title: sGC-cGMP-PKG pathway stimulation protects the healthy but not the failing right ventricle of rats against ischemia and reperfusion injury.
abstract: BACKGROUND
  To investigate whether modulation of the sGC-cGMP-PKG pathway protects against ischemia and reperfusion injury in the healthy and the failing right ventricle (RV).
  
  
  METHODS
  Hearts from male Wistar rats with a healthy RV (n=39) or a hypertrophic and failing RV induced by pulmonary trunk banding (n=57) were isolated and perfused in a pressure-controlled modified Langendorff setup. The isolated hearts were randomized to control, ischemic preconditioning (IPC, 2×5min of global ischemia), a phosphodiesterase-5 (PDE5) inhibitor vardenafil (66nM) alone and in combination with a cGMP-dependent protein kinase (PKG) blocker KT 5823 (1μM). Failing hearts were exposed to the same protocols and to soluble guanylate cyclase stimulation/activation, and phosphodiesterase 9 inhibition. All interventions were followed by 40min of global ischemia and 120min of reperfusion. The effects on the RV were evaluated by measurement of the infarct size/area-at-risk ratio (IS/AAR).
  
  
  RESULTS
  In healthy hearts, IPC and pharmacological preconditioning with vardenafil reduced RV infarct size. PKG blockade by KT-5823 did not alter infarct size per se but abolished the cardioprotective effect of vardenafil. In the hypertrophic and failing hearts, none of the conditioning strategies altered RV infarct size.
  
  
  CONCLUSIONS
  PDE-5 inhibition by vardenafil protects the healthy right ventricle against ischemia and reperfusion injury by a PKG dependent mechanism. Neither ischemic preconditioning nor pharmacologic stimulation of the sGC-cGMP-PKG pathway induces cardioprotection in the hypertrophic and failing RV.
authors: Department of Cardiology - Research, Clinical Institute, Aarhus University Hospital, Skejby, Denmark. Electronic address: asger.andersen@clin.au.dk.
authors: Asger
authors: A
authors: Andersen
authors: Department of Cardiology - Research, Clinical Institute, Aarhus University Hospital, Skejby, Denmark.
authors: Jonas Agerlund
authors: JA
authors: Povlsen
authors: Department of Cardiology - Research, Clinical Institute, Aarhus University Hospital, Skejby, Denmark.
authors: Jacob
authors: J
authors: Johnsen
authors: Department of Cardiology - Research, Clinical Institute, Aarhus University Hospital, Skejby, Denmark.
authors: Nichlas Riise
authors: NR
authors: Jespersen
authors: Department of Cardiology - Research, Clinical Institute, Aarhus University Hospital, Skejby, Denmark.
authors: Hans Erik
authors: HE
authors: Bøtker
authors: Department of Cardiology - Research, Clinical Institute, Aarhus University Hospital, Skejby, Denmark.
authors: Jens Erik
authors: JE
authors: Nielsen-Kudsk
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D002227:Carbazoles; D047428:Protein Kinase Inhibitors; C073601:KT 5823; D017869:Cyclic GMP-Dependent Protein Kinases
keywords: Cardioprotection; Heart failure; Ischemia reperfusion injury; NO/cGMP-pathway; Right ventricle