New research results show that nitric oxide (NO) independently enhances contraction and inhibits relaxation pathways in hypoxic pulmonary artery smooth muscle cells (PASMCs).
write in the forefront of physiology, The researchers explained that this process is partly due to mechanisms involving nitrogen radical formation and protein nitrosylation.
“These observations may partially explain the reduced effectiveness of NO in treating hypoxic pulmonary hypertension,” they wrote.
Neonatal hypoxic persistent pulmonary hypertension (PPHN) is usually treated with oxygen and inhaled NO, but treatment failure with NO occurs in approximately one quarter of cases. Complications may include “protein nitrosylation, a reversible post-translational modification with covalent attachment of NO to cysteine thiol groups.”
In the current study, researchers set out to investigate the effects of sodium nitroprusside (SNP) as an NO donor on thromboxane-mediated contractile and NO-independent relaxation pathways and the accumulation of reactive oxygen species in PASMC. Did. Their previous study demonstrated that “72-h exposure to hypoxia, which models PPHN, sensitizes PASMC to the contractile agonist thromboxane and inhibits the relaxant adenylyl cyclase (AC) activity.” it was done.
PPHN complicates 0.2% to 0.6% of births and 10% of neonatal intensive care unit admissions. About 1000 people die each year in the United States.
Approximately 40% of endothelial and smooth muscle dysfunction in PPHN is attributed to hypoxic ventilation/perfusion mismatch or meconium aspiration, and a quarter to inflammation or sepsis, researchers explain. Pulmonary hypertension can also complicate neonatal conditions such as chronic lung disease and congenital diaphragmatic hernia.
- Protein nitrosylation levels were higher in hypoxic PASMC and control groups
- SNPs resulted in more total protein nitrosylation and intracellular nitrite in normoxic and hypoxic cells, which were associated with 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinate decreased by iron(III) (FeTPPS).
- Addition of FeTPPS did not affect hypoxia-induced reduction in mitochondrial activity
- Compared with controls, baseline calcium (Ca2+) was higher in hypoxic PASMCs and enhanced Ca2+ responses to thromboxane challenge.
- FeTPPS helped normalize AC-mediated relaxation after it was impaired in hypoxic PASMC versus controls
Overall, the findings represent a major investigation of the effects of NO on the generation of key second messengers in neonatal pulmonary artery PASMC, the authors write. However, further investigation is needed to understand the mechanisms of these effects. The NO donor used marks a limitation to the study.
The study is also limited to myocytes obtained at the first passage from normal neonatal pulmonary arteries and exposed to hypoxia or other treatments in vitro, the authors added.
“NO independently enhances contraction and inhibits the relaxation pathway of hypoxic PASMC,” they concluded. Together, these phenomena may hinder the efficacy of NO in treating hypoxic pulmonary hypertension.”
Hinton M, Thliveris JA, Hatch GM, Dakshinamurti S. Nitric oxide enhances contractile signaling in hypoxic pulmonary artery smooth muscle—implications for hypoxic pulmonary hypertension. front physiology. Published online March 29, 2023. doi:10.3389/fphys.2023.1144574