PMID- 23551931
OWN - NLM
STAT- MEDLINE
DCOM- 20131023
LR  - 20211021
IS  - 1365-2982 (Electronic)
IS  - 1350-1925 (Print)
IS  - 1350-1925 (Linking)
VI  - 25
IP  - 5
DP  - 2013 May
TI  - Heme deficiency of soluble guanylate cyclase induces gastroparesis.
PG  - e339-52
LID - 10.1111/nmo.12120 [doi]
AB  - 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: sGCbeta1 (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.
CI  - (c) 2013 Blackwell Publishing Ltd.
FAU - Cosyns, S M R
AU  - Cosyns SM
AD  - Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
FAU - Dhaese, I
AU  - Dhaese I
FAU - Thoonen, R
AU  - Thoonen R
FAU - Buys, E S
AU  - Buys ES
FAU - Vral, A
AU  - Vral A
FAU - Brouckaert, P
AU  - Brouckaert P
FAU - Lefebvre, R A
AU  - Lefebvre RA
LA  - eng
GR  - R01 EY022746/EY/NEI NIH HHS/United States
GR  - R01 HL070896/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130328
PL  - England
TA  - Neurogastroenterol Motil
JT  - Neurogastroenterology and motility
JID - 9432572
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 42VZT0U6YR (Heme)
RN  - EC 4.6.1.2 (Guanylate Cyclase)
RN  - EC 4.6.1.2 (Soluble Guanylyl Cyclase)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Gastric Mucosa/metabolism
MH  - Gastrointestinal Motility/*physiology
MH  - Gastroparesis/*metabolism
MH  - Gene Knock-In Techniques
MH  - Guanylate Cyclase/chemistry/*metabolism
MH  - Heme/*deficiency
MH  - Mice
MH  - Nitric Oxide/metabolism/pharmacology
MH  - Oxidative Stress/physiology
MH  - Receptors, Cytoplasmic and Nuclear/chemistry/*metabolism
MH  - Soluble Guanylyl Cyclase
PMC - PMC4932850
MID - NIHMS797807
COIS- CONFLICT OF INTEREST The authors have no disclosures relevant to this subject or 
      any conflicts of interest.
EDAT- 2013/04/05 06:00
MHDA- 2013/10/24 06:00
PMCR- 2016/07/05
CRDT- 2013/04/05 06:00
PHST- 2012/10/01 00:00 [received]
PHST- 2013/02/27 00:00 [accepted]
PHST- 2013/04/05 06:00 [entrez]
PHST- 2013/04/05 06:00 [pubmed]
PHST- 2013/10/24 06:00 [medline]
PHST- 2016/07/05 00:00 [pmc-release]
AID - 10.1111/nmo.12120 [doi]
PST - ppublish
SO  - Neurogastroenterol Motil. 2013 May;25(5):e339-52. doi: 10.1111/nmo.12120. Epub 
      2013 Mar 28.