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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 356; no. 2; p. 284
• Main Authors: Lux, Arpad, Pokreisz, Peter, Swinnen, Melissa, Caluwe, Ellen, Gillijns, Hilde, Szelid, Zsolt, Merkely, Bela, Janssens, Stefan P
• Format: Journal Article
• Language: English
• Published: United States 01-02-2016
• Subjects: Administration, Inhalation; Animals; Cardiotonic Agents - administration & dosage; Drug Therapy, Combination; Male; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury - diagnostic imaging; Myocardial Reperfusion Injury - prevention & control; Nitric Oxide - administration & dosage; Phosphodiesterase 5 Inhibitors - administration & dosage; Ultrasonography
• ISSN: 1521-0103
• DOI: 10.1124/jpet.115.227850

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.