Sodium nitrite augments lung S-nitrosylation and reverses chronic hypoxic pulmonary hypertension in juvenile rats

Deficient nitric oxide (NO) signaling plays a critical role in the pathogenesis of chronic neonatal pulmonary hypertension (PHT). Physiological NO signaling is regulated by S-nitrosothiols (SNOs), which act both as a reservoir for NO and as a reversible modulator of protein function. We have previously reported that therapy with inhaled NO (iNO) increased peroxynitrite-mediated nitration in the juvenile rat lung, although having minimal reversing effects on vascular remodeling. We hypothesized that sodium nitrite (NaNO₂) would be superior to iNO in enhancing lung SNOs, thereby contributing to reversal of chronic hypoxic PHT. Rat pups were exposed to air or hypoxia (13% O₂) from postnatal days 1 to 21. Dose-response prevention studies were conducted from days 1–21 to determine the optimal dose of NaNO₂. Animals then received rescue therapy with daily subcutaneous NaNO₂ (20 mg/kg), vehicle, or were continuously exposed to iNO (20 ppm) from days 14–21. Chronic PHT secondary to hypoxia was both prevented and reversed by treatment with NaNO₂. Rescue NaNO₂ increased lung NO and SNO contents to a greater extent than iNO, without causing nitration. Seven lung SNO proteins upregulated by treatment with NaNO₂ were identified by multiplex tandem mass tag spectrometry, one of which was leukotriene A4 hydrolase (LTA4H). Rescue therapy with a LTA4H inhibitor, SC57461A (10 mg·kg⁻¹·day⁻¹ sc), partially reversed chronic hypoxic PHT. We conclude that NaNO₂ was superior to iNO in increasing tissue NO and SNO generation and reversing chronic PHT, in part via upregulated SNO-LTA4H.