Smooth muscle cholinergic denervation hypersensitivity in diverticular disease.

Hdl Handle:
http://hdl.handle.net/10142/92736
Title:
Smooth muscle cholinergic denervation hypersensitivity in diverticular disease.
Authors:
Golder, Mark; Burleigh, David E.; Belai, A.; Ghali, Lucy; Ashby, Deborah; Lunniss, Peter J.; Navsaria, Harry A.; Williams, Norman S.
Abstract:
Evidence from clinical and laboratory investigations into the causes of diverticular disease suggests that disturbances in cholinergic activity are important, the effector mechanisms of which have yet to be established. We aimed to investigate the role of smooth muscle and neural cholinergic activity in the pathogenesis of this disease. METHODS: Two investigators independently did a blinded immunohistochemical image analysis of localising antibodies to choline acetyltransferase, co-localised with protein gene product (PGP)--a marker of general neural tissue-and smooth muscle muscarinic M3 receptors, on three histological sections of sigmoid colons from ten patients with diverticular disease and ten controls, after resections for rectal tumours. We also did isotonic organ bath experiments to assess muscle strip sensitivities to exogenous acetylcholine. FINDINGS: In circular muscle, activity of choline acetyltransferase was lower in patients with diverticular disease than in controls: median percentage surface area of choline acetyltransferase over PGP was 17.5% (range 10.0-37.0) in patients with diverticular disease and 47.0% (29.0-54.0) in controls (p<0.0001). M3 receptors were upregulated in patients with diverticular disease compared with controls: the median surface area was 13.2% (6.0-23.3) in patients with diverticular disease and 2.5% (1.6-3.7) in controls (p<0.0001). The sensitivity to exogenous acetylcholine was increased in patients with diverticular disease (mean -log EC(50) 5.6 [SD 0.3]) compared with controls (4.9 [0.5]; difference 0.7 [95% CI 0.3-1.1], p=0.006). In longitudinal muscle, choline acetyltransferase activity was lower in patients with diverticular disease (median 19.5%, range 12.0-30.0) than in controls (47.0%, 35.0-60.0; p<0.0001), with upregulation of M3 receptors in diverticular disease (diverticular disease 7.8% [1.9-20.4], controls 1.7% [0.8-3.0]; p<0.0001). However, sensitivity to exogenous acetylcholine did not differ between the two groups (diverticular disease mean 5.6% [SD 0.3], controls 5.2% [0.4]; difference 0.4% [95% CI -0.02-0.7], p=0.06). Our results suggest that cholinergic denervation hypersensitivity can affect smooth muscle. Upregulation of smooth muscle M3 receptors might account for specific clinical, physiological, and pharmacological abnormalities associated with diverticular disease.
Citation:
Smooth muscle cholinergic denervation hypersensitivity in diverticular disease. 2003, 361 (9373):1945-51 Lancet
Journal:
Lancet
Issue Date:
7-Jun-2003
URI:
http://hdl.handle.net/10142/92736
DOI:
10.1016/S0140-6736(03)13583-0
PubMed ID:
12801738
Type:
Article
Language:
en
ISSN:
0140-6736
Appears in Collections:
Department of Life Sciences Collection

Full metadata record

DC FieldValue Language
dc.contributor.authorGolder, Marken
dc.contributor.authorBurleigh, David E.en
dc.contributor.authorBelai, A.en
dc.contributor.authorGhali, Lucyen
dc.contributor.authorAshby, Deborahen
dc.contributor.authorLunniss, Peter J.en
dc.contributor.authorNavsaria, Harry A.en
dc.contributor.authorWilliams, Norman S.en
dc.date.accessioned2010-02-23T11:09:30Z-
dc.date.available2010-02-23T11:09:30Z-
dc.date.issued2003-06-07-
dc.identifier.citationSmooth muscle cholinergic denervation hypersensitivity in diverticular disease. 2003, 361 (9373):1945-51 Lanceten
dc.identifier.issn0140-6736-
dc.identifier.pmid12801738-
dc.identifier.doi10.1016/S0140-6736(03)13583-0-
dc.identifier.urihttp://hdl.handle.net/10142/92736-
dc.description.abstractEvidence from clinical and laboratory investigations into the causes of diverticular disease suggests that disturbances in cholinergic activity are important, the effector mechanisms of which have yet to be established. We aimed to investigate the role of smooth muscle and neural cholinergic activity in the pathogenesis of this disease. METHODS: Two investigators independently did a blinded immunohistochemical image analysis of localising antibodies to choline acetyltransferase, co-localised with protein gene product (PGP)--a marker of general neural tissue-and smooth muscle muscarinic M3 receptors, on three histological sections of sigmoid colons from ten patients with diverticular disease and ten controls, after resections for rectal tumours. We also did isotonic organ bath experiments to assess muscle strip sensitivities to exogenous acetylcholine. FINDINGS: In circular muscle, activity of choline acetyltransferase was lower in patients with diverticular disease than in controls: median percentage surface area of choline acetyltransferase over PGP was 17.5% (range 10.0-37.0) in patients with diverticular disease and 47.0% (29.0-54.0) in controls (p<0.0001). M3 receptors were upregulated in patients with diverticular disease compared with controls: the median surface area was 13.2% (6.0-23.3) in patients with diverticular disease and 2.5% (1.6-3.7) in controls (p<0.0001). The sensitivity to exogenous acetylcholine was increased in patients with diverticular disease (mean -log EC(50) 5.6 [SD 0.3]) compared with controls (4.9 [0.5]; difference 0.7 [95% CI 0.3-1.1], p=0.006). In longitudinal muscle, choline acetyltransferase activity was lower in patients with diverticular disease (median 19.5%, range 12.0-30.0) than in controls (47.0%, 35.0-60.0; p<0.0001), with upregulation of M3 receptors in diverticular disease (diverticular disease 7.8% [1.9-20.4], controls 1.7% [0.8-3.0]; p<0.0001). However, sensitivity to exogenous acetylcholine did not differ between the two groups (diverticular disease mean 5.6% [SD 0.3], controls 5.2% [0.4]; difference 0.4% [95% CI -0.02-0.7], p=0.06). Our results suggest that cholinergic denervation hypersensitivity can affect smooth muscle. Upregulation of smooth muscle M3 receptors might account for specific clinical, physiological, and pharmacological abnormalities associated with diverticular disease.en
dc.description.provenanceSubmitted by Abi Belai (a.belai@roehampton.ac.uk) on 2010-02-22T11:12:21Z No. of bitstreams: 0en
dc.description.provenanceApproved for entry into archive by Emily Selvidge(e.selvidge@roehampton.ac.uk) on 2010-02-23T11:09:29Z (GMT) No. of bitstreams: 0en
dc.description.provenanceMade available in DSpace on 2010-02-23T11:09:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2003-06-07en
dc.language.isoenen
dc.subject.meshAcetylcholine-
dc.subject.meshAged-
dc.subject.meshAged, 80 and over-
dc.subject.meshAntibodies-
dc.subject.meshCase-Control Studies-
dc.subject.meshCholine O-Acetyltransferase-
dc.subject.meshColon, Sigmoid-
dc.subject.meshDiverticulum, Colon-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMuscle, Smooth-
dc.subject.meshNerve Tissue Proteins-
dc.subject.meshReceptor, Muscarinic M3-
dc.subject.meshReceptors, Muscarinic-
dc.subject.meshUp-Regulation-
dc.titleSmooth muscle cholinergic denervation hypersensitivity in diverticular disease.en
dc.typeArticleen
dc.identifier.journalLanceten

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