Endothelin receptor blockade in the management of pulmonary arterial hypertension: selective and dual antagonism.
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.
Trow
Terence K
TK
Yale University School of Medicine, Division of Internal Medicine, Section of Pulmonary and Critical Care Medicine, Yale Pulmonary Hypertension Center, 333 Cedar Street, LCI 105D, PO Box 208057, New Haven, CT 06520-8057, USA. terence.trow@yale.edu
Taichman
Darren B
DB
D042783:Endothelial Cells / Q000378:metabolism*; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D011651:Pulmonary Artery / Q000378:metabolism*; D016032:Randomized Controlled Trials as Topic; D020239:Receptor Cross-Talk; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D014481:United States; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B