Does nitric oxide (NO) cause bronchodilation or bronchoconstriction?

From the Guidelines

Nitric oxide primarily acts as a bronchodilator in the respiratory system, causing relaxation of the smooth muscle in the airways and improving airflow and gas exchange in the lungs. This effect is particularly useful in clinical settings such as treating persistent pulmonary hypertension of the newborn (PPHN) at doses of 5-20 parts per million 1. The mechanism behind this bronchodilation involves nitric oxide activating guanylate cyclase, which increases cyclic guanosine monophosphate (cGMP) levels in smooth muscle cells, leading to relaxation.

Some key points to consider:

• Inhaled nitric oxide (iNO) has been shown to be a potent pulmonary vasodilator in multiple settings, including newborns with pulmonary hypertension, children with congenital heart disease, and adults with various forms of pulmonary hypertension 1.
• The use of iNO is based on extensive safety and efficacy data obtained from large placebo-controlled trials, particularly in the context of PPHN 1.
• While nitric oxide can potentially contribute to bronchoconstriction in specific inflammatory conditions or at very high concentrations through the formation of peroxynitrite or other reactive nitrogen species, its dominant effect in standard therapeutic applications is bronchodilation 1.
• The measurement of exhaled nitric oxide levels can provide information about airway inflammation and has been explored as a noninvasive method to diagnose asthma and monitor the response to anti-inflammatory therapy 1.

In the context of exercise-induced bronchoconstriction, the role of nitric oxide is less clear, with some studies suggesting that increased levels of exhaled nitric oxide may be associated with susceptibility to exercise-induced bronchoconstriction, particularly in asthmatic patients 1. However, the primary effect of nitric oxide in the respiratory system remains its bronchodilatory action, which is beneficial in improving oxygenation in certain respiratory conditions.

From the FDA Drug Label

The structural formula of nitric oxide (NO) is shown below: Nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation When inhaled, nitric oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature INOmax appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

Nitric oxide is a pulmonary vasodilator. It dilates the pulmonary vasculature, which can lead to bronchodilation. However, the label does not directly address whether nitric oxide causes bronchodilation or bronchoconstriction in the airways.

• The label discusses the effects of nitric oxide on pulmonary vascular tone and its use in treating persistent pulmonary hypertension of the newborn (PPHN).
• It also mentions that nitric oxide can cause methemoglobinemia, which can lead to hypoxemia.
• However, it does not provide direct information on the effects of nitric oxide on airway smooth muscle or bronchial tone. 2 2

From the Research

Nitric Oxide Effects on Airways

• Nitric oxide (NO) has been identified as an important, short-acting, endogenous vasodilator 3.
• The bronchodilatory effect of NO may be an alternative therapy for treating asthma and bronchospasm, suggesting that it can cause bronchodilation 3.
• There is no direct evidence in the provided studies that nitric oxide causes bronchoconstriction.
• The studies primarily focus on the use of inhaled nitric oxide for the treatment of pulmonary arterial hypertension and persistent pulmonary hypertension of the newborn, highlighting its vasodilatory effects 4, 5, 6, 7.

Clinical Use of Inhaled Nitric Oxide

• Inhaled NO has been shown to decrease pulmonary vascular resistance in newborns and improve systemic oxygenation 5.
• It is commonly used for acute pulmonary vasoreactivity testing and for treating pediatric and adult patients with PAH associated with various disorders 4.
• The use of inhaled NO with different oxygen concentrations can affect the inflammatory cascade in newborns with hypoxic respiratory failure secondary to persistent pulmonary hypertension 6.