title: Heme deficiency of soluble guanylate cyclase induces gastroparesis.
abstract: BACKGROUND
  Soluble guanylate cyclase (sGC) is the principal target of nitric oxide (NO) to control gastrointestinal motility. The consequence on nitrergic signaling and gut motility of inducing a heme-free status of sGC, as induced by oxidative stress, was investigated.
  
  
  METHODS
  sGCβ1 (H105F) knock-in (apo-sGC) mice, which express heme-free sGC that has basal activity, but cannot be stimulated by NO, were generated.
  
  
  RESULTS
  Diethylenetriamine NONOate did not increase sGC activity in gastrointestinal tissue of apo-sGC mice. Exogenous NO did not induce relaxation in fundic, jejunal and colonic strips, and pyloric rings of apo-sGC mice. The stomach was enlarged in apo-sGC mice with hypertrophy of the muscularis externa of the fundus and pylorus. In addition, gastric emptying and intestinal transit were delayed and whole-gut transit time was increased in the apo-sGC mice, while distal colonic transit time was maintained. The nitrergic relaxant responses to electrical field stimulation at 1-4 Hz were abolished in fundic and jejunal strips from apo-sGC mice, but in pyloric rings and colonic strips, only the response at 1 Hz was abolished, indicating the contribution of other transmitters than NO.
  
  
  CONCLUSIONS
  The results indicate that the gastrointestinal consequences of switching from a native sGC to a heme-free sGC, which cannot be stimulated by NO, are most pronounced at the level of the stomach establishing a pivotal role of the activation of sGC by NO in normal gastric functioning. In addition, delayed intestinal transit was observed, indicating that nitrergic activation of sGC also plays a role in the lower gastrointestinal tract.
authors.affiliation: Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
authors.forename: S M R
authors.initials: SM
authors.lastname: Cosyns
authors.forename: I
authors.initials: I
authors.lastname: Dhaese
authors.forename: R
authors.initials: R
authors.lastname: Thoonen
authors.forename: E S
authors.initials: ES
authors.lastname: Buys
authors.forename: A
authors.initials: A
authors.lastname: Vral
authors.forename: P
authors.initials: P
authors.lastname: Brouckaert
authors.forename: R A
authors.initials: RA
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005753:Gastric Mucosa / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000502:physiology*; D018589:Gastroparesis / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism*; D006418:Heme / Q000172:deficiency*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
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