Piriprost: A Putative Leukotriene Synthesis Inhibitor Increases Pulmonary Blood Flow in Fetal Lambs

Abstract

ABSTRACT. Leukotrienes may control fetal pulmonary vascular tone since infusions of putative leukotriene receptor antagonists markedly increase pulmonary blood flow and decrease pulmonary vascular resistance in fetal lambs. 'This hypothesis would be strengthened if inhibition of leukotriene synthesis also produced similar hemodynamic changes. We therefore studied the effects of piriprost (U 60257), a putative leukotriene synthesis inhibitor, on thirteen fetal lambs at 137 to 140 days gestation. In preliminary studies in four fetal lambs, doses of U 60257 greater than 20 mg/kg increased pulmonary blood flow. In the nine other fetal lambs, U 60257 (31.7 + 4.1 mg/kg) increased pulmonary blood flow by 502% ( p < 0.05) and decreased pulmonary vascular resistance by 87% ( p < 0.05). Pulmonary arterial and left atrial pressures were unchanged.Descending aortic pressure was increased ( p < 0.05) and heart rate was decreased ( p < 0.05). The abilities of both putative leukotriene synthesis inhibitors and leukotriene receptor antagonists to similarly increase fetal pulmonary blood flow and decrease pulmonary vascular resistance are consistent with the hypothesis that leukotrienes play a role in regulating fetal pulmonary vascular tone. (Pediatr Res 22: 350-354, 1987) Abbreviation SaOz, hemoglobin oxygen saturationIn the fetus, pulmonary blood flow is low, representing less than 10% of combined ventricular output. This low pulmonary blood flow is maintained by a high pulmonary vascular resistance (I). During the early part of gestation, the high pulmonary vascular resistance is likely maintained by the small cross-sectional area of the pulmonary vascular bed. During the latter part of gestation, the high pulmonary vascular resistance is likely maintained in part by active vasoconstriction of the muscularized small pulmonary arteries (1-3). The mechanisms involved in this vasoconstriction remain to be fully explored.Leukotrienes C4 and D4, products of 5'-lipoxygenase pathway of arachidonic acid metabolism, induce pulmonary vasoconstriction in various species (4-8). They also may play a role in the development of hypoxic pulmonary hypertension (9-14). We have investigated'the role of leukotrienes in the control of high pulmonary vascular resistance and low pulmonary blood flow in fetal lambs. Infusions of putative leukotriene receptor antagonists (FPL 55712 and FPL 57231, Fisons, plc Loughborough, UK) increased pulmonary blood flow (3). This increase was similar in magnitude to the 8-to 10-fold increase in pulmonary blood flow occurring spontaneously with ventilation at birth (I). We concluded that leukotrienes may regulate pulmonary vascular resistance in the fetus. However, the hemodynamic effects produced by these leukotriene receptor antagonists may have been caused by nonspecific effects of these compounds. Our hypothesis that leukotrienes are involved in maintaining the pulmonary vascular resistance in the fetus would be strengthened if inhibition of leukotriene synthesis also produced similar hemodynamic changes....