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

Abstract

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, while 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 s.c. 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 up-regulated 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/d s.c.), 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 up-regulated SNO-LTA4H.

Oral nitrite treatment increases S-nitrosylation of vascular protein kinase C and attenuates the responses to angiotensin II

“…In fact, this response was also found with nitrate administration and significantly attenuated by the use of oral mouthwash, which impaired the enterosalivary cycle of nitrate and prevented nitrate from being reduced to nitrite, thus reducing the increases in circulating S-nitrosothiols and vascular protein nitrosylation [ 3 , 10 , 11 ]. Several recent studies by other groups have described vascular effects of nitrite that are not necessarily associated with increased NO production [ [27] , [28] , [29] ], thus strongly suggesting the involvement of other pathways such as catalase inhibition [ 28 ] or increased S-nitrosylation 26 as possible mechanisms activated by nitrite.…”

Nitric Oxide–cGMP Pathway Modulation in an Experimental Model of Hypoxic Pulmonary Hypertension

“…Likewise, a large number of drugs and approaches were not examined in this study, but we focused in a representative drug for every site of modulation. As far as NO donors are considered, alternative drugs/treatments include inhaled NO therapy, 57 administration of inorganic nitrite and nitrate, 58 such as sodium nitrite, 59 as well as diethylamine NONOate diethylammonium, sodium nitroprusside and the sGC stimulator riociguat. 60 As for PDE5 inhibitors, several other drugs besides Sild have been proposed, each with different pharmacokinetics, efficiency and persistence in the circulation, but with essentially similar mechanisms of action and outcomes.…”

Tracing the Path of Inhaled Nitric Oxide: Biological Consequences of Protein Nitrosylation

“…Nebulized NaNO 2 acutely reduces pulmonary vascular resistance in pulmonary hypertensive patients with β-thalassemia 109 . In chronically hypoxic rat pups, subcutaneous NaNO 2 increases tissue NO, ameliorating pulmonary hypertension comparably to inhaled NO, while also increasing R-SNO content in the lung 110 . NaNO 2 increases lung NO and SNO contents to a greater extent than does inhaled NO, albeit without causing protein nitration [111][112][113] .…”