Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure.
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.
Fratz
Sohrab
S
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
Meyrick
Barbara
B
Ovadia
Boaz
B
Johengen
Michael J
MJ
Reinhartz
Olaf
O
Azakie
Anthony
A
Ross
Greg
G
Fitzgerald
Robert
R
Oishi
Peter
P
Hess
John
J
Black
Stephen M
SM
Fineman
Jeffrey R
JR
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
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