title: Effects of soluble guanylate cyclase activation on heart transplantation in a rat model.
abstract: BACKGROUND
  The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is an important key mechanism to protect the heart from ischemia/reperfusion injury. However, this pathway is disrupted in several cardiovascular diseases as a result of decreased NO bioavailability and increased NO-insensitive forms of sGC. Cinaciguat preferentially activates these NO-insensitive, oxidized forms of sGC.
  
  
  METHODS
  We assessed the hypothesis that targeting NO-unresponsive sGC would protect the graft against ischemia/reperfusion injury in a rat heart transplantation model. Before explantation, donor Lewis rats received methylcellulose (1%) vehicle or cinaciguat 10 mg/kg. The hearts were excised, stored in cold preservation solution, and heterotopically transplanted. We evaluated in vivo left ventricular function of the graft.
  
  
  RESULTS
  After transplantation, decreased left ventricular systolic pressure (77 ± 3 mm Hg vs 123 ± 13 mm Hg, p < 0.05), dP/dt(max) (1,703 ± 162 mm Hg vs 3,350 ± 444 mm Hg, p < 0.05), and dP/dt(min) (995 ± 110 mm Hg vs 1,925 ± 332 mm Hg, p < 0.05) were significantly increased by cinaciguat. Coronary blood flow was significantly higher in the cinaciguat group compared with the control group. Additionally, cinaciguat increased adenosine triphosphate levels (1.9 ± 0.4 µmol/g vs 6.6 ± 0.8 µmol/g, p < 0.05) and improved energy charge potential. After transplantation, increased c-jun messenger RNA expression was downregulated, whereas superoxide dismutase-1 and cytochrome-c oxidase mRNA levels were upregulated by cinaciguat. Cinaciguat also significantly decreased myocardial DNA strand breaks induced by ischemia/reperfusion during transplantation and reduced death of cardiomyocytes in a cellular model of oxidative stress.
  
  
  CONCLUSIONS
  By interacting with NO-unresponsive sGC, cinaciguat enhances the protective effects of the NO/cGMP pathway at different steps of signal transduction after global myocardial ischemia/reperfusion. Its clinical use as pre-conditioning agent could be a novel approach in cardiac surgery.
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany; Department of Anesthesiology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. Electronic address: sivakkanan@gmail.com.
authors.forename: Sivakkanan
authors.initials: S
authors.lastname: Loganathan
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sevil
authors.initials: S
authors.lastname: Korkmaz-Icöz
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Radovits
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Mikles
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Enikő
authors.initials: E
authors.lastname: Barnucz
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Kristóf
authors.initials: K
authors.lastname: Hirschberg
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
mesh_terms: D000818:Animals; D001565:Benzoates / Q000627:therapeutic use*; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000502:physiology*; D016027:Heart Transplantation / Q000009:adverse effects*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D019172:Transplantation Conditioning; D016277:Ventricular Function, Left
chemical_list: D001565:Benzoates; D018160:Receptors, Cytoplasmic and Nuclear; C480588:BAY 58-2667; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
keywords: cinaciguat; heart transplantation; ischemia/reperfusion; nitric oxide; soluble guanylate cyclase; soluble guanylate cyclase activation