Endothelin-1 does not mediate acute hypoxic pulmonary vasoconstriction in the intact newborn lamb.
The mechanisms by which acute alveolar hypoxia induces pulmonary vasoconstriction remain unclear. Previous studies suggest that hypoxia-induced vasoconstriction is endothelium-dependent and is associated with the release of endothelin-1 (ET-1), a potent vasoactive paracrine hormone produced by vascular endothelial cells. The vasoconstrictive effects of ET-1 are likely to be mediated by ETA receptors located on vascular smooth-muscle cells. BQ-123 is a selective ETA receptor antagonist. To determine the role of ET-1 and ETA receptors on resting tone and hypoxic pulmonary vasoconstriction, we studied the effects of ET-1 and BQ-123 at rest and during hypoxia-induced pulmonary vasoconstriction in 12 intact newborn lambs (< 1 week old). At rest, the intrapulmonary infusion of BQ-123 did not change resting pulmonary arterial pressure but completely blocked the rapid increase in pulmonary artery pressure produced by high doses of ET-1 (2,000 ng/kg) (23.0 +/- 10.8% versus -12.6 +/- 27.5%; p < 0.05). During mechanical ventilation there was no difference in the increase in mean pulmonary arterial pressure and pulmonary vascular resistance induced by alveolar hypoxia before and after BQ-123 (34.0 +/- 8.9% versus 30.5 +/- 10.9% and 25.3 +/- 11.6% versus 35.2 +/- 22.4%). This study suggests that the pulmonary vasoconstrictive effects of ET-1 are mediated by ETA receptors and that ET-1 does not mediate acute hypoxic pulmonary vasoconstriction in intact newborn lambs.
Wong
J
J
Department of Pediatrics, University of California, San Francisco 94143-0106.
Vanderford
P A
PA
Winters
J W
JW
Chang
R
R
Soifer
S J
SJ
Fineman
J R
JR
D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology*; D009129:Muscle Tonus / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects*; D017466:Receptors, Endothelin / Q000187:drug effects; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)