Abstract 102: Differential Effects of NOS Inhibition on CPR Outcomes in Pigs
Background: Nitric oxide is produced by three nitric oxide synthases (NOS) isoforms. Inducible NOS (iNOS) is produced primarily after stimulation by cytokines or inflammatory mediators, endothelial derived (eNOS) is constitutively expressed, and neuronal NOS (nNOS) is constitutively expressed in the heart and neural tissue. Cardiopulmonary resuscitation (CPR) is a model of whole body ischemia reperfusion injury in which NO plays a pivotal role. We investigated three NOS isoforms during CPR by selective and non-selective inhibition of NOS in pigs. We hypothesized that inhibition of the NOS isoforms would yield different effects on CPR outcomes. Further, we investigated whether inhibition of any NOS isoform has cardioprotective effects in this model.
Methods: Thirty-two anesthetized pigs (27.6 ± 3.4 kg) were monitored for hemodynamics and echocardiographic parameters. Thirty min after NOS inhibitor or placebo administration, ventricular fibrillation (VF) was induced and was untreated for 3 min, followed by closed chest CPR using Thumper® for 15 min. After 18 min of VF, defibrillation was attempted. Four groups were studied:
L-NAME (non-selective NOS inhibitor).
Aminoguanidine (AG) (iNOS selective inhibitor) and
TRIM, (nNOS selective inhibitor).
Results: ROSC to 180 min occurred in 5/8 controls, 1/8 L-NAME, 6/8 AG, and 0/8 TRIM animals. There were no significant differences in hemodynamics or regional blood flow at baseline and during CPR between groups. AG treated animals had significantly better fractional shortening (%FS) ejection fraction (% EF) and wall motion score index (WMSI). X±(SD) *p < 0.05 AG vs other groups.
Conclusion: eNO and nNO show predominantly protective effects while iNO is detrimental in CPR. iNOS inhibition may offer cardioprotection in CPR. Whether similar results will be obtained for humans in cardiogenic shock given a non selective NOS inhibitor remains to be studied in the ongoing TRIUMPH trial.