Endothelin receptor blockade in the management of pulmonary arterial hypertension: Selective and dual antagonism

Abstract

Various treatments approved by the United States Food and Drug Administration for the management of pulmonary arterial hypertension (PAH) target three of the many pathways implicated in the development of PAH: prostacyclin-, endothelin-1 (ET-1)-, and nitric oxide-mediated pathways. The objectives of this manuscript are to provide background information on the role of ET-1 in the pathogenesis of PAH, to provide theoretical considerations for the advantages and disadvantages of dual vs single endothelin receptor antagonists (ERAs) for the management of PAH, and to describe the clinical study results from randomized, double-blind, placebo-controlled trials for the various ERAs. ET receptors (ET(A) and ET(B)) have different densities and distributions throughout the body and are dynamically regulated, such that blockade of ET(A) and ET(B) receptors may have different results in normal vs pathological conditions. Although differences in biological effects can be found in studies of isolated cells, blood vessels and animal models, clinical treatment studies have not identified clear differences in efficacy among the various ERAs. The main differences appear to be in safety profiles, with a greater frequency of serum liver function abnormalities occurring with the available dual ET(A)/ET(B) antagonist, and possibly higher rates of peripheral edema noted with selective ET(A) agents. Head-to-head studies will be necessary to resolve the question of whether single vs dual blockade produces better clinical results with fewer side effects in patients with PAH.

Endothelin Receptor Antagonists

“…Peripheral edema is a clinical consequence of worsening PH, but it is also a known class effect of ERAs (Battistini et al 2006;Kohan et al 2011). Even though ET B receptors have been suggested to play a role in sodium excretion, ET A -selective antagonists pose a greater risk of fluid overload than dual ET A /ET B antagonists (Barton and Kohan 2011;Trow and Taichman 2009). The mechanism of this fluid retention has been studied in rodents and the results show that ET Aselective receptor antagonists cause water retention by stimulating, via the activation of un-antagonized ET B receptors, the release of vasopressin and the expression of V2 receptors.…”

Endotelina-1: vasoconstrictor intrínseco del endotelio vascular

“…Este nuevo péptido identificado como un péptido vasoconstrictor potente tiene un peso molecular de 2492 Da. y es considerado como el más potente vasoconstrictor conocido por el hombre (4,5). Desde ese año y hasta la fecha se han realizado más de 18.000 publicaciones por diversos investigadores del mundo con la finalidad de lograr conocer sus propiedades biológicas y encontrar sus aplicaciones clínicas a favor de la comunidad médica mundial (6).…”

Management of Pulmonary Arterial Hypertension with Sitaxentan Sodium

“…Big ET is converted to the 21-amino acid peptide ET by the endothelin-converting enzyme. [12][13][14] ET is produced mainly in the vascular endothelial cells and, to a lesser extent, in pulmonary smooth muscle cells and fibroblasts.…”

“…13,15 Two types of endothelin receptor antagonists (ERAs) have been developed for the treatment of PAH, one nonselective ERA (bosentan) and two selective ET A receptor antagonists (sitaxentan and ambrisentan). 13 The rationale for using an ET A -selective antagonist is based on the evidence that the ET B receptor is involved in endothelin clearance from the blood, so blocking this receptor could increase circulating ET. Also, blockade of endothelial luminal side ET B receptor might theoretically decrease nitric oxide and prostacyclin production, favoring vasoconstriction.…”

“…Also, blockade of endothelial luminal side ET B receptor might theoretically decrease nitric oxide and prostacyclin production, favoring vasoconstriction. 13,15,18 Sitaxentan is an orally active competitive ERA that has more selectivity for the ET A receptor. 5,19 In vitro studies have shown that sitaxentan binds almost completely to the ET A receptor, and its ET A :ET B affinity ratio is about 6000:1 (compared to bosentan (40:1) or ambrisentan (77:1)).…”