title: Dual ET(A)/ET(B) vs. selective ET(A) endothelin receptor antagonism in patients with pulmonary hypertension.
abstract: Since the identification of endothelin as a key mediator in the pathogenesis of several diseases, including pulmonary arterial hypertension (PAH), the pharmacologic control of the activated endothelin system with endothelin receptor antagonists (ETRA) has been a major therapeutic achievement for the treatment of patients with PAH. To date, dual ET(A)/ET(B) and selective ET(A) receptor antagonists have clinically been evaluated. To answer the question of whether selective or dual ETRA is preferable in patients with PAH, experimental and clinical data with relevance to the pulmonary circulation are reviewed in this article. Whereas experimental and clinical data provide unambiguous evidence that ET(A) receptors mediate the detrimental effects of ET-1, such as vasoconstriction and cell proliferation, the elucidation of the role of ET(B) receptors has been more complex. It has been shown that there is a subpopulation of ET(B) receptors on smooth muscle cells and fibroblasts mediating vasoconstriction and proliferation. On the contrary, there is clear evidence that endothelial ET(B) receptors continue to mediate vasodilation, vasoprotection and ET-1 clearance despite the pathology associated with pulmonary hypertension. More difficult to assess is the net effect of these mechanisms in patients to be treated with ETRA. When considering the available data from controlled clinical trials, nonselectivity does not appear to carry a relevant clinical benefit for the treatment of patients with PAH when compared with selective ET(A) receptor antagonism.
authors.affiliation: Medizinische Klinik II, DRK-Kliniken Berlin, Westend, Berlin, Germany. c.opitz@drk-kliniken-westnd.de
authors.forename: C F
authors.initials: CF
authors.lastname: Opitz
authors.forename: R
authors.initials: R
authors.lastname: Ewert
mesh_terms: D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use; D000077300:Bosentan; D002455:Cell Division / Q000502:physiology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D007555:Isoxazoles / Q000009:adverse effects / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000209:etiology; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; D013449:Sulfonamides; D013876:Thiophenes; C106276:sitaxsentan; D000077300:Bosentan