Concomitant Phosphodiesterase 5 Inhibition Enhances Myocardial Protection by Inhaled Nitric Oxide in Ischemia-Reperfusion Injury

• DOI: 10.1124/jpet.115.227850
• Publication Date: 2015-12-01T04:15:14Z
• Authors: Arpad Lux; Peter Pokreisz; Melissa Swinnen; Ellen Caluwe; Hilde Gillijns; Zsolt Szelid; Bela Merkely; Stefan P. Janssens
• Keywords: Concomitant

Enhanced cyclic guanosine monophosphate (cGMP) signaling may attenuate myocardial ischemia-reperfusion injury (I/R) and improve left ventricular (LV) functional recovery after infarction (MI). We investigated the cardioprotection afforded by inhaled NO (iNO), phosphodiesterase 5 (PDE5)-specific inhibitor tadalafil (TAD), or their combination (iNO+TAD) in C57Bl6J mice subjected to 6-minute anterior descending artery ligation followed reperfusion. measured plasma cardiac concentrations of cGMP during early reperfusion, quantified necrosis inflammation serial troponin-I (TnI) myeloperoxidase-positive cell infiltration at day 3, evaluated LV function remodeling 4 weeks using echocardiography pressure-conductance catheterization. Administration iNO, TAD, both I/R was safe hemodynamically well tolerated. Compared with untreated (CON), only iNO+TAD increased cardiac-cGMP levels reperfusion (80 ± 12 versus 36 6 pmol/ml 0.15 0.02 0.05 0.01 pmol/mg protein, <i>P</i> &lt; for both). Moreover, reduced TnI hours a greater extent (<i>P</i> 0.001 CON) than either alone associated significantly less inflammatory 3. After compared CON, fractional shortening (43 1 33 2%, 0.01), larger stroke volumes (14.9 1.2 10.2 0.9 <i>μ</i>l, 0.05), enhanced septal posterior wall thickening 0.001, respectively), attenuated dilatation 0.001), whereas iNO TAD conferred benefit. Thus, has superior efficacy limit adverse remodeling. Combination long-acting PDE5 represent promising strategy reduce ischemic damage following better preserve function.