NO was first identified as an endogenous endothelial-derived vasodilator in 1987, and is now widely used for the treatment of pulmonary hypertension. NO is a colorless, odorless gas that can easily be blended into various types of respiratory gas therapies. After inhalation, NO is rapidly absorbed from the alveolar space into the adjacent capillary where it activates guanylate cyclase in the pulmonary vascular smooth muscles. Activated guanylate cyclase in turn promotes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (c-GMP), which promotes the relaxation of vascular smooth muscle. A key feature of inhaled NO therapy is its selectivity for the pulmonary vascular bed due to the rapid binding of NO by hemoglobin. In the blood, NO reacts with oxyhemoglobin to form methemoglobin, and with deoxyhemoglobin to form iron-nitrosyl-hemoglobin. Ultimately, approximately 70% of inhaled NO is excreted in the urine as nitrate. Certain phosphodiesterase inhibiting drugs, such as sildenafil and others, allow for a higher level of activated c-GMP, which in turn promotes pulmonary vasodilatation.

In clinical use, inhaled NO can be administered through a mechanical ventilator, nasal cannula, or mask. In the past, doses of 5 to 80 ppm were used, but subsequent evaluation has shown that doses >20 ppm do not produce greater hemodynamic effects. One of the common uses of NO is for the treatment of pulmonary hypertension of the newborn (PPHN). PPHN can be seen in association with meconium aspiration, neonatal pneumonia, pulmonary hypoplasia of various etiologies, prematurity, and premature ductal closure, as well as other idiopathic causes. Profound hypoxemia can result from PPHN when patients have a persistent patent ductus arteriosus or patent foramen ovale, which allows for right-to-left shunting of deoxygenated venous blood into the systemic circulation. In cases where the ductus arteriosus and foramen ovale have closed, the right ventricle will be unable to pump blood through the high pressure pulmonary bed and, heart failure and shock will ensue. Although PPHN was treated with aggressive hyperventilation in the past, current initial treatment includes vasoactive agents and volume expansion to support cardiac function, treatment of metabolic acidosis, and treatment of underlying disorders. In patients with refractory
PPHN, inhaled NO has been shown to improve oxygenation and to reduce the need for initiation of extracorporeal membrane oxygenation (ECMO), a costly and invasive but lifesaving mechanical support therapy for refractory PPHN. On the basis of multicenter randomized trials, the U.S. Food and Drug Administration have approved inhaled NO as treatment for respiratory failure in neonates with clinical or echocardiographic evidence of pulmonary hypertension.