0625. Nitric oxide (NO), L-arginine and PDE5 inhibition in cystic fibrosis (CF)

Previous summaries in this series have drawn attention to the role of NO in various situations of lung pathology (e.g. neonatal respiratory distress and pulmonary hypertension), and the potential for the PDE5 inhibitor sildenafil (Viagra) to treat the pathology (see 2003 no’s 1 and 5, and 2005 no 40). It is therefore not particularly surprising to find CF as a candidate for study and intervention. Endogenous formation of NO in airways is thought to play a role in both lung immunity and smooth muscle function (bronchodilatation), so clearly any deficiencies in these areas would contribute to CF symptomatology. A number of studies have now shown that levels of exhaled NO are low in CF, and to these studies one must add results showing that arginase (a urea cycle enzyme) is elevated during exacerbations of lung infection in CF subjects, and might divert or ‘steal’ arginine, thereby reducing the amount of substrate available for conversion to NO. On the L-arginine front there is also research showing that inhalation of L-arginine in CF patients increases exhaled NO, improves FEV1 and significantly increases oxygen saturation. Given the role of sildenafil and other PDE5 inhibitors as NO ‘potentiators’, the obvious next step would be the testing of these drugs in the situation of CF. In vitro studies have shown that sildenafil is able to correct intracellular protein trafficking abnormalities in nasal epithelial cells from CF subjects with the Δ508 mutation, while in the clinical situation sildenafil use has been associated with significant improvements in exercise tolerance and pulmonary hypertension.

Read more:
Am J Respir Crit Care Med 2006;Apr 20 Epub
Pediatr Pulmonol 2006; 41: 383-5
Thorax 2006; 61: 514-20 and 2005; 60: 55-9