In reality a balancing act exists whereby all three mediators may be present to maintain pulmonary vascular tone at an optimal level. Increases or decreases in the amounts of any one agent produced or changes to the receptors/signaling pathway they stimulate may therefore AEB071 alter the balance towards vasodilation or vasoconstriction. The Hagen-Poiseuille law states that the resistance to flow in a tube is equal to the product of the length of the tube, the viscosity of the fluid, divided

by π and the fourth power of the internal radius of the tube. Thus it can be seen that a small change in the radius of the vessel wall will have a significant change to the resistance to flow. 15 Under physiological conditions, such as exercise, this allows for changes in pulmonary vascular resistance due to dilation of pulmonary vessels as well as the recruitment of previously closed capillaries. In PAH, the profile of endothelium-derived vasoactive factors is changed, with reduced

production of vasodilator agents NO and prostacyclin. 16–18 In addition to their action on vessel diameter, these agents also have an inhibitory effect on the regulation of smooth muscle cell proliferation and platelet activation. 19 Both prostacyclin and NO systems have therefore been the target of potential pharmacological interventions for the treatment of the disease. NO-releasing agents were shown to not be long-acting enough and also had the potential to stimulate a reflex tachycardia due to any effect on peripheral vessels. Agents that target the phosphodiesterase-5 enzyme, the predominant isoform of the phosphodiesterase enzymes that are responsible for the breakdown of cyclic guanosine monophosphate (cGMP), the second messenger for NO, have shown some encouraging long-term benefits. 20–22 Agents that can directly activate cGMP have also been a focus of attention and are the subject of clinical trials that are currently in progress. 23,24 Similarly,

there are pharmacological agents that stimulate the IP receptors and mimic the effects of prostacyclin that have been used for the treatment of the disease. However, difficulties in the administration of these drugs (they Dacomitinib need to be given by inhalation, subcutaneous injection or continuous intravenous infusion), their short half-life and their relative non-specific action at other receptors have limited their use and effectiveness in the treatment of PAH patients. In contrast to trying to stimulate vasodilation in order to resolve PAH, targeting the vasoconstrictor peptide ET-1 is an alternative or additional strategy that has also been explored. This review will focus on the role of ET-1 in the lung, its biosynthesis, pharmacology, and the evidence for its participation in the pathogenesis of the disease.