Nitric Oxide: physiology and therapeutic applications

The biology of nitric oxide (NO) has been extensively reviewed. NO was largely regarded as an environmental pollutant until 1987, when its biological similarities to endothelium-derived relaxing factor (EDRF) were noted. Subsequently, NO and EDRF were demonstrated to be identical, modulating vascular tone through stimulated formation of cyclic cAMP. Endogenous NO is formed from L-arginine by one of three (neural, inducible, and endothelial) isoforms of NO synthase, NOS. The physiological role of endogenous NO was first shown when an infusion of an inhibitor of NOS in healthy volunteers led to systemic and pulmonary pressor responses. In 1991, inhaled NO was shown to be a selective pulmonary vasodilator in patients with pulmonary hypertension and in 1993 inhaled NO emerged as a potential therapy for the acute respiratory distress syndrome (ARDS), because it decreases pulmonary vascular resistance without affecting systemic blood pressure and improved oxygenation by redistributing pulmonary blood flow toward ventilated lung units. In patients with acute lung injury and mild pulmonary hypertension, inhaled NO has been associated with a small, short-lived decrease in pulmonary arterial pressure, which has encouraged the use of NO as a supportive treatment for acute right ventricular dysfunction complicating cardiac surgery. Currently, NO is only approved in the US for the treatment of term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hyper-tension in conjunction with ventilatory support where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation. Endogenously produced NO contributes to the control and killing of multiple bacterial species, and while NO is not bactericidal per se, its cytotoxic effect is most likely realized by its reactive nitrogen oxides such as peroxynitrite, to produce potent cytotoxic actions against membrane lipids, nucleic acids, and proteins. In conclusion, several preclinical and clinical studies are providing evidence that the nitrate–nitrite–NO pathway critically subserves physiological hypoxic NO signalling, providing an opportunity for new nitric-oxide-based therapeutics.