In Vivo and In Vitro Actions of a New Selective Inhibitor of Leukotriene C and D Synthesis

Mk, Bach; Brashler,; Fa, Fitzpatrick; Rl, Griffin; Ss, Iden; Hg, Johnson; Ml, McNee; Jc, McGuire; Hw, Smith; Rj, Smith; Ff, Sun; Ma, Wasserman

doi:10.1016/b978-0-08-029775-0.50075-4

Cited by 10 publications

(5 citation statements)

References 6 publications

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“…U 60257 has been shown to inhibit lcukotricnc production Ssom calcium ionophorc-challcrrgcd rat peritoneal m o n o n u c l c :~~ cclls and l'rorn human polyrnorl~lior~~~clcar leukocytes as \lie11 as fiom antigen-sensitid chopped human lung (22)(23)(24)(25)(26). 11 00757 also prevents the pulmonary hqpcrtcnsion induced h> hypoxia in isolated pcrfused rat Ii~ngs ( I I ) and intact newborn lambs (14) anci prevents in a dose-dcpcncicnt manner the bronc1ioconst1-iction and pulmonary function ahnormalitics in anir-nal models of' asthma (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

“…U 60257 inhibits leukotriene synthesis by inhibiting both the 5'-lipoxygenase and LTD4 synthetase enzyme steps (22)(23)(24)(25)(26). U 60257 has been shown to inhibit lcukotricnc production Ssom calcium ionophorc-challcrrgcd rat peritoneal m o n o n u c l c :~~ cclls and l'rorn human polyrnorl~lior~~~clcar leukocytes as \lie11 as fiom antigen-sensitid chopped human lung (22)(23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1987

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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....

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 1987

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“…U60257 inhibits leukotriene synthesis from human leukocytes, antigen-sensitized human lung and rat mononuclear cells at both the 5' lipoxygenase and leukotriene D4 synthetase steps (3 1-34). Although U60257 is an analog of prostacyclin, it does not have any platelet antiaggregating effects (33,34). The hemodynamic effects of U60257 are therefore likely not mediated by prostacyclin.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene Antagonists Attenuate Thromboxane-Inducible Pulmonary Hypertension

1989

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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...

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“…We have attempted to investigate the contribution of sulphidopeptide LTs to allergen-induced bronchoconstriction using the LT synthesis inhibitor, piriprost (U-60,257). Both in human lung fragments [51] and in dispersed lung cells [52], piriprost has been shown to inhibit the synthesis and release of 5-lipoxygenase products. When administered in an inhaled dose of 1 mg, which on a milligram-per-kilogram basis had been shown to attenuate allergen-induced bronchoconstriction in guinea-pigs [53], we have been unable to detect any reduction in the airways response to in haled allergen at any time point up to 60 min [54].…”

Section: Pharmacological Dissection O F the Immediate Asthmatic Reactionmentioning

confidence: 99%

Primary and Secondary Effector Cells in the Pathogenesis of Bronchial Asthma

Holgate¹,

Twentyman²,

Rafferty³

et al. 1987

Int Arch Allergy Immunol

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The immediate and late asthmatic reactions provoked by inhaled allergens have provided useful models enabling the dissection of individual inflammatory cells and their mediators that may contribute to the pathogenesis of asthma. The immediate reaction is considered to be mast cell-mediated on the basis that about 50% of the response is inhibitable by potent and selective H₁-receptor antagonists such as terfenadine and astemizole. Additional inhibition (∼30%) by the potent cyclooxygenase inhibitor flurbiprofen implies an important role for prostanoids in the immediate response, the most likely mast cell-derived product being prostaglandin (PG) D₂. In man, PGD2 is selectively metabolised to 9α1 1β-PGF₂, a unique prostaglandin which shares with PGD₂ contractile properties on guinea-pig and human airways smooth muscle. The inability of piriprost, a potent leukotriene synthesis inhibitor, to influence the allergen-provoked immediate reaction raises the possibility that sulphidopeptide leukotrienes play a minor role in this response. The late asthmatic reaction is considered to resemble clinical asthma since it is accompanied by increased responsiveness of the airways to a wide range of stimuli. The late reaction in man is inhibited by nedocromil sodium (4 mg) but only marginally attenuated by salbutamol (200 μg) if both drugs are administered prior to allergen challenge. Since salbutamol, in the dose administered, is a potent mast cell-stabilising agent, these findings must question the obligatory role of mast cell mediator release in the pathogenesis of the late response. A model of the late reaction in conscious guinea-pigs demonstrates a selective influx of neutrophils followed by eosinophils 6–12 h after challenge in relation to the late reaction, suggesting a role for these secondary effector cells in mediating this response and possibly the acquisition of increased bronchial responsiveness. These human and animal studies demonstrate a complex interaction of primary and secondary effector cells in the pathogenesis of bronchoconstrictor responses to allergen and should help to clarify the contribution of ‘inflammation’ to clinical asthma.

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In Vivo and In Vitro Actions of a New Selective Inhibitor of Leukotriene C and D Synthesis

Cited by 10 publications

References 6 publications

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

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

Leukotriene Antagonists Attenuate Thromboxane-Inducible Pulmonary Hypertension

Primary and Secondary Effector Cells in the Pathogenesis of Bronchial Asthma

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