title: Influence of cinaciguat on gastrointestinal motility in apo-sGC mice.
abstract: BACKGROUND
  Cinaciguat (BAY 58-2667), an NO- and heme-independent sGC activator, was shown to be more effective when the heme-group of sGC is oxidized in vascular tissue. In apo-sGC mice (sGCβ1 (His105Phe) knockin) both sGC isoforms (sGCα1 β1 and sGCα2 β1 ) are heme-deficient and can no longer be activated by NO; these mice, showing decreased gastrointestinal nitrergic relaxation and decreased gastric emptying, can be considered as a model to study the consequence of heme-oxidation in sGC. Our aim was to compare the influence of cinaciguat, on in vitro muscle tone of gastrointestinal tissues, and on gastric emptying in WT and apo-sGC mice.
  
  
  METHODS
  Gastrointestinal smooth muscle strips were mounted in organ baths for isometric force recording and cGMP levels were determined by enzyme immunoassay. Protein levels of sGC subunits were assessed by immunoblotting. Gastric emptying was determined by phenol red recovery.
  
  
  RESULTS
  Although protein levels of the sGC subunits were lower in gastrointestinal tissues of apo-sGC mice, cinaciguat induced concentration-dependent relaxations and increased cGMP levels in apo-sGC fundus and colon to a similar or greater extent than in WT mice. The sGC inhibitor ODQ increased cinaciguat-induced relaxations and cGMP levels in WT fundus and colon. In apo-sGC antrum, pylorus and jejunum, cinaciguat was not able to induce relaxations. Cinaciguat did not improve delayed gastric emptying in apo-sGC mice.
  
  
  CONCLUSIONS
  Cinaciguat relaxes the fundus and colon efficiently when sGC is in the heme-free condition; the non-effect of cinaciguat in pylorus explains its inability to improve the delayed gastric emptying in apo-sGC mice.
authors.affiliation: Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
authors.forename: Sarah M R
authors.initials: SM
authors.lastname: Cosyns
authors.forename: Leander
authors.initials: L
authors.lastname: Huyghe
authors.forename: Robrecht
authors.initials: R
authors.lastname: Thoonen
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.forename: Romain A
authors.initials: RA
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005748:Gastric Fundus / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology*; D055879:Gene Knock-In Techniques; D006162:Guanylate Cyclase / Q000378:metabolism*; D015151:Immunoblotting; D007527:Isoenzymes; D008297:Male; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques
chemical_list: D001565:Benzoates; D007527:Isoenzymes; C480588:BAY 58-2667; D006162:Guanylate Cyclase
keywords: BAY 58-2667; cinaciguat; gastric emptying; gastrointestinal motility; soluble guanylate cyclase; stomach