title: Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow.
abstract: BACKGROUND
  Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow.
  
  
  RESULTS
  Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2+/-113.8 versus 209.8+/-61.8 pg/g, P<0.05). In shunt lambs (n=9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n=3). This pulmonary vasoconstriction was mimicked by exogenous Ala1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n=3). However, in control lambs (n=7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs.
  
  
  CONCLUSIONS
  Over time, increased pulmonary blood flow and/or pressure results in the emergence of ETB-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Ill, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Eugenia
authors.initials: E
authors.lastname: Mata-Greenwood
authors.forename: Robert W
authors.initials: RW
authors.lastname: Dettman
authors.forename: Boaz
authors.initials: B
authors.lastname: Ovadia
authors.forename: Robert K
authors.initials: RK
authors.lastname: Fitzgerald
authors.forename: Olaf
authors.initials: O
authors.lastname: Reinhartz
authors.forename: Stefan
authors.initials: S
authors.lastname: Thelitz
authors.forename: Robin H
authors.initials: RH
authors.lastname: Steinhorn
authors.forename: Rene
authors.initials: R
authors.lastname: Gerrets
authors.forename: Karen
authors.initials: K
authors.lastname: Hendricks-Munoz
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Ross
authors.forename: Janine M
authors.initials: JM
authors.lastname: Bekker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Johengen
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
mesh_terms: D000818:Animals; D004149:Dioxoles / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D006330:Heart Defects, Congenital / Q000150:complications*; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000737:chemistry; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011652:Pulmonary Circulation; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D012756:Sheep; D014661:Vasoconstriction
chemical_list: D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D009842:Oligopeptides; C093321:PD 156707; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C061779:endothelin 1, Ala(1,3,11,15)-; C086539:BQ 788