Alterations in ET-1, not nitric oxide, in 1-week-old lambs with increased pulmonary blood flow

Boaz Ovadia, Olaf Reinhartz, Robert Fitzgerald, Janine M. Bekker, Michael J. Johengen, Anthony Azakie, Stephan Thelitz, Stephen M. Black, Jeffrey R. Fineman

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Altered pulmonary vascular reactivity is a source of morbidity and mortality for children with congenital heart disease and increased pulmonary blood flow. Nitric oxide (NO) and endothelin (ET)- 1 are important mediators of pulmonary vascular reactivity. We hypothesize that early alterations in endothelial function contribute to the altered vascular reactivity associated with congenital heart disease. The objective of this study was to characterize endothelial function in our lamb model of increased pulmonary blood flow at 1 wk of life. Eleven fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 7 days after delivery. The pulmonary vasodilator response to both intravenous ACh (endothelium dependent) and inhaled NO (endothelium independent) was similar in shunted and control lambs. In addition, tissue NOx, NO synthase (NOS) activity, and endothelial NOS protein levels were similar. Conversely, the vasodilator response to both ET-1 and 4Ala-ET-1 (an ETB receptor agonist) were attenuated in shunted lambs, and tissue ET-1 concentrations were increased (P < 0.05). Associated with these changes were an increase in ET-converting enzyme-1 protein and a decrease in ETB receptor protein levels (P < 0.05). These data demonstrate that increased pulmonary blood flow induces alterations in ET-1 signaling before NO signaling and suggest an early role for ET-1 in the altered vascular reactivity associated with increased pulmonary blood flow.

Original languageEnglish (US)
Pages (from-to)H480-H490
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume284
Issue number2 53-2
DOIs
StatePublished - Feb 1 2003

Keywords

  • Endothelin
  • Pulmonary circulation
  • Pulmonary hypertension

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