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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 18, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm013
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Carbon monoxide: A novel pulmonary artery vasodilator in neonatal llamas of the Andean altiplano

Emilio A. Herreraa,b,h,*, Roberto V. Reyesa,*, Dino A. Giussanib, Raquel A. Riquelmec, Emilia M. Sanhuezaa, Germán Ebenspergera,i, Paola Casanelloa,{dagger}, Natalia Méndeza, Renato Ebenspergera, Esteban Sepúlveda-Kattana,{ddagger}, Victor M. Pulgara,{ddagger}, Gertrudis Cabellod,i, Carlos E. Blancoe, Mark A. Hansonf, Julian T. Parerg and Aníbal J. Llanosa,h,i,#

a Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago
b Department of Physiology, Development & Neuroscience, University of Cambridge, UK
c Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago
d Facultad de Ciencias, Universidad de Tarapacá, Arica, Chile
e Department of Pediatrics, University of Maastricht, he Netherlands
f Centre for Developmental Origins of Health and Disease, University of Southampton, UK
g Department of Obstetrics and Gynecology, University of California San Francisco, USA
h International Centre for Andean Studies (INCAS), Universidad de Chile, Santiago-Arica
i Universidad de Tarapacá y Centro de Investigaciones del Hombre en el Desierto, Arica

# Corresponding author: Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Salvador 486, CP6640871, Santiago, Chile; Phone: 56-2-3419147; Fax: 56-2-2741628; email: allanos{at}med.uchile.cl

Aims: To study the nitric oxide (NO) and carbon monoxide roles in the regulation of the pulmonary circulation in lowland and highland newborn sheep and llamas.

Methods: We used neonatal sheep (Ovis aries) and llamas (Lama glama) whose gestation and delivery took place at low (580 m) or high (3,600 m) altitude. In vivo, we measured the cardiopulmonary function basally and with a NO synthase (NOS) blockade and calculated the production of carbon monoxide by the lung. In vitro, we determined NOS and soluble guanylate cyclase (sGC) expression, NOS activity and heme-oxygenase (HO) expression in the lung.

Results: Pulmonary arterial pressure was elevated at high altitude in sheep but not in llamas. Sheep at high altitude relative to sea level had significantly greater total lung NOS activity and eNOS protein, but reduced sGC and HO expression and carbon monoxide production. In contrast, llamas showed no difference in NO function between altitudes, but a pronounced increase in pulmonary carbon monoxide production and HO expression at high altitude.

Conclusions: In the llama, enhanced pulmonary carbon monoxide, rather than NO, protects against pulmonary hypertension in the newborn period at high altitude. This shift in pulmonary dilator strategy from NO to carbon monoxide has not been previously described, and it may give insight into new treatments for excessive pulmonary vasoconstriction.

KEYWORDS hypoxia/anoxia; pulmonary circulation; endothelial function; nitric oxide; vasoconstriction/dilation

Time for primary review: 17 days

* These authors contributed equally.

{dagger} Current address: Pontificia Universidad Católica de Chile, Santiago, Chile.

{ddagger} Current address: Department of Obstetrics and Gynecology, Wake Forest University, Winston Salem NC 27157, USA.


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