nonselective Kv7 blockers XE991 and linopirdine increased the integral of tension. Increases in the integral of tension were also observed under conditions of neuronal blockade. Similar effects, although less marked, were observed in the proximal colon. As expected, the Kv7.1-selective blocker chromanol 293B had no effect in either type of segment. These data show that Kv7.x especially Kv7.4 and Kv7.5 are expressed in different regions of the murine gastrointestinal tract and blockers of Kv7 channels augment inherent contractile activity. Drugs that selectively block Kv7.4/7.5 might be promising therapeutics for the treatment of motility disorders such as constipation associated with irritable bowel syndrome.

Electrical neuromodulation at acupoint ST36 normalizes impaired colonic motility induced by rectal distension in dogs

2015 ◽  
Vol 309 (5) ◽  
pp. G368-G376 ◽  
Author(s):  
Haifeng Jin ◽  
Jiemin Liu ◽  
Robert D. Foreman ◽  
Jiande D. Z. Chen ◽  
Jieyun Yin
Keyword(s):  
Contractile Activity ◽  
Colonic Motility ◽  
Colonic Transit ◽  
Vagal Activity ◽  
Rectal Distension ◽  
Autonomic Functions ◽  
Motility Index ◽  
Cholinergic Pathway ◽  
Underlying Mechanisms ◽  
Electrical Neuromodulation

Electroacupuncture (EA) has been shown to improve impaired gastric motility and slow waves in both humans and animals. However, its effects on colonic motility have rarely been investigated. The aim of this study was to investigate the effects and underlying mechanisms of EA on impaired colonic motility induced by rectal distension (RD)in dogs. Colon contractions and transit were measured in various sessions with and without EA in hound dogs chronically placed with a colonic cannula. Colonic contractile activity was assessed by motility index (MI). Autonomic functions were determined by the spectral analysis of the heart rate variability derived from the electrocardiogram. It was found 1) RD suppressed colonic motility by 40.5% (10.8 ± 0.9 with RD vs. 6.4 ± 0.8 at baseline, P < 0.002). EA at ST36 normalized colonic contractions suppressed by RD (12.9 ± 2.8, P < 0.002 vs. RD and P = 0.1 vs. control). 2) Administration of atropine blocked the ameliorating effect of EA on colon motility. 3) RD also delayed colonic transit (65.0 ± 2.0% with RD vs. 86.0 ± 1.9% without RD, P < 0.001) that was restored with EA (84.0 ± 1.9%, P = 0.178 vs. control). 4) EA increased vagal activity suppressed by RD (0.37 ± 0.07 with RD + EA vs. 0.09 ± 0.03 with RD without EA, P < 0.001). In conclusion, RD inhibits colonic contractions and delays colonic transit in dogs; EA at ST36 restores the RD-induced impairment in both colonic contraction and transit by enhancing vagal activity and mediated via the cholinergic pathway.

Effects ofHange-shashin-to(TJ-14) andKeishi-ka-shakuyaku-to(TJ-60) on contractile activity of circular smooth muscle of the rat distal colon

2012 ◽  
Vol 303 (9) ◽  
pp. G1059-G1066 ◽  
Author(s):  
Yoshihiko Kito ◽  
Noriyoshi Teramoto
Keyword(s):  
Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Contractile Activity ◽  
Distal Colon ◽  
Sk Channels ◽  
Inhibitory Effects ◽  
Traditional Medicines ◽  
Circular Smooth Muscle ◽  
Rat Distal Colon ◽  
Spontaneous Contractions

The Japanese Kampo medicines Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) have been used to treat symptoms of human diarrhea on an empirical basis as Japanese traditional medicines. However, it remains unclear how these drugs affect smooth muscle tissues in the distal colon. The aim of the present study was to investigate the effects of TJ-14 and TJ-60 on the contractile activity of circular smooth muscle from the rat distal colon. TJ-14 and TJ-60 (both 1 mg/ml) inhibited spontaneous contractions of circumferentially cut preparations with the mucosa intact. Blockade of nitric oxide (NO) synthase or soluble guanylate cyclase activity abolished the inhibitory effects of TJ-60 but only attenuated the inhibitory effects of TJ-14. Apamin (1 μM), a blocker of small-conductance Ca2+-activated K+channels (SK channels), attenuated the inhibitory effects of 5 mg/ml TJ-60 but not those of 5 mg/ml TJ-14. TJ-14 suppressed contractile responses (phasic contractions and off-contractions) evoked by transmural nerve stimulation and increased basal tone, whereas TJ-60 had little effect on these parameters. These results suggest that 1 mg/ml TJ-14 or TJ-60 likely inhibits spontaneous contractions of the rat distal colon through the production of NO. Activation of SK channels seems to be involved in the inhibitory effects of 5 mg/ml TJ-60. Since TJ-14 has potent inhibitory effects on myogenic and neurogenic contractile activity, TJ-14 may be useful in suppressing gastrointestinal motility.

scholarly journals An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Thao Thi Thanh Nguyen ◽  
Masato Shingyoji ◽  
Michiko Hanazono ◽  
Boya Zhong ◽  
Takao Morinaga ◽  
...  
Keyword(s):  
Wild Type ◽  
Inhibitory Effects ◽  
Cytotoxic Effects ◽  
P53 Expression ◽  
Nuclear Factor I ◽  
Infected Cells ◽  
Wild Type P53 ◽  
Mdm2 Inhibitor ◽  
P16 Expression

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

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