Endothelin receptor blockade does not alter the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs.
At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs with oxygen. Both mechanical and humoral factors are involved, including the release of vasoactive substances such as prostacyclin and endothelium-derived nitric oxide (EDNO). However, the exact mechanisms remain unclear. Because endothelin-1 (ET-1) produces potent pulmonary vasodilation in the fetus via EDNO release and ET-1 concentrations are increased at birth, we considered that ET-1 activity may participate in the pulmonary vasodilation that occurs with O2 ventilation. Therefore, we studied and compared the changes in pulmonary hemodynamics associated with in utero O2 ventilation with and without ET-1 receptor blockade induced by an infusion of Ro 47-0203 (Bosentan, a nonselective ET receptor antagonist), in 13 late-gestation fetal lambs. In all fetal lambs, prostaglandin synthesis was prevented by an infusion of meclofenamate, and ductus arteriosus constriction was prevented by prior formalin infiltration. The infusion of Ro 47-0203 blocked the decrease in pulmonary vascular resistance induced by injections of either ET-1 (-0.985 versus +0.012 mm Hg/mL/min/100 g of lung, p < 0.05) or 4-Ala-ET-1 (an ETb receptor agonist) (-0.717 versus -0.052 mm Hg/mL/min/100 g of lung, p < 0.05). However, ET receptor blockade did not change the increase in pulmonary blood flow or decrease in pulmonary vascular resistance associated with in utero O2 ventilation. This study suggests that endogenous ET-1 activity does not play an important role in the vasodilatory response to ventilation with O2 in utero.
Winters
J W
JW
Department of Pediatrics, University of California San Francisco 94143, USA.
Wong
J
J
Van Dyke
D
D
Johengen
M
M
Heymann
M A
MA
Fineman
J R
JR
D000818:Animals; D000077300:Bosentan; D005314:Embryonic and Fetal Development / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular; D005865:Gestational Age; D006439:Hemodynamics / Q000187:drug effects; D007263:Infusions, Parenteral; D010100:Oxygen / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D012121:Respiration, Artificial; D012756:Sheep; D013449:Sulfonamides / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D013449:Sulfonamides; C061779:endothelin 1, Ala(1,3,11,15)-; D000077300:Bosentan; D010100:Oxygen