Key result
Sildenafil prevented the increase in pulmonary artery pressure and limited the increase in arteriolar medial thickness to 41% compared to 91% in controls in a piglet model of early PAH.
Why the study?
Does sildenafil improve hemodynamics and signaling molecules in a piglet model of overcirculation-induced early pulmonary arterial hypertension?
RCT (n=30)
randomized
Does sildenafil improve hemodynamics and signaling molecules in a piglet model of overcirculation-induced early pulmonary arterial hypertension?
In a piglet model of overcirculation-induced PAH, sildenafil partially prevents pulmonary hypertension and medial thickening, though it does not fully correct the angiopoietin-1/BMPR-2 or angiotensin II signaling pathways.
Does not support clinical use in early PAH; leaves open translation from piglet models to human disease.
BACKGROUND: The phosphodiesterase type-5 (PDE-5) inhibitor sildenafil has been reported to improve pulmonary arterial hypertension (PAH), but the mechanisms that account for this effect are incompletely understood. Severe pulmonary hypertension has been characterized by defects in a signaling pathway involving angiopoietin-1 and the bone morphogenetic receptor-2 (BMPR-2). We investigated the effects of sildenafil on hemodynamics and signaling molecules in a piglet overcirculation-induced model of early PAH. METHODS AND RESULTS: Thirty 3-week-old piglets were randomized to placebo or sildenafil therapy 0.75 mg/kg TID after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by pulmonary tissue sampling for morphometry, immunohistochemistry or radioimmunoassay, and real-time quantitative-polymerase chain reaction. Chronic systemic-to-pulmonary shunting increased pulmonary mRNA for angiopoietin-1, endothelin-1 (ET-1), angiotensin II, inducible nitric oxide synthase, vascular endothelial growth factor, and PDE-5. Pulmonary messenger RNA for BMPR-1A and BMPR-2 decreased. Pulmonary angiotensin II, ET-1, and vascular endothelial growth factor proteins increased. Pulmonary artery pressure increased from 20+/-2 to 33+/-1 mm Hg, and arteriolar medial thickness increased by 91%. The expressions of angiopoietin-1, ET-1, and angiotensin II were tightly correlated to pulmonary hypertension. Sildenafil prevented the increase in pulmonary artery pressure, limited the increase in medial thickness to 41%, and corrected associated biological perturbations except for the angiopoietin-1/BMPR-2 pathway, PDE-5, and angiotensin II. CONCLUSIONS: Sildenafil partially prevents overcirculation-induced PAH and associated changes in signaling molecules. Angiotensin II, PDE-5, and angiopoietin-1/BMPR-2 signaling may play a dominant role in the early stages of the disease.
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Rondelet et al. (2004) conducted an RCT in Overcirculation-induced early pulmonary arterial hypertension (n=30). Sildenafil vs. Placebo was evaluated on Pulmonary artery pressure and arteriolar medial thickness. Sildenafil prevented the increase in pulmonary artery pressure and limited the increase in arteriolar medial thickness to 41% compared to 91% in controls in a piglet model of early PAH.
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