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Neurogastroenterol Motil. 2013 May;25(5):e339-52. doi: 10.1111/nmo.12120. Epub 2013 Mar 28.

Heme deficiency of soluble guanylate cyclase induces gastroparesis.

Author information

1
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.

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.

KEY 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 & INFERENCES:

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.

PMID:
23551931
PMCID:
PMC4932850
DOI:
10.1111/nmo.12120
[Indexed for MEDLINE]
Free PMC Article

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