Abstract
Perinatal exposure to chronic hypoxia induces sustained hypertension and structural and functional changes in the pulmonary vascular bed. We hypothesized that highland newborn lambs (HLNB, 3600 m) have a higher pulmonary arterial pressure (PAP) due in part to a higher activity/expression of phosphodiesterase 5 (PDE5). We administered sildenafil, a PDE5 inhibitor, during basal and hypoxic conditions in the pulmonary hypertensive HLNB and compared them to lowland newborn lambs (LLNB, 580 m). Additionally, we compared the vasodilator responses to sildenafil in isolated small pulmonary arteries and the PDE5 mRNA expression and evaluated the vascular remodeling by histomorphometric analysis in these newborn lambs. Under basal conditions, HLNB had a higher PAP and cardiac output compared with LLNB. Sildenafil decreased the PAP during basal conditions and completely prevented the PAP increase during hypoxia in both groups. HLNB showed a greater contractile capacity and a higher maximal dilation to sildenafil. PDE5 mRNA expression did not show significant differences between HLNB and LLNB. The distal pulmonary arteries showed an increased wall thickness in HLNB. Our results showed that HLNB are more sensitive to sildenafil and therefore could be useful for treatment of pulmonary hypertension in high-altitude neonates.
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Abbreviations
- cGMP:
-
cyclic guanosine monophosphate
- CO:
-
cardiac output
- HLNB:
-
highland gestated and born neonatal lamb
- HR:
-
heart rate
- LLNB:
-
lowland gestated and born neonatal lamb
- PAP:
-
pulmonary arterial pressure
- PDE5:
-
phosphodiesterase 5
- PVR:
-
pulmonary vascular resistance
- SAP:
-
systemic arterial pressure
- sGC:
-
soluble guanylate cyclase
- SNP:
-
sodium nitroprusside
- SVR:
-
systemic vascular resistance
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Acknowledgements
The authors thank Carlos Brito, Gabino Llusco, and Enrique Pérez for technical assistance. Sildenafil was kindly donated by Laboratorio Chile S.A. Emilio Herrera is a fellow of Programa MECESUP UCh0115 and Beca Universidad de Chile PG/54/2005.
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Provided by grants FONDECYT 1010636-1050479, The Wellcome Trust CRIG 072256 and ALFA Program Project No. II-0379-FCD.
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Herrera, E., Ebensperger, G., Krause, B. et al. Sildenafil Reverses Hypoxic Pulmonary Hypertension in Highland and Lowland Newborn Sheep. Pediatr Res 63, 169–175 (2008). https://doi.org/10.1203/PDR.0b013e31815ef71c
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DOI: https://doi.org/10.1203/PDR.0b013e31815ef71c
