Smooth muscle cholinergic denervation hypersensitivity in diverticular disease

Golder, Mark; Burleigh, David; Belai, Abebech; Ghali, Lucy; Ashby, Deborah; Lunniss, Peter J.; Navsaria, Harry A; Williams, Norman S.

doi:10.1016/s0140-6736(03)13583-0

Cited by 119 publications

(89 citation statements)

References 23 publications

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“…note, compensatory increments of muscarinic receptor density, as a consequence of cholinergic denervation, have been previously described in the colons of patients with diverticular disease, where cholinergic denervation and related motor abnormalities of isolated colonic muscle were associated with an upregulation of muscular muscarinic M3 receptors (Golder et al, 2003). Overall, it is conceivable that the lowering of colonic transit in 6-OHDA rats depends, at least in part, on the impairment of cholinergic enteric neurotransmission.…”

Section: Discussionmentioning

confidence: 66%

Enteric Dysfunctions in Experimental Parkinsons Disease: Alterations of Excitatory Cholinergic Neurotransmission Regulating Colonic Motility in Rats

Fornai

Pellegrini

Antonioli

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Parkinson's disease is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiologic assay. Electrically induced and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, whereas acetylcholine levels were assayed in the incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors were assessed by immunohistochemistry or western blot assay. As compared with control rats, at week 4, 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate, impaired electrically evoked neurogenic cholinergic contractions, enhanced carbachol-induced contractions, decreased basal and electrically stimulated acetylcholine release from colonic tissues, decreased ChAT immunopositivity in the neuromuscular layer, unchanged density of HuC/D immunoreactive myenteric neurons, and increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were also detected at week 8 post 6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate.

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Section: Discussionmentioning

confidence: 66%

Enteric Dysfunctions in Experimental Parkinsons Disease: Alterations of Excitatory Cholinergic Neurotransmission Regulating Colonic Motility in Rats

Fornai

Pellegrini

Antonioli

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Fortunately, recent studies contradict this finding [21] , and this work may have been confounded by the morphological distortions associated with the colon shortening in DD. Golder et al [51] show histological evidence for decreased nerve content of longitudinal muscle in DD as evidenced by reduced prostaglandin immunoreactivity. They have also found that individual nerve fibers were smaller in cases vs controls and were less likely to stain positively for choline acetyltransferase [52] and NOS 1 [51] , suggestive of cholinergic and nitrergic denervation in these samples.…”

Section: Electrophysiology and Neuromuscular Dysfunctionmentioning

confidence: 98%

“…Golder et al [51] show histological evidence for decreased nerve content of longitudinal muscle in DD as evidenced by reduced prostaglandin immunoreactivity. They have also found that individual nerve fibers were smaller in cases vs controls and were less likely to stain positively for choline acetyltransferase [52] and NOS 1 [51] , suggestive of cholinergic and nitrergic denervation in these samples. Again the primary potential confounder to these studies is the fact that the colon shortens, and that the muscle layers become thicker (due to elastin and collagen deposition), in DD; it is not clear as to how the authors have controlled for this.…”

Section: Electrophysiology and Neuromuscular Dysfunctionmentioning

confidence: 98%

Diet, ageing and genetic factors in the pathogenesis of diverticular disease

Commane¹,

Arasaradnam²,

Mills³

et al. 2009

WJG

115

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Diverticular disease (DD) is an age-related disorder of the large bowel which may affect half of the population over the age of 65 in the UK. This high prevalence ranks it as one of the most common bowel disorders in western nations. The majority of patients remain asymptomatic but there are associated life-threatening co-morbidities, which, given the large numbers of people with DD, translates into a considerable number of deaths per annum. Despite this public health burden, relatively little seems to be known about either the mechanisms of development or causality. In the 1970s, a model of DD formulated the concept that diverticula occur as a consequence of pressureinduced damage to the colon wall amongst those with a low intake of dietary fiber. In this review, we have examined the evidence regarding the influence of ageing, diet, inflammation and genetics on DD development. We argue that the evidence supporting the barotrauma hypothesis is largely anecdotal. We have also identified several gaps in the knowledge base which need to be filled before we can complete a model for the etiology of diverticular disease.

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“…Additional examples of diseases associated with alternations in SMC function include asthma (195), obstructive bladder disease (142), and numerous gastrointestinal and reproductive disorders (76). Although the precise role of the SMC in the initial cause of these diseases is controversial, there is clear evidence that the plethora of changes that occur play a key role in the clinical consequences of these diseases.…”

Section: Introduction: Phenotypic Modulation/ Switching Of the Smomentioning

confidence: 99%

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

Owens

Kumar²,

Wamhoff³

2004

Physiological Reviews

2,930

3,134

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The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

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Smooth muscle cholinergic denervation hypersensitivity in diverticular disease

Cited by 119 publications

References 23 publications

Enteric Dysfunctions in Experimental Parkinsons Disease: Alterations of Excitatory Cholinergic Neurotransmission Regulating Colonic Motility in Rats

Enteric Dysfunctions in Experimental Parkinsons Disease: Alterations of Excitatory Cholinergic Neurotransmission Regulating Colonic Motility in Rats

Diet, ageing and genetic factors in the pathogenesis of diverticular disease

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

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