title: Leukotriene D4 and hypoxia: differential effects on the pulmonary and systemic circulations in newborn piglets.
abstract: Hypoxia-induced release of cysteinyl leukotriene from pulmonary macrophages has been considered an important mechanism mediating hypoxic pulmonary vasoconstriction in the immature circulation. However, studies leading to this conclusion blocked hypoxic pulmonary vasoconstriction by relatively nonspecific LT antagonists. We have evaluated this hypothesis further by separate measurement of the hemodynamic effects of leukotriene D4 (LTD4) and hypoxia before and after administration of the highly specific leukotriene D4/E4 antagonist LY 171883 (LY). Anesthetized, open-chest newborn piglets were exposed to LTD4 0.1-3 micrograms/kg IV, or to hypoxia (12% 02 + 88% N2, for 3 min) prior and subsequent to LY 30 mg/kg IV (n = 7) or saline vehicle (n = 5). LTD4 administration before LY caused a 37% - 446% increase in pulmonary vascular resistance index (PVRI) (p less than 0.05). With LTD4 mean pulmonary artery pressure (PAP) rose 14% - 69% (p less than 0.05), left ventricular end-diastolic pressure (LVEDP) rose 18% - 160% (p less than 0.05) and systemic vascular resistance index (SVRI) increased 88% - 100% (p less than 0.05). Cardiac index (CI) and left ventricular shortening fraction (LVSF) fell only at peak LTD4 dose (92 +/- 7 to 49 +/- 8 ml/kg/min, 12 +/- 1 to 6 +/- 1%, both p less than 0.05). Hypoxia produced a 69% rise in PAP and a 122% increase in PVRI, both p less than 0.01. LY abolished LTD4-induced changes in PVRI, PAP, LVEDP, CI, SVRI, and LVSF, but had no effect on the hypoxic rise in PAP and PVRI. Thus, doses of LY which completely inhibited the substantial circulatory actions of LTD4 failed to alter hypoxic pulmonary vasoconstriction. The results suggest that acute hypoxic pulmonary vasoconstriction in newborn piglets is not attenuated by selective LTD4/E4 receptor antagonism.
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
authors.forename: L M
authors.initials: LM
authors.lastname: Bradley
authors.forename: G
authors.initials: G
authors.lastname: Feuerstein
authors.forename: R E
authors.initials: RE
authors.lastname: Goldstein
authors.forename: J F
authors.initials: JF
authors.lastname: Czaja
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D010100:Oxygen / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000098:Acetophenones; D013189:SRS-A; D013777:Tetrazoles; C044660:LY 171883; D010100:Oxygen