Inhaled NO as a therapeutic agent

Abstract

In 1991, Frostell and colleagues reported that breathing low concentrations of nitric oxide (NO) decreased pulmonary artery pressure (PAP) in awake lambs with experimental pulmonary hypertension (PH) [Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:2038-47]. Subsequently, efforts of multiple research groups studying animals and patients led to approval of inhaled NO by the US Food and Drug Administration in 1999 and the European Medicine Evaluation Agency and European Commission in 2001. Inhaled NO is currently indicated for the treatment of term and near-term neonates with hypoxemia and PH. Since regulatory approval, several studies have suggested that NO inhalation can prevent chronic lung disease in premature infants. In addition, unanticipated systemic effects of inhaled NO may lead to treatments for a variety of disorders including ischemia-reperfusion injury. This review summarizes the pharmacology and physiological effects of breathing NO. The application of inhaled NO to hypoxemic neonates with PH is discussed including recent studies exploring the use of inhaled NO to prevent bronchopulmonary dysplasia in premature infants. This review also highlights the application of inhaled NO to treat adults with cardiopulmonary disease, strategies to augment the efficacy of inhaled NO, and potential applications of the systemic effects of the gas.

Figure

Inhaled NO is a selective pulmonary vasodilator with actions on the systemic vasculature. A schematic of an alveolar-capillary unit is presented highlighting the ability of inhaled NO to dilate pulmonary arterioles and reduce pulmonary artery pressure (PAP). Although inhaled NO does not dilate systemic arterioles or alter systemic arterial pressure (SAP) under normal conditions, inhaled NO does have systemic effects which are described in the text and may be mediated by circulating cells exposed to NO in the lungs and blood-borne NO derivatives: SNO-proteins—S-nitroso proteins including SNO-albumin; SNO-Hb—S-nitroso-hemoglobin (nitrosylated on Cys⁹³ of the β chain); NO-Fe-Hb—nytrosyl-hemoglobin; and nitrite.