Peroxynitrite inhibits relaxation and induces pulmonary artery muscle contraction in the newborn rat

Nitric oxide (NO) reacts with superoxide anion to form the peroxynitrite anion (ONOO-), a molecule with pulmonary vasodilator properties in the adult rat. The purpose of this study was to compare the effects of ONOO- on intrapulmonary arteries from the newborn (days 4-7), juvenile (day 14), and adult rat. Following thromboxane A2 (TXA2) analogue (U46619) prestimulation, newborn vessels were more sensitive to ONOO- -induced muscle contraction, compared to both the juvenile and the adult vessels. Peroxynitrite-induced contraction in newborn vessels was abrogated by ibuprofen, an endothelin B-receptor blocker (A-192621), or a rho-kinase-specific inhibitor (Y27632) (all p < 0.01). Following KCl stimulation and TXA2 receptor blockade, ONOO- induced NO-dependent muscle relaxation in newborn vessels via stimulation of the endothelial and inducible nitric oxide synthases. However, in the presence of ONOO-, the pulmonary artery relaxation response to endothelium-dependent stimulation was significantly reduced (p < 0.01). Finally, newborn but not adult pulmonary arteries exposed to ONOO- showed a 10-fold increase in 8-isoprostane production, a possible mediator of ONOO- -induced contraction. We conclude that exposure to ONOO- results in a unique response in newborn intrapulmonary arteries characterized by increased 8-isoprostane generation, which we believe is responsible for its vasoconstrictor effect. This unique response potentially renders the newborn more susceptible to ONOO- -induced pulmonary hypertension than older animals.