sGC-cGMP-PKG pathway stimulation protects the healthy but not the failing right ventricle of rats against ischemia and reperfusion injury

BackgroundTo investigate whether modulation of the sGC-cGMP-PKG pathway protects against ischemia and reperfusion injury in the healthy and the failing right ventricle (RV).MethodsHearts 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 × 5 min of global ischemia), a phosphodiesterase-5 (PDE5) inhibitor vardenafil (66 nM) alone and in combination with a cGMP-dependent protein kinase (PKG) blocker KT 5823 (1 μM). Failing hearts were exposed to the same protocols and to soluble guanylate cyclase stimulation/activation, and phosphodiesterase 9 inhibition. All interventions were followed by 40 min of global ischemia and 120 min of reperfusion. The effects on the RV were evaluated by measurement of the infarct size/area-at-risk ratio (IS/AAR).ResultsIn 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.ConclusionPDE-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.