Pulmonary arterial hypertension is defined as adisease characterized by a progressive increase inpulmonary vascular resistance, leading to right ventricularfailure and premature death. Pathobiologic mechanisms ofthe disease include pulmonary endothelial dysfunction,which leads to impaired production of vasodilators, such asnitric oxide and prostacyclin, and over expression ofvasoconstrictors, such as endothelin-1. Treatment includesconventional agents (anticoagulants, diuretics, digoxin, andsupplemental oxygen, as well as calcium-channel blockersin selected patients), vasodilators, and antiproliferativeagents such as prostanoids and endothelin-receptorantagonists, which are targeted at abnormalities ofendothelial function.Four agents are currently approved for the treatmentof pulmonary arterial hypertension in the United States andEurope: (a) intravenous epoprostenol, (b) the inhaledprostacyclin analogue iloprost, (c) the subcutaneously andintravenously administered prostacyclin analoguetreprostinil, (d) the oral endothelin-receptor antagonistbosentan. Although these drugs are efficacious, adverseeffects in terms of safety, tolerability, drug delivery, or allof these factors occur with all of these agents. In addition, some medical therapy may fail in some patients in whichcase they may be considered for lung transplantation.Changes in nitric oxide pathways have been detectedin patients with pulmonary arterial hypertension, andalthough inhaled nitric oxide is used for testing acutevasoreactivity, the long-term administration of this agent iscumbersome and requires a complex delivery system.By selectively inhibiting phosphodiesterase type 5,sildenafil citrate promotes the accumulation of intracellularcGMP and thereby enhances nitric oxide–mediatedvasodilatation; it may also have antiproliferative effects onpulmonary vascular smooth-muscle cells. Initial studiessuggest that sildenafil is beneficial in the treatment ofpulmonary arterial hypertension. Sildenafil improvesexercise capacity, WHO functional class, andhemodynamics in patients with symptomatic pulmonaryarterial hypertension.Presently, there are few data on effects of long termsildenafil treatment for the new cardiovascular indications.The available evidence contribute to a building sense ofexcitement that sildenafil may be an effective agent incardiovascular disorders especially in pulmonaryhypertension. However, the safety and dosage of sildenafilfor this condition has still not been fully established. Moreover, sildenafil therapy in most of the novelcardiovascular indications will require continuous exposureto larger doses, suggesting that adverse effects may bemore widespread, especially given that the PDEs aredistributed in a variety of tissues.