Endothelinbreceptor agonists produce pulmonary vasodilation in intact newborn lambs with pulmonary hypertension

Jackson Wong, Paula A. Vanderford, John Winters, Scott J. Soifer, Jeffrey R. Fineman

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

The hemodynamic effects of endothelin-1 (ET-1) are mediated by at least two distinct receptors: ETaand ETbreceptors. Recently, ETbreceptor agonists (4 Ala ET-1 and IRL 1620) were developed. To investigate the role of ETbreceptor activation on the pulmonary and systemic circulations, we studied the hemodynamic effects of intrapulmonary arterial injections of these receptor agonists in 10 intact newborn lambs. At rest, 4 Ala ET-1 (290-1,725 ng/kg) changed no hemodynamic variables. IRL 1620 (180-1,095 ng/kg) decreased mean pulmonary arterial pressure (PAP, 16.8% ± 15.0 and 17.8% ± 8.5, p < 0.05) and left pulmonary artery blood flow (21.6% ± 22.1 and 33.4% ± 27.7, p < 0.05) at the two highest doses only. During U46619-induced pulmonary hypertension, both 4 Ala ET-1 (3.2% ± 8.0 to 15.9% ± 6.4, p < 0.05) and IRL 1620 (8.7% ± 6.3 to 21.9% ±4.1, p < 0.05) produced selective dose-dependent decreases in PAP. The decrease in mean PAP induced by 4 Ala ET-1 and IRL 1620 was attenuated by Nω-nitro-L-arginine [an inhibitor of endothelium-derived nitric oxide (EDNO) synthesis] (16.6% ± 3.5 vs. 5.9% ± 2.3 and 16.2% ± 3.4 vs. 6.6% ± 2.8, p < 0.05) and by glybenclamide (a blocker of ATP-dependent potassium channels) (18.2% ± 7.9 vs. 7.5% ± 8.3 and 14.7% ± 3.6 vs. 6.3% ± 3.2, p < 0.05). ETbreceptor activation produces selective pulmonary vasodilation during pulmonary hypertension in intact newborn lambs. The vasodilating properties are mediated in part by release of EDNO and by potassium channel activation.

Original languageEnglish (US)
Pages (from-to)207-215
Number of pages9
JournalJournal of Cardiovascular Pharmacology
Volume25
Issue number2
DOIs
StatePublished - Feb 1995

Keywords

  • ET-1 receptors
  • Endothelin-1
  • Endothelium-derived nitric oxide
  • Potassium channels
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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