title: Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure.
abstract: Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in utero placement of an aortopulmonary shunt. Immediately after spontaneous birth, shunt lambs were treated lifelong with either an endothelin A receptor antagonist (PD-156707) or placebo. At 4 wk of age, PD-156707-treated shunt lambs (n = 6) had lower pulmonary vascular resistance and right atrial pressure than placebo-treated shunt lambs (n = 8, P < 0.05). Smooth muscle thickness or arterial number per unit area was not different between the two groups. However, the number of alveolar profiles per unit area was increased in the PD-156707-treated shunt lambs (190.7 +/- 5.6 vs. 132.9 +/- 10.0, P < 0.05). Plasma endothelin-1 and cGMP levels and lung NOS activity, cGMP, eNOS, preproendothelin-1, endothelin-converting enzyme-1, endothelin A, and endothelin B receptor protein levels were similar in both groups. We conclude that chronic endothelin A receptor blockade attenuates the progression of pulmonary hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.
authors.affiliation: Dept. of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum München, Klinik an der Technischen Universität München, Lazarettstr. 36, 80636 Munich, Germany. fratz@dhm.mhn.de
authors.forename: Sohrab
authors.initials: S
authors.lastname: Fratz
authors.forename: Barbara
authors.initials: B
authors.lastname: Meyrick
authors.forename: Boaz
authors.initials: B
authors.lastname: Ovadia
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Johengen
authors.forename: Olaf
authors.initials: O
authors.lastname: Reinhartz
authors.forename: Anthony
authors.initials: A
authors.lastname: Azakie
authors.forename: Greg
authors.initials: G
authors.lastname: Ross
authors.forename: Robert
authors.initials: R
authors.lastname: Fitzgerald
authors.forename: Peter
authors.initials: P
authors.lastname: Oishi
authors.forename: John
authors.initials: J
authors.lastname: Hess
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D008666:Metalloendopeptidases; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011247:Pregnancy; D011652:Pulmonary Circulation / Q000502:physiology*; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism; D012756:Sheep
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D009566:Nitrates; D009573:Nitrites; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D006152:Cyclic GMP