Effect of nitric oxide synthase modulation on resuscitation success in a swine ventricular fibrillation cardiac arrest model.
BACKGROUND
We have demonstrated previously that the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine (L-NNA) decreases free radical generation and nitrosative injury via peroxynitrite formation after epicardial dc shocks.


OBJECTIVE
Our purpose was to explore the effects of NOS inhibition and NOS donation on cardiopulmonary resuscitation (CPR) success after cardiac arrest of variable duration. We used the non-selective NOS inhibitor L-NNA and the selective neuronal NOS inhibitor ARR-17477, the NOS donor S-nitroso-N-acetylpenicillamine (SNAP) and the vasodilator Enalaprilat, which lowers arterial pressure via a non-NO mechanism.


METHODS
Part I: 17 pigs undergoing 4 min supported (i.e. with closed-chest compression and ventilation) ventricular fibrillation (VF) were divided into two groups: a no-L-NNA group (n=8) receiving IV saline and an L-NNA group (n=9) receiving IV L-NNA (5 mg/kg) for 8 min before VF was induced. Part II: 35 pigs undergoing 6-8 min VF were randomized to three groups: a no-L-NNA group (n=13) receiving IV saline, an L-NNA group (n=11) receiving IV L-NNA (5 mg/kg) and an ARR17477 group (n=11) receiving IV ARR17477 (5 mg/kg) before VF. All animals in Part II underwent unsupported VF (no chest compression or ventilation) for 6 min (n=13) or 8 min (n=22); closed-chest compression, ventilation and epinephrine (adrenaline) were employed after defibrillation. Part III: 12 swine were divided into two groups: control (n=6) receiving saline and an LNNA group (n=6) receiving IV LNNA (5 mg/kg). Swine underwent 6 min unsupported VF and 2 min supported VF before defibrillation. Part IV: 25 animals were studied to determine the effect of the NO donor SNAP and the angiotensin-converting enzyme inhibitor Enalaprilat on coronary perfusion pressure (CPP).


RESULTS
In Part I, after defibrillation, with continued ventilation, chest compression and epinephrine, 8/9 L-NNA pigs achieved ROSC versus 4/8 control pigs (p=0.11). After 60 s of CPR, 7/9 pigs in the L-NNA group achieved ROSC versus 2/8 pigs in the no-L-NNA group (p<0.05). Only 2/9 pigs receiving L-NNA required epinephrine (1 mg) after defibrillation, compared to 6/8 pigs requiring at least one dose of epinephrine in the no-L-NNA group (p<0.05). In Part II, there was no significant difference between L-NNA, ARR17477 and control pigs in ROSC. However, control pigs required 6.8+/-1.4S.E. mg epinephrine; L-NNA pigs and ARR17477 pigs required less epinephrine (3.7+/-0.7 and 3.0+/-0.3 mg, both p=0.01). Shorter chest compression was required in the L-NNA group (252+/-38 s, p<0.05) and in ARR17477 group (222+/-15 s, p<0.05) compared to the control group (405+/-77 s). In Part III, L-NNA infusion caused a significant increase in mean blood pressure at baseline, but did not change CPP throughout the experiment. In Part IV, there were no significant differences in the changes of mean blood pressure and CPP between SNAP and Enalaprilat group in all animals throughout the experiment.


CONCLUSIONS
NOS inhibition pre-arrest did not improve survival, but did reduce requirements for epinephrine and closed-chest compression in a swine resuscitation model.
Zhang
Yi
Y
The Cardiovascular Center, College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Boddicker
Kimberly A
KA
Rhee
Benjamin J
BJ
Davies
Loyd R
LR
Kerber
Richard E
RE
D000818:Animals; D016887:Cardiopulmonary Resuscitation / Q000379:methods; D003131:Combined Modality Therapy; D003326:Coronary Circulation / Q000502:physiology; D004195:Disease Models, Animal; D004554:Electric Countershock / Q000379:methods*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006323:Heart Arrest / Q000401:mortality / Q000628:therapy*; D006439:Hemodynamics / Q000502:physiology; D008955:Models, Cardiovascular; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology*; D011897:Random Allocation; D012680:Sensitivity and Specificity; D015996:Survival Rate; D034421:Sus scrofa; D014693:Ventricular Fibrillation / Q000401:mortality / Q000628:therapy*
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019001:Nitric Oxide Synthase