Endothelin and Pulmonary Arterial Hypertension

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US Cardiology 2006;2005:2(1):1-5

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Pulmonary arterial hypertension (PAH) is a progressive and debilitating disease with limited treatment options. Although some patients do well with calcium channel blockers, most ultimately need more advanced therapy, such as prostanoids. Recently, a new class of therapeutic agents has been developed to treat these patients: the endothelin receptor antagonists (ERAs). Although they are not offering a complete cure, ERAs represent a dramatic breakthrough in the treatment of PAH patients, improving hemodynamics, as well as functional and clinical outcomes. This article describes the preclinical foundations for the development of ERAs, presents the current clinical trial evidence, and discusses future directions for research and debate.

The discoveries of endothelial cell-derived vasoconstricting compounds and extraordinarily potent vasoconstrictor peptides from the venom of Atractaspis engaddensis (Israeli burrowing asp), known as sarafotoxins, prepared the foundation for the isolation and characterization of a novel peptide called endothelin (ET).1,2 ET is homologous to sarafotoxin and an extraordinarily potent vasoconstrictor, synthesized predominantly by endothelial cells.3 The initial gene product is preproendothelin-1, which is serially processed to the 21 amino acid end-product ET-1. Endothelial cells release over 75% of ET abluminally into the muscular media, consistent with an autocrine/paracrine mechanism of action. ET signals via two main types of seven transmembrane-spanning G-protein-coupled receptors, known as ET receptor subtype A (ETA) and ET receptor subtype B (ETB). ETA receptors are found predominantly in vascular smooth muscle cells (VSMCs) and cardiac myocytes, while the ETB receptors are found in endothelial cells and VSMCs. Stimulation of VSMC ETA and ETB receptors produces profound and long-lasting vasoconstriction,4,5 and increases mitogenic activity. Stimulation of endothelial ETB receptors results in increased nitric oxide (NO) and prostacyclin release, producing minor vasodilation. Endothelial ETB receptors also act as a major clearance mechanism for circulating ET-1 in the pulmonary and renal circulations. In addition to causing pulmonary vascular vasoconstriction and VSMC hyperplasia and hypertrophy, ET receptor activation can cause fibrosis through fibroblast proliferation and extracellular matrix deposition, increased pulmonary vascular permeability, stimulation of inflammation through increased neutrophil and mast cell activation, production of inflammatory signaling peptides and cytokines, and increased expression of integrins. These effects are all believed to contribute to the development of PAH.

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