Prevention of Pulmonary Vascular Remodelling and of Decreased Bmpr-2 Expression by Losartan Therapy in Shunt-induced Pulmonary Hypertension

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. These results suggest that angiotensin-II contributes to in left-to-right shunt-induced PAH.