The saga of the explosive growth in understanding the physiological role of nitric oxide (NO) that followed its identification in 1986 as the “endothelium-derived relaxing factor” of smooth muscle, has been told many times (1). For much of the decade-and-a-half since the initial identification of NO as a ubiquitous biological effector molecule, it has seemed likely that this knowledge would lead quickly to robust therapeutic applications. Surprisingly, this has not happened — yet another example of the difficult nature of translational research.
In December 1999 the US Food and Drug Administration (FDA) approved inhalational administration of NO “for the treatment of term and near-term (> 34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation” (2). This approval for NO as a pulmonary vasodilator for neonates built on intensive laboratory and clinical study of the effects of inhaled NO on cardiopulmonary processes in animals, as well as in children and adults with a variety of lung pathologies (3). Although there have been many indications that this treatment could be beneficial for patients with these syndromes, clinical benefit has been shown only in the two trials (the NINOS study and the CINRGI study) that led to the limited 1999 FDA approval. Perhaps it is time to re-evaluate some of the assumptions that have focused so much of the pharmacological effort up to now on inhalation uses of NO and primarily on diseases of the lung.