Impaired acetylcholine-induced smooth muscle contraction in colitis involves altered calcium mobilization and AKT phosphorylation

Wells, Ron W.; Lourenssen, Sandra; Blennerhassett, Michael G.

doi:10.1007/s00424-007-0415-z

Cited by 4 publications

(5 citation statements)

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“…This has shown that significant Development of techniques of enzymatic isolation allowing study of contractility of single isolated CSMC has allowed development of a culture model in which there is survival and adaptation to culture of a high percentage of CSMC, with minimal presence of glia or other cell types (25,31). These cells displayed strong labeling for the smooth muscle markers ␣-SM actin, desmin, and SM22-␣, but examination showed that cyclin D1 expression, evidence for the onset of mitosis, was correlated with decreased expression of these markers.…”

Section: Discussionmentioning

confidence: 99%

“…To induce inflammation, 500 l of 200 mM TNBS (Sigma) dissolved in 50% ethanol were infused into the colon (8 cm proximal to the anus) of rats lightly anesthetized with inhaled isoflurane, as previously described (25,31). All experimental procedures were approved by the Queen's University Animal Care Committee.…”

Section: Animalsmentioning

confidence: 99%

“…For example, intestinal wall thickening and proliferation of intestinal SMCs (ISMC) occurs in intestinal inflammation in both human disease, as well as in animal models, with poorly understood consequences (3,6,19,24). Furthermore, in studies of isolated ISMC obtained from animal models, we and others have shown that inflammation causes substantial alterations to the contractile responses to neural stimuli, including altered regulation of intracellular calcium (30,31), with evidence for persistence of these changes after inflammation has resolved (29).…”

mentioning

confidence: 92%

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Proliferation modulates intestinal smooth muscle phenotype in vitro and in colitis in vivo

Nair

Han

Lourenssen

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Intestinal inflammation causes an increased intestinal wall thickness, in part, due to the proliferation of smooth muscle cells, which impairs the contractile phenotype elsewhere. To study this, cells from the circular muscle layer of the rat colon (CSMC) were isolated and studied, both in primary culture and after extended passage, using quantitative PCR, Western blot analysis, and immunocytochemistry. By 4 days in vitro, both mRNA and protein for the smooth muscle marker proteins α-smooth muscle actin, desmin, and SM22-α were reduced by >50%, and mRNA for cyclin D1 was increased threefold, evidence for modulation to a proliferative phenotype. Continued growth caused significant further decrease in expression, evidence that phenotypic loss in CSMC was proportional to the extent of proliferation. In CSMC isolated at day 2 of trinitrobenzene sulfonic acid-induced colitis, flow cytometry and Western blotting showed that these differentiated markers were reduced in mitotic CSMC, while similar to control in nonmitotic CSMC. By day 35 post-trinitrobenzene sulfonic acid, when inflammation has resolved, CSMC were hypertrophic, but, nonetheless, showed markedly decreased expression of smooth muscle protein markers per cell. In vitro, day 35 CSMC displayed an accelerated loss of phenotype and increased thymidine uptake in response to serum or PDGF-BB. Furthermore, carbachol-induced expression of phospho-AKT (a marker of cholinergic response) was lost from day 35 CSMC in vitro, while retained in control cells. Therefore, proliferation reduces the expression of smooth-muscle-specific markers in CSMC, possibly leading to altered contractility. However, inflammation-induced proliferation in vivo also causes lasting changes that include unexpected priming for an exaggerated response to proliferative stimuli. Identification of the molecular mechanisms of intestinal smooth muscle cell phenotypic modulation will be helpful in reducing the detrimental effects of inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 92%

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Proliferation modulates intestinal smooth muscle phenotype in vitro and in colitis in vivo

Nair

Han

Lourenssen

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…However, some research poited out that ACh bound to M3 receptors and subsquently activated the PLC signaling pathway, which released Ca 2+ from ER and induced smooth muscle contraction . In the inflamatory intestine, ACh‐induced contraction of smooth muscles was caused by both Akt phosphorylation and Ca 2+ release . These results indicated that cholinergic contraction of smooth muscles is caused by PLC activation.…”

Section: Discussionmentioning

confidence: 99%

7,8‐dihydroxyflavone enhanced cholinergic contraction of rat gastric smooth muscle via augmenting muscarinic M3 receptor expression

Tian

et al. 2018

Clin Exp Pharma Physio

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Although 7,8-dihydroxyflavone (7,8-DHF), a synthetic agonist specific for tyrosine kinase receptor B (TrkB), has been reported to promote intestinal dynamics, its effect on gastric dynamics has not been studied as yet. In this study, we explored how 7,8-DHF affected the carbachol (CCh)-induced contraction of rat gastric muscle by way of measuring the contractile tension of muscular strips. We found that although 7,8-DHF did not directly cause contraction of gastric muscle, it enhanced CCh-induced, instead of substance P- or high K -induced, contraction. The enhancing role of 7,8-DHF was partially blocked by ANA-12, a blocker specific for TrkB the activation of which in the gastric strips was evidenced by its phosphorylation. Although 7,8-DHF alone did not activate : phospholipase C (PLC)-γ in gastric muscle, CCh did, and importantly, the combined treatment with CCh + 7,8-DHF activated more PLC-γ. U73122, an antagonist to PLC-γ blocked both the CCh-induced and the 7,8-DHF-enhanced/CCh-induced contraction by ~30%. To pursue how 7,8-DHF could augment CCh-activated PLC-γ phosphorylation, we first examined the effect of 7,8-DHF on the expression of muscarinic receptors in gastric muscle and found that 7,8-DHF specifically increased M3 but not M2 receptor expression possibly through TrkB/Akt (protein kinase B) pathway because the Akt antagonist, LY294002 significantly suppressed the 7,8-DHF-augmemted M3 expression and completely blocked the 7,8-DHF-enhanced cholinergic contraction. Supporting the result, Akt phosphorylation in the gastric muscle was enhanced by 7,8-DHF treatment. The in vivo experiment showed that orally fed 7,8-DHF increased gastric emptying rate. The results imply a possibility that 7,8-DHF may be developed into a drug in the future for enhancing gastric dynamics.

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“…So, the extract can affect through adrenergic as well as nitric oxide receptors. Increasing the intracellular calcium and potassium is the controlling factor of tension of gastrointestinal smooth muscle (Wells et al, 2008). So, the existence of extract may have been inhibiting the normal function of calcium and potassium, through which the present extract could have inhibited the contraction.…”

Section: Discussionmentioning

confidence: 99%

Antispasmodic effects of yarrow (<i>Achillea millefolium l</i>.) extract in the isolated ileum of rat

Moradi¹,

Rafieian-Koupaei²,

Imani³

et al. 2013

Afr. J. Trad. Compl. Alt. Med.

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Achillea millefolium L. is cultivated in Iran and widely used in traditional medicine for gastrointestinal disorders. The aim of this study was to determine the effect of hydroalcoholic extract of A. millefolium on the contraction and relaxation of isolated ileum in rat. In this experimental study, aerial parts of A. millefolium were extracted by maceration in ethanol 70% for 72h. Terminal portion of ileum in 100 male Wistar rats was dissected and its contractions were recorded isotonically in an organ bath containing Tyrode solution (37 ºC, pH 7.4) under one gram tension. Acetylcholine (1mM) and KCl (60mM) were used to create isotonic contractions. Propranolol and Nω-Nitro-L-arginine methylester hydrochloride (L-NAME) were used to investigate the mechanisms of action prior to giving the extract to the relevant groups. Data were compared by ANOVA and Turkey's post hoc test.. The results showed that the ileum contraction was induced by KCl and acetylcholine induced contraction was significantly reduced by A. millefolium extract. The cumulative concentrations of A. millefolium relaxed the KCl and acetylcholine induced contractions (n=14, p<0.001). The inhibitory effect of extract on contraction induced by KCl and acetylcholine was not significantly affected neither by propranolol (1μM) nor by L-NAME (100 μM). There was no significant difference in the rate of relaxation by propranolol and L-NAME between the two groups. In conclusion, A. millefolium can inhibit contraction of smooth muscle of ileum in rat, and it can be used for eliminating intestinal spasms. These results suggest that the relaxatory effect of A. millefolium on ileum contractions can be due to the blockade of voltage dependent calcium channels. In addition, the β-adrenoceptors, cholinergic receptors and nitric oxide production are not powerful actors in inhibitory effect of A. millefolium. So, the nitric oxide and adrenergic systems may also be involved in the antispasmodic effect of A. millefolium.

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Impaired acetylcholine-induced smooth muscle contraction in colitis involves altered calcium mobilization and AKT phosphorylation

Cited by 4 publications

References 36 publications

Proliferation modulates intestinal smooth muscle phenotype in vitro and in colitis in vivo

Proliferation modulates intestinal smooth muscle phenotype in vitro and in colitis in vivo

7,8‐dihydroxyflavone enhanced cholinergic contraction of rat gastric smooth muscle via augmenting muscarinic M3 receptor expression

Antispasmodic effects of yarrow (<i>Achillea millefolium l</i>.) extract in the isolated ileum of rat

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