Endothelin and pulmonary arterial hypertension

Background and Objectives: Pulmonary arterial hypertension (PHT) is a potentially fatal disease. The purpose of this article is to review the current knowledge of the role played by endothelin (ET) in PHT and the relevant drug regimens used in the treatment of this condition. Methods: A detailed search via MEDLINE (PubMed) was performed by using PHT and ET as the key terms. Results: PHT could be a primary or a secondary diagnosis associated with various heart and lung diseases. PHT appears during the late stage of systemic sclerosis and may complicate other systemic diseases such as systemic lupus erythematosus. The vascular endothelium and activation of various mediators and growth factors such as the ET system are thought to play a crucial role in the development of this condition. The pathologic process progresses very rapidly from vasoconstriction to widespread pulmonary vascular obstruction. The use of high doses of calcium channel blockers is of limited value. Life-long anticoagulant therapy is recommended for the treatment of PHT. Currently, the drug being used in PHT therapy is continuous central-venous prostacyclin infusion. Prostacyclin is a strong vasodilator with antiaggregate and antifibrotic properties and has the potential to reduce endothelial injury and to induce vasculature remodeling. This treatment results in improved functional status and increased life span. Unfortunately, its use is accompanied by various side effects, technical difficulties, and high cost. The role of other therapeutic modalities (inhaled prostacyclin, subcutaneous treprostinil, oral beraprost, sildenafil) in vascular remodeling, and the improvement in functional capacity and survival of patients with PHT, are currently under investigation. Bosentan, administered orally, is a recently developed active ET receptor antagonist. It is a promising new therapeutic tool in the treatment of PHT because of its potent vasodilator, antiproliferative, and vascular remodeling activity. Conclusions: The revolutionary conceptual shift in understanding the pathogenesis of PHT from a vasoconstrictive process to a vasoproliferative one, has led to a modification in the treatment of this disease from the use of vasodilators to the use of drugs with antiproliferative and vascular remodeling activity. Until now, prostacyclin was the only drug of this type available for the treatment of PHT. ET blockade seems to be a reasonable and potential therapeutic option.