Post-resuscitation NOS inhibition does not improve hemodynamic recovery of hypoxic newborn pigs.
BACKGROUND
Significant improvement in myocardial recovery has been shown previously with interventions to decrease reactive oxygen species after ischemia/hypoxia. We investigated whether co-administration of N-acetylcysteine (NAC, a scavenger for reactive oxygen species) and N (G)-monomethyl-L: -arginine (L-NMMA, a non-selective nitric oxide synthase inhibitor) results in better hemodynamic recovery.


METHODS
Controlled, block-randomized study.


METHODS
University research laboratory.


METHODS
Mixed breed piglets (1-4d, 1.6-2.4 kg).


METHODS
Acutely instrumented piglets received normocapnic alveolar hypoxia (10-15% oxygen) for 2 h followed by reoxygenation with 100% oxygen (1 h) then 21% oxygen (3 h). After reoxygenation, hypoxic-reoxygenated piglets were given either saline (controls), NAC [30 mg/kg bolus + 20 mg/(kg h) infusion], NMMA [0.1 mg/kg bolus + 0.1 mg/(kg h) infusion] or NAC + L-NMMA via intravenous infusion in a blinded, randomized fashion (n = 8/group). Sham-operated piglets had no hypoxia-reoxygenation (n = 5).


RESULTS
Both cardiac index and stroke volume of hypoxia-reoxygenation controls remained depressed during reoxygenation (vs. normoxic baseline, p < 0.05). Post-resuscitation treatment with L-NMMA alone did not improve systemic hemodynamic recovery, but caused pulmonary hypertension (vs. controls). In contrast, treating the piglets with either NAC or NAC + L-NMMA improved cardiac index and stroke volume, with no effect on heart rate and blood pressure (vs. controls). These treatments also decreased various oxidative stress markers in myocardial tissues (vs. controls). However, there was no significant difference between NAC- and NAC + L-NMMA groups in all examined parameters.


CONCLUSIONS
Post-resuscitation administration of NAC improved cardiac function and reduced oxidative stress in newborn pigs with hypoxia-reoxygenation insult. Low-dose, non-selective inhibitor of nitric oxide synthase activity did not provide any further beneficial effect.
Lee
Tze-fun
TF
Department of Pediatrics, University of Alberta, NICU Royal Alexandra Hospital, Edmonton, Alberta T5H 3V9, Canada.
Tymafichuk
Corinne N
CN
Schulz
Richard
R
Cheung
Po-Yin
PY
D000111:Acetylcysteine / Q000008:administration & dosage; D000416:Alberta; D000818:Animals; D000975:Antioxidants; D001784:Blood Gas Analysis; D006439:Hemodynamics / Q000187:drug effects*; D000860:Hypoxia; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D011897:Random Allocation; D012151:Resuscitation; D013318:Stroke Volume / Q000502:physiology; D013552:Swine
D000975:Antioxidants; D009569:Nitric Oxide; D000111:Acetylcysteine