The discovery of nitric oxide (NO) as the endothelial-derived relaxing factor has revolutionized the concept of many diseases and their treatment. NO is formed in endothelial cells by oxidation of the amino acid l-arginine in the presence of a NO synthase. It is highly soluble and rapidly enters the smooth muscle cell and activates soluble guanylate cyclase, resulting in increased levels of cGMP, which is responsible for most of the vasodilatory effects of NO (1). Its biologic half-life is short, as it is rapidly degraded by a family of phosphodiesterases (PDEs) (2). The pulmonary circulation is uniquely accessible to direct supplementation of gaseous NO by inhalation. It is used in the treatment of acute pulmonary disorders associated with pulmonary hypertension (PHT) such as acute respiratory distress syndrome (3), persistent pulmonary hypertension of the newborn (4), and postoperative pulmonary hypertension (5). There are potential disadvantages to its use, however; the danger of pulmonary hypertensive rebound upon discontinuation, concerns about toxicity at high dosage, enhancement of inflammation and alteration of coagulation, and, recently, its costs (6) all have been highlighted. Nonetheless, for many, it has become established as the treatment of choice for selective pulmonary vasodilation. With newer agents, such as sildenafil, arriving on the scene, it is timely to reevaluate the role of both NO and these novel substances.

Sildenafil has been touted as a candidate to inherit the role of NO in the treatment of pulmonary hypertensive disorders. Originally synthesized as compound UK 92480 by Pfizer, its action as a PDE5 inhibitor was 100-fold (IC50 3.5 nM) that of its source compound zaprinast. PDE5 is particularly richly expressed in lung tissue (7), and although sildenafil is administered systemically, because of this it provides a selective pulmonary vasodilating effect. A significant therapeutic effect has been described in primary PHT (8), PHT associated with the lupus syndrome (9), chronic thromboembolism (10), thalassemia (11), HIV (12), lung fibrosis (13), and congenital heart disease (14). Oral sildenafil markedly augments and prolongs the pulmonary vasodilating effect of inhaled prostanoids (8), and it shows an additive effect when combined with inhaled NO (15) in patients with primary PHT.

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