title: Concomitant Phosphodiesterase 5 Inhibition Enhances Myocardial Protection by Inhaled Nitric Oxide in Ischemia-Reperfusion Injury.
abstract: Enhanced cyclic guanosine monophosphate (cGMP) signaling may attenuate myocardial ischemia-reperfusion injury (I/R) and improve left ventricular (LV) functional recovery after myocardial infarction (MI). We investigated the cardioprotection afforded by inhaled NO (iNO), the phosphodiesterase 5 (PDE5)-specific inhibitor tadalafil (TAD), or their combination (iNO+TAD) in C57Bl6J mice subjected to 6-minute left anterior descending artery ligation followed by reperfusion. We measured plasma and cardiac concentrations of cGMP during early reperfusion, quantified myocardial necrosis and inflammation by serial troponin-I (TnI) and myeloperoxidase-positive cell infiltration at day 3, and evaluated LV function and remodeling after 4 weeks using echocardiography and pressure-conductance catheterization. Administration of iNO, TAD, or both during I/R was safe and hemodynamically well tolerated. Compared with untreated mice (CON), only iNO+TAD increased plasma and cardiac-cGMP levels during early reperfusion (80 ± 12 versus 36 ± 6 pmol/ml and 0.15 ± 0.02 versus 0.05 ± 0.01 pmol/mg protein, P < 0.05 for both). Moreover, iNO+TAD reduced TnI at 4 hours to a greater extent (P < 0.001 versus CON) than either alone (P < 0.05 versus CON) and was associated with significantly less myocardial inflammatory cell infiltration at day 3. After 4 weeks and compared with CON, iNO+TAD was associated with increased fractional shortening (43 ± 1 versus 33 ± 2%, P < 0.01), larger stroke volumes (14.9 ± 1.2 versus 10.2 ± 0.9 μl, P < 0.05), enhanced septal and posterior wall thickening (P < 0.05 and P < 0.001, respectively), and attenuated LV dilatation (P < 0.001), whereas iNO or TAD alone conferred less benefit. Thus, iNO+TAD has superior efficacy to limit early reperfusion injury and attenuate adverse LV remodeling. Combination of inhaled NO with a long-acting PDE5 inhibitor may represent a promising strategy to reduce ischemic damage following reperfusion and better preserve LV function.
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.L., Zs.Sz., B.M.); Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium (P.P., M.S., E.C., H.G., S.P.J.); Division of Cardiology, University Hospitals KU Leuven, Leuven, Belgium (S.P.J.).
authors.forename: Arpad
authors.initials: A
authors.lastname: Lux
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.L., Zs.Sz., B.M.); Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium (P.P., M.S., E.C., H.G., S.P.J.); Division of Cardiology, University Hospitals KU Leuven, Leuven, Belgium (S.P.J.).
authors.forename: Peter
authors.initials: P
authors.lastname: Pokreisz
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.L., Zs.Sz., B.M.); Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium (P.P., M.S., E.C., H.G., S.P.J.); Division of Cardiology, University Hospitals KU Leuven, Leuven, Belgium (S.P.J.).
authors.forename: Melissa
authors.initials: M
authors.lastname: Swinnen
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.L., Zs.Sz., B.M.); Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium (P.P., M.S., E.C., H.G., S.P.J.); Division of Cardiology, University Hospitals KU Leuven, Leuven, Belgium (S.P.J.).
authors.forename: Ellen
authors.initials: E
authors.lastname: Caluwe
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.L., Zs.Sz., B.M.); Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium (P.P., M.S., E.C., H.G., S.P.J.); Division of Cardiology, University Hospitals KU Leuven, Leuven, Belgium (S.P.J.).
authors.forename: Hilde
authors.initials: H
authors.lastname: Gillijns
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.L., Zs.Sz., B.M.); Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium (P.P., M.S., E.C., H.G., S.P.J.); Division of Cardiology, University Hospitals KU Leuven, Leuven, Belgium (S.P.J.).
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szelid
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.L., Zs.Sz., B.M.); Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium (P.P., M.S., E.C., H.G., S.P.J.); Division of Cardiology, University Hospitals KU Leuven, Leuven, Belgium (S.P.J.).
authors.forename: Bela
authors.initials: B
authors.lastname: Merkely
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.L., Zs.Sz., B.M.); Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium (P.P., M.S., E.C., H.G., S.P.J.); Division of Cardiology, University Hospitals KU Leuven, Leuven, Belgium (S.P.J.) stefan.janssens@med.kuleuven.be.
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Janssens
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging* / Q000517:prevention & control*; D009569:Nitric Oxide / Q000008:administration & dosage*; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage*; D014463:Ultrasonography
chemical_list: D002316:Cardiotonic Agents; D058986:Phosphodiesterase 5 Inhibitors; D009569:Nitric Oxide