Post-resuscitation NOS inhibition does not improve hemodynamic recovery of hypoxic newborn pigs
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 NG-monomethyl-l-arginine (L-NMMA, a non-selective nitric oxide synthase inhibitor) results in better hemodynamic recovery.
Controlled, block-randomized study.
University research laboratory.
Mixed breed piglets (1-4d, 1.6–2.4 kg).
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).
Measurements and 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.
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.
KeywordsAntioxidant Nitric oxide Heart Swine Newborn
Fractional inspired oxygen concentration
Mean arterial pressure
Pulmonary arterial pressure
Reactive oxygen species
- 16.Brunet J, Boily MJ, Cordeau S, Des Rosiers C (1995) Effects of N-acetylcysteine in the rat heart reperfused after low-flow ischemia: evidence for a direct scavenging of hydroxyl radicals and a nitric oxide-dependent increase in coronary flow. Free Radic Biol Med 19:627–638PubMedCrossRefGoogle Scholar
- 19.Conesa EL, Valero F, Nadal JC, Fenoy FJ, López B, Arregui B, Salom MG (2001) N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure. Am J Physiol 281:R730–R737Google Scholar
- 23.Ichinose F, Hataishi R, Wu JC, Kawai N, Rodrigues AC, Mallari C, Post JM, Parkinson JF, Picard MH, Bloch KD, Zapol WM (2003) A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice. Am J Physiol Heart Circ Physiol 285:H2524–H2530PubMedGoogle Scholar
- 30.Lee TF, Tymafichuk C, Cheung PY (2008) Treating hypoxic neonatal piglets with NG-monomethyl-l-arginine after resuscitation worsened hemodynamic recovery despite reducing oxidative state (Abstract). Arch Dis Child 93:97Google Scholar