PT  - JOURNAL ARTICLE
AU  - Arpad Lux
AU  - Peter Pokreisz
AU  - Melissa Swinnen
AU  - Ellen Caluwe
AU  - Hilde Gillijns
AU  - Zsolt Szelid
AU  - Bela Merkely
AU  - Stefan P. Janssens
TI  - Concomitant phosphodiesterase 5-inhibition enhances myocardial protection of inhaled nitric oxide in ischemia-reperfusion injury
AID  - 10.1124/jpet.115.227850
DP  - 2015 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.115.227850
4099  - http://jpet.aspetjournals.org/content/early/2015/11/30/jpet.115.227850.short
4100  - http://jpet.aspetjournals.org/content/early/2015/11/30/jpet.115.227850.full
AB  - Enhanced cyclic guanosine monophosphate (cGMP) signaling may attenuate myocardial ischemia reperfusion injury (I/R) and improve LV functional recovery after myocardial infarction (MI). We investigated cardioprotection of inhaled NO (iNO), the phosphodiesterase 5-specific inhibitor, tadalafil (TAD), or the combination (iNO+TAD) in C57Bl6J mice subjected to 6min LAD 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 to untreated mice (CON), only iNO+TAD increased plasma and cardiac cGMP-levels during early reperfusion (80±12 vs 36±6pmol/mL and 0.15±0.02 vs 0.05±0.01pmol/mg protein, P<0.05 for both). Moreover, iNO+TAD reduced TnI at 4h to a greater extent (P<0.001 vs CON) than either alone (P<0.05 vs CON) and was associated with significantly less myocardial inflammatory cell infiltration at day 3. After 4 weeks and compared to CON, iNO+TAD was associated with increased fractional shortening (43±1 vs 33±2%, P<0.01), larger stroke volumes (14.9±1.2 vs 10.2±0.9μL, P<0.05), enhanced septal and posterior wall thickening (P<0.05 and P<0.001, respectively) and attenuated LV dilatation (P<0.001), while 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.