Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 287; no. 3; pp. L592 - L597
• Main Authors: Fratz, Sohrab, Meyrick, Barbara, Ovadia, Boaz, Johengen, Michael J, Reinhartz, Olaf, Azakie, Anthony, Ross, Greg, Fitzgerald, Robert, Oishi, Peter, Hess, John, Black, Stephen M, Fineman, Jeffrey R
• Format: Journal Article
• Language: English
• Published: United States 01.09.2004
• Subjects: Animals; Aspartic Acid Endopeptidases - metabolism; Cyclic GMP - metabolism; Endothelin A Receptor Antagonists; Endothelin-1 - blood; Endothelin-1 - metabolism; Endothelin-Converting Enzymes; Female; Hypertension, Pulmonary - physiopathology; Metalloendopeptidases; Nitrates - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase - metabolism; Nitrites - metabolism; Pregnancy; Pulmonary Circulation - physiology; Receptor, Endothelin A - metabolism; Receptor, Endothelin B - metabolism; Sheep
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00093.2004

1 Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum München, 80636 Munich, Germany; 2 Department of Pediatrics and the Cardiovascular Research Institute, University of California, San Francisco, California 94143; 3 Departments of Pathology and Medicine, Vanderbilt University, Nashville, Tennessee 37235; and 4 Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana 59812 Submitted 15 March 2004 ; accepted in final form 17 May 2004 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. pulmonary heart disease; congenital heart defect Address for reprint requests and other correspondence: S. Fratz, Dept. of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum München, Klinik an der Technischen Universität München, Lazarettstr. 36, 80636 Munich, Germany (E-mail: fratz{at}dhm.mhn.de )