Abstract 19898: Systemic Nitroglycerin Administration Mitigates the Protective Effects of Inhaled Nitric Oxide During Cardiac Ischemia-Reperfusion

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Introduction: Inhaled nitric oxide (iNO) reduces infarct size during experimental myocardial ischemia-reperfusion (I/R). Concomitant intra-arterial administration of nitroglycerin (NTG) during percutaneous coronary intervention offsets the benefit of iNO in STEMI patients. In the absence of specific STEMI guidelines on pharmacological NO-donor use, we studied the interaction between NTG and iNO in porcine myocardial I/R.

Methods: Myocardial ischemia was induced by 50 min balloon occlusion of the mid LAD followed by 4 h R. Pigs were randomized to receive iNO (80 ppm for 4 h) mixed in 50% O2 10 min before balloon deflation with or without intra-arterial bolus of 0.5 mg NTG and 2.5 mg verapamil (iNONTG n=8 and iNO n=9) or NTG alone (0.5mg bolus, n=6) 5 min before R. Control pigs (CON, n=8) received 50% O2. Oxidative NO-species, NOx, were measured in arterial and coronary sinus plasma at baseline, after 40 min LAD occlusion, and at 5 and 240 min R. Infarct size (IS, % LV mass) and extent of microvascular obstruction (MVO, % LV mass) were assessed using MRI.

Results: Plasma NOx and its myocardial gradients significantly increased after 4 h R in iNO and iNONTG (p < 0.01), but not in NTG alone (Figure 1A). IS was smaller in iNO than in NTG (18±10% vs 33±6% respectively, P<0.05, n=4 for both) and significantly correlated with cardiac necrosis markers (total CK and TnT, R=0.63, P<0.01 and R=0.5, P<0.05 respectively). Cardioprotection was not observed with iNONTG (IS 25±7% vs 27±6% in CON). MVO tended to decrease with iNO (1.6±3% vs 15±10% in CON, P=0.15, n=4 for both) and was associated with lower hemorrhage on H&E-stained infarct sections (R=0.87, P<0.01). The secondary messenger cGMP transiently increased at 5 min R in iNO with or without NTG, but not in CON or NTG only (Figure 1B).

Conclusions: iNO, but not NTG increased NOx and cGMP levels during I/R and reduced infarct size and cardiac necrosis markers. NTG partially blunted the beneficial effects of iNO and warrants further studies in clinical I/R.

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