Chronic
pulmonary hypertension in the neonate and infant frequently presents with right-ventricular (RV) failure. Current clinical management may include protracted treatment with inhaled
nitric oxide (iNO), with the goal of reducing RV afterload. We have previously reported that prolonged exposure to iNO causes RV systolic dysfunction in the chronic
hypoxia-exposed juvenile rat, which was prevented by a
peroxynitrite decomposition catalyst. Given that inhalation of CO2 (therapeutic
hypercapnia) may limit oxidative stress and upregulated
cytokine expression in the lung and other organs, we hypothesized that therapeutic
hypercapnia would attenuate
cytokine-mediated
nitric oxide synthase (NOS) upregulation, thus limiting
peroxynitrite generation. Sprague-Dawley rat pups were exposed to chronic
hypoxia (13% O2) from postnatal day 1 to 21, while receiving iNO (20 ppm) from day 14 to 21, with or without therapeutic
hypercapnia (10% CO2). Therapeutic
hypercapnia completely normalized RV systolic function, RV
hypertrophy, and remodeling of pulmonary resistance arteries in animals exposed to iNO. Inhaled
nitric oxide-mediated increases in RV
peroxynitrite, apoptosis, and contents of
tumor necrosis factor (TNF)-α,
interleukin (IL)-1α, and NOS-2 were all attenuated by therapeutic
hypercapnia. Inhibition of NOS-2 activity with
1400 W (1 mg/kg/day) prevented iNO-mediated upregulation of
peroxynitrite and led to improved RV systolic function. Blockade of
IL-1 receptor signaling with
anakinra (500 mg/kg/day) decreased NOS-2 content and had similar effects compared to NOS-2 inhibition on iNO-mediated effects, whereas blockade of TNF-α signaling with
etanercept (0.4 mg/kg on alternate days) had no effects on these parameters. We conclude that therapeutic
hypercapnia prevents the adverse effects of sustained exposure to iNO on RV systolic function by limiting IL-1-mediated NOS-2 upregulation and consequent nitration. Therapeutic
hypercapnia also acts synergistically with iNO in normalizing RV
hypertrophy,
vascular remodeling, and raised pulmonary vascular resistance secondary to chronic
hypoxia.