The role of NO synthase (NOS) and l-arginine metabolism in endothelial-dependent blood vessel dilation (A) under normal conditions and (B) in an oxidative environment such as that seen in COPD. NO-dependent vasodilators or an increase in localised blood flow stimulate the release of intracellular calcium through receptor (R) binding or an increase in shear flow, respectively. This in turn up-regulates the activity of constitutive NO synthase (cNOS), causing the catalytic conversion of the amino acid l-arginine into NO. NO then diffuses from the superficial endothelial cell layer to the underlying smooth muscle. In smooth muscle cells, guanylyl cyclase (GC) activity is induced by an increase in NO, causing this enzyme to convert guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP) and thus resulting in a vasodilatory response. In an oxidative environment (i.e. smokers with COPD) there is an overall reduction in the bioavailability of l-arginine because of overexuberant ROS production and therefore reduced NO expression and impaired vasodilation.