title: Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment.
abstract: Endothelin receptor antagonists are used to treat idiopathic pulmonary arterial hypertension (IPAH), but human pulmonary arterial endothelin receptor expression is not well defined. We hypothesised that disease and treatment would modify normal receptor distribution in pulmonary resistance arteries of children. Using immunohistochemistry and semiquantitative analysis, we investigated endothelin receptor subtypes A and B (ET(A) and ET(B), respectively), and endothelial nitric oxide synthase (eNOS) expression in peripheral pulmonary arteries of tissue from untreated children with IPAH (n=7), following extended combined bosentan and epoprostenol therapy (n=5) and from normal subjects (n=5). Clinical, haemodynamic and pathological abnormalities were severe and advanced in all IPAH cases. ET(A) was detected in pulmonary arterial endothelial cells of all normal and diseased tissue and cultured cells. Endothelial ET(A), ET(B) and eNOS expression was reduced in patent, plexiform and dilatation lesions of untreated cases, but in treated cases, ET(A) and ET(B) were normal and eNOS increased. In smooth muscle, ET(A) expression was reduced in treated cases but ET(B) expression increased in all arteries of both treated and untreated cases. In summary, ET(A) is expressed on human pulmonary arterial endothelium. In IPAH, combination treatment with bosentan and epoprostenol had a more marked influence on endothelin receptor expression of endothelial than smooth muscle cells.
authors.affiliation: Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. s.hall@ich.ucl.ac.uk
authors.forename: S M
authors.initials: SM
authors.lastname: Hall
authors.forename: N
authors.initials: N
authors.lastname: Davie
authors.forename: N
authors.initials: N
authors.lastname: Klein
authors.forename: S G
authors.initials: SG
authors.lastname: Haworth
mesh_terms: D000293:Adolescent; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000077300:Bosentan; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D011464:Epoprostenol / Q000627:therapeutic use*; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000627:therapeutic use; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D011687:Purines / Q000627:therapeutic use; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000627:therapeutic use*; D013450:Sulfones / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D010879:Piperazines; D011687:Purines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D011464:Epoprostenol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D009543:Nifedipine; D000077300:Bosentan