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Am J Physiol Heart Circ Physiol (July 15, 2005). doi:10.1152/ajpheart.00518.2005
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Submitted on May 18, 2005
Accepted on July 11, 2005

PREVENTION OF PULMONARY VASCULAR REMODELLING AND OF DECREASED BMPR-2 EXPRESSION BY LOSARTAN THERAPY IN SHUNT-INDUCED PULMONARY HYPERTENSION

Benoit Rondelet1*, Francois Kerbaul2, Ronald Van Beneden1, Ives Hubloue1, Sandrine Huez1, Pierre Fesler1, Myriam Remmelink3, Serge Brimioulle1, Isabelle Salmon3, and Robert Naeije1

1 Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium
2 Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium; Department of Anesthesiology and Critical Care, La Timone Hospital, Marseille, France
3 Department of Pathology, Erasme Hospital, Free University of Brussels, Brussels, Belgium

* To whom correspondence should be addressed. E-mail: benoit.rondelet{at}ulb.ac.be.

The renin-angiotensin-system is has been reported to be overexpressed in pulmonary arterial hypertension (PAH). We investigated the effects of angiotensin receptor-1 blockade by losartan on hemodynamics and signaling molecules in a piglet overflow model of early PAH. Twenty-six 3-weeks-old piglets were randomized to placebo or losartan therapy 1mg/kg/day after anastomosis of the inominate to the main pulmonary artery or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time-quantitative-PCR. Chronic systemic-to-pulmonary shunting increased the pulmonary vascular resistance from 2.5 ± 0.2 to 6.2 ± 0.3 mmHg.l-1.min.m-2 and arteriolar medial thickness from 13.6 to 25.4 %. These changes were associated with increased expressions of angiotensin-II and its type 1 (AT-1) and type 2 (AT-2) receptors, endothelin-1 and its receptor-B (ET-B), and angiopoietin-1, together with decreased expressions of bone morphogenic protein receptor-1A and -2 (BMPR-1A and BMPR-2) and unchanged expression of Tie-2. Pretreatment with losartan decreased shunt-induced pulmonary vascular resistance and medial thickness by respectively 51 % and 35%. Losartan therapy was associated with persistent overexpressions of angiotensin-II, AT-2, endothelin-1, ET-B, angiopoietin-1, and with a return to normal of the expression of BMPR-2. Conclusions: These results suggest that angiotensin-II contributes to in left-to-right shunt-induced PAH.




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