Submitted on March 15, 2004
Accepted on May 17, 2004
Chronic Endothelin-A Receptor Blockade in Lambs with Increased Pulmonary Blood Flow and Pressure
Sohrab Fratz1*, Barbara Meyrick2, Boaz Ovadia3, Michael J. Johengen3, Olaf Reinhartz3, Anthony Azakie3, Greg Ross3, Robert Fitzgerald3, Peter Oishi3, John Hess4, Stephen M. Black5, and Jeffrey R. Fineman3
1 Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum Muenchen, Munich, Germany; Department of Pediatrics and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA
2 Departments of Pathology and Medicine, Vanderbilt University, Nashville, TN, USA
3 Department of Pediatrics and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA
4 Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum Muenchen, Munich, Germany
5 Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, USA
* To whom correspondence should be addressed. E-mail: fratz{at}dhm.mhn.de.
Endothelin-receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signalling of chronic endothelinA-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 signalling of chronic endothelinA-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 endothelinA-receptor antagonist (PD156707) or placebo. At four weeks age, PD156707-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 PD156707-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, endothelinconverting-
enzyme-1, endothelinA and endothelinB-receptors protein levels were similar in both groups.
We conclude that chronic endothelinA-receptor blockade attenuates the progression of pulmonary
hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.
