ABSTRACT. Leukotrienes C4 and Dd and thromboxane A2 are potent vasoconstrictors that may mediate pulmonary vasoconstriction in many clinical situations. There is a complex interaction among leukotrienes and thromboxane A2, because inhibition of thromboxane synthesis prevents some of the hemodynamic effects of exogenous leukotrienes. Similarly, if leukotrienes mediate thromboxane A*-induced pulmonary vasoconstriction, then leukotriene antagonists should attenuate the effects of a thromboxane A2-mimetic such as U46619. First, dose response curves for the hemodynamic effects of U46619 were performed on seven spontaneously breathing newborn lambs. Then a putative leukotriene receptor antagonist, FPL57231,l mg/ kg/min, or a putative leukotriene synthesis antagonist, U60257, 30 mg/kg, was given before infusing U46619 (1 pg/kg/min). U46619 caused significant dose-dependent increases in pulmonary and systemic arterial pressures (p < Metabolites of arachidonic acid may mediate the pulmonary vasoconstriction seen in utero (1,2) and during alveolar hypoxia (3-6). They may also be important mediators of the hemodynamic changes occumng in the adult respiratory distress syndrome (7), endotoxic shock (8-14), and the syndrome of persistent pulmonary hypertension of the newborn (15). The most potent pulmonary vasoconstricting metabolites of arachidonic acid are the peptidoleukotrienes (leukotrienes C4 and D4) (16-IS), formed via the lipooxygenase pathway, and thromboxane A2 (8, 10, 1 1, 13, 14), formed via the cyclooxygenase pathway. There is a complex interaction among these leukotrienes and thromboxane Az. TO date, the evidence suggests that leukotriene C4 and D4 stimulate the production of thromboxane A2 (16, 18-2 1). These studies would imply that thromboxane A2 is involved in leukotriene-induced pulmonary vasoconstriction. The pur- Supported by Grants HL 355 18 and HL 24056 from the National Heart, Lung and Blood Institute and by a Grant-in-Aid from the American Lung Association.
8pose of the present study was to investigate the other possibility: that thromboxane A2 stimulates the production or release of leukotrienes. Because of the instability of thromboxane A2 and the limited potency of its stable measurable metabolite, thromboxane Bz, we used the specific thromboxane Az-mimetic, U46619 (Upjohn Co., Kalamazoo, MI) (22-29). In newborn lambs, after characterizing the pulmonary and systemic hemodynamic effects of U466 19 by performing dose-response studies, we attempted to block or attenuate the hemodynamic response to U466 19 using FPL5723 1, a putative leukotriene receptor antagonist (Fisons plc, Loughborough, England) (2, 5, 16) and U60257, a putative leukotriene synthesis inhibitor (Upjohn) (1, 6, 30-34).
MATERIALS AND METHODS
Surgical Preparations.Under local anesthesia with 1 % lidocaine hydrochloride, seven newborn lambs at 1 to 3 d of age had polyvinyl catheters placed into a hind leg artery and vein and advanced to the descending aorta and inferior vena cava, respectively. General anesthesia was then induced by ha...