Research Explores Causes Behind Ineffective NO Treatment for Hypoxic Pulmonary Hypertension

Nitric oxide (NO) independently augments contraction and inhibits relaxation pathways in hypoxic pulmonary artery smooth muscle cells (PASMC), new study results show.

Writing in Frontiers in Physiology, researchers explained the process is due in part to a mechanism involving nitrogen radical formation and protein nitrosylation.

“These observations may partially explain impaired effectiveness of NO when treating hypoxic pulmonary hypertension,” they wrote.

Although hypoxic persistent pulmonary hypertension in newborns (PPHN) is typically treated with oxygen and inhaled NO, treatment failure with NO occurs in around one quarter of cases. Complications can include “protein nitrosylation, a reversible posttranslational modification where NO covalently attaches to the thiol group on a cysteine.”

In the current study, the researchers set out to examine the effects of sodium nitroprusside (SNP), as NO donor, on the thromboxane-mediated contraction and NO-independent relaxation pathways and on reactive oxygen species accumulation in PASMC. Their previous work demonstrated “that 72-hour exposure to hypoxia, modeling PPHN, sensitized PASMC to the contractile agonist thromboxane and inhibited relaxant adenylyl cyclase (AC) activity.”

PPHN complicates 0.2% to 0.6% of births and 10% of neonatal intensive care unit admissions. In the United States, it accounts for around 1000 deaths each year.

Around 40% of endothelia and smooth muscle dysfunction in PPHN results from hypoxia ventilation/perfusion mismatch or meconium aspiration, the researchers explained, while a quarter is due to inflammation or sepsis. Pulmonary hypertension can also complicate neonatal conditions like chronic lung disease or congenital diaphragmatic hernia.

Analyses revealed:

• There were higher levels of protein nitrosylation in hypoxic PASMC vs controls
• SNP led to more total protein nitrosylation and intracellular nitrite in normoxic and hypoxic cells, but this was reduced via 5,10,15,20-Tetrakis(4-sulfonatophenyl)porphyrinato iron(III) (FeTPPS)
• Adding FeTPPS did not have an impact on decreased mitochondrial activity resulting from hypoxia
• Compared with controls, baseline calcium (Ca2+) was higher in hypoxic PASMC and there was a heightened Ca2+ response to thromboxane challenge
• FeTPPS helped to normalize AC-mediated relaxation after it was impaired in hypoxic PASMC vs controls

Overall, findings represent a primary survey of the effects of NO on the generation of major second messengers in neonatal pulmonary artery PASMC, the authors wrote. However, more investigation is needed to understand the mechanisms for these effects. The NO donor used marks a limitation to the study.

The study is also limited to myocytes obtained in first passage from normal neonatal pulmonary arteries and exposed to hypoxia or other treatments in vitro, the authors added.

“NO independently augments contraction and inhibits relaxation pathways in hypoxic PASMC,” they concluded. “This is temporally linked to the formation of nitrogen radicals and may involve increased protein nitrosylation. Together, these phenomena may impede the effectiveness of NO in treating hypoxic pulmonary hypertension.”

Reference

Hinton M, Thliveris JA, Hatch GM, Dakshinamurti S. Nitric oxide augments signaling for contraction in hypoxic pulmonary arterial smooth muscle—Implications for hypoxic pulmonary hypertension. Front Physiol. Published online March 29, 2023. doi:10.3389/fphys.2023.1144574