title: Smooth muscle cholinergic denervation hypersensitivity in diverticular disease.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Academic Department of Surgery, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK. m.s.golder@qmul.ac.uk <m.s.golder@qmul.ac.uk>
authors.forename: Mark
authors.initials: M
authors.lastname: Golder
authors.forename: David E
authors.initials: DE
authors.lastname: Burleigh
authors.forename: Abi
authors.initials: A
authors.lastname: Belai
authors.forename: Lucy
authors.initials: L
authors.lastname: Ghali
authors.forename: Deborah
authors.initials: D
authors.lastname: Ashby
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lunniss
authors.forename: Harry A
authors.initials: HA
authors.lastname: Navsaria
authors.forename: Norman S
authors.initials: NS
authors.lastname: Williams
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies; D016022:Case-Control Studies; D002795:Choline O-Acetyltransferase / Q000276:immunology / Q000378:metabolism*; D012809:Colon, Sigmoid / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D004241:Diverticulum, Colon / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000201:enzymology / Q000294:innervation / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000276:immunology; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000906:Antibodies; C029152:G-substrate; D009419:Nerve Tissue Proteins; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine