Effects of timolol, indomethacin, and MK-571 on bronchoconstriction to infused leukotriene D4 in guinea pigs

1990 ◽  
Vol 68 (7) ◽  
pp. 783-790 ◽  
Author(s):  
P. Masson ◽  
T. R. Jones
Keyword(s):  
Receptor Antagonist ◽  
Guinea Pigs ◽  
Dynamic Compliance ◽  
Cyclooxygenase Inhibitor ◽  
Leukotriene D4 ◽  
Duration Of Action ◽  
Adrenoceptor Antagonist ◽  
Lung Resistance ◽  
Leukotriene Receptor ◽  
Delayed Time

Continuous intravenous infusions of leukotriene D4 produced a prolonged but variable bronchoconstriction (approximately a 200% increase in lung resistance (RL) and a 50% decrease in dynamic compliance (Cdyn)) in anesthetized and paralysed guinea pigs that peaked within 1–1.5 min and was followed by a somewhat smaller secondary plateau response. The overall response was delayed (time to peaks) but not significantly reduced by pretreatment with the cyclooxygenase inhibitor indomethacin (1 mg/kg), was markedly potentiated by the β-adrenoceptor antagonist timolol (5 μg/kg), and was partially and completely blocked by pretreatment with 0.1 and 1.0 mg/kg, respectively, of the leukotriene D4 receptor antagonist MK-571. MK-571 prevented the response in indomethacin-treated guinea pigs but was considerably more active at preventing and reversing the potentiated responses (lower dose of leukotriene D4) in animals treated with indomethacin and timolol. Additional studies in indomethacin- and timolol-treated animals demonstrated that MK-571 was active with good duration of action by the aerosol route of administration (30 min and 4 h pretreatment). The technique of infusing leukotrienes into untreated, indomethacin-treated, and indomethacin- and timolol-treated guinea pigs is a useful method to study the action and interaction of leukotriene receptor antagonists.Key words: leukotriene receptor antagonists, cyclooxygenase inhibitor, β-adrenoceptor blockade in guinea pigs, MK-571, L-648,051.

Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist

1989 ◽  
Vol 67 (1) ◽  
pp. 17-28 ◽  
Author(s):  
T. R. Jones ◽  
R. Zamboni ◽  
M. Belley ◽  
E. Champion ◽  
L. Charette ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Receptor Antagonist ◽  
Guinea Pigs ◽  
Competitive Inhibitor ◽  
Dose Ratio ◽  
Leukotriene D4 ◽  
Small Component ◽  
Human Trachea ◽  
D4 Receptor ◽  
Orally Active

L-660,711 (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl) ((3-dimethyl amino-3-oxo propyl)thio)methyl)thio)propanoic acid is a potent and selective competitive inhibitor of [3H]leukotriene D4 binding in guinea pig (Ki value, 0.22 nM) and human (Ki value, 2.1 nM) lung membranes but is essentially inactive versus [3H]leukotriene C4 binding (IC50 value in guinea pig lung, 23 μM). Functionally it competitively antagonized contractions of guinea pig trachea and ileum induced by leukotriene (LT) D4 (respective pA2 values, 9.4 and 10.5) and LTE4 (respective pA2 values, 9.1 and 10.4) and contractions of human trachea induced by LTD4 (pA2 value, 8.5). L-660,711 (5.8 × 10−8 M) antagonized contractions of guinea pig trachea induced by LTC4 in the absence (dose ratio = 28) but not in the presence of 45 mM L-serine borate (dose ratio <2). L-660,711 (1.9 × 10−5 M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2α, U-44069, or PGD2. In the presence of atropine, mepyramine, and indomethacin, L-660,711 (1.9 × 10−5 M) inhibited a small component of the response to antigen on guinea pig trachea but completely blocked anti-IgE-induced contractions of human trachea. L-660,711 (i.v.) antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. LTC4, LTD4, and LTE4 but did not block bronchoconstriction to arachidonic acid, U-44069, 5-hydroxytryptamine, histamine, or acetylcholine. Intraduodenal L-660,711 antagonized LTD4 (0.2–12.8 μg/kg) -induced bronchoconstriction in guinea pigs, and p. o. L-660,711 blocked LTD4- and Ascaris-induced bronchoconstriction in conscious squirrel monkeys and ovalbumin-induced bronchoconstriction in conscious sensitized rats treated with methysergide (3 μg/kg). The pharmacological profile of L-660,711 indicates that it is a potent, selective, orally active leukotriene receptor antagonist which is well suited to determine the role played by LTD4 and LTE4 in asthma and other pathophysiologic conditions.

Sulfidopeptide leukotrienes mediate acrolein-induced bronchial hyperresponsiveness

1989 ◽  
Vol 66 (4) ◽  
pp. 1838-1845 ◽  
Author(s):  
G. D. Leikauf ◽  
C. A. Doupnik ◽  
L. M. Leming ◽  
H. E. Wey
Keyword(s):  
Receptor Antagonist ◽  
Guinea Pigs ◽  
Bronchoalveolar Lavage Fluid ◽  
Bronchial Hyperresponsiveness ◽  
Lavage Fluid ◽  
Lipid Mediators ◽  
Leukotriene Receptor Antagonist ◽  
Bronchial Responsiveness ◽  
Lipoxygenase Inhibitors ◽  
Leukotriene Receptor

The sulfidopeptide leukotrienes are bronchoconstrictive lipid mediators thought to have an important role in the pathophysiology of asthma. The objective of this study was to determine if treatment with a leukotriene receptor antagonist and 5-lipoxygenase inhibitors could diminish acrolein-induced bronchial hyperresponsiveness and to determine whether leukotriene (LT) C4 generation is augmented by acrolein exposure. Guinea pigs (groups of 6–7) were exposed to 1.3 ppm acrolein for 2 h and bronchial responsiveness to intravenous acetylcholine determined twice before, and once 1, 2, 6, and 24 h after exposure. Immediately after acrolein exposure (5 min) specific total airway resistance (sRt) increased from 0.86 +/- 0.01 to 1.29 +/- 0.07 ml.cmH2O.ml-1.s. Within 1 h after exposure, the effective dose of acetylcholine sufficient to double sRt (ED200) decreased from 114.0 +/- 6.6 to 58.5 +/- 6.5 micrograms.kg-1.min-1. Bronchial hyperresponsiveness became maximal at 2 h with ED200 = 44.7 +/- 4.2 and persisted for up to 24 h after exposure (24 h ED200 = 60.2 +/- 11.6 micrograms.kg-1.min). A LTC4/LTD4 receptor antagonist, L-649,923 (10 mg/kg iv), and two putative inhibitors of 5-lipoxygenase, L-651,392 (10 mg/kg po) and U-60,257 (5 mg/kg i.v.), diminished the immediate bronchoconstriction and markedly inhibited bronchial hyperresponsiveness. Analysis of bronchoalveolar lavage fluid obtained from guinea pigs after acrolein exposure revealed a significant increase in immunoreactive LTC4 concentrations (control LTC4 = 8.8 +/- 0.3, n = 7; exposed LTC4 = 15.9 +/- 2.4 pg/ml, n = 6). Treatment with L-651,392 inhibited this response (acrolein exposed = 9.4 +/- 2.4 pg/ml, n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of combined leukotriene D4 and thromboxane A2 receptor antagonist on mediator-controlled resistance in guinea pigs

2000 ◽  
Vol 403 (1-2) ◽  
pp. 169-179 ◽  
Author(s):  
Yasuhito Arakida ◽  
Keiko Ohga ◽  
Yohei Okada ◽  
Hiroki Morio ◽  
Kiyomi Suwa ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Guinea Pigs ◽  
Thromboxane A2 ◽  
Leukotriene D4 ◽  
Thromboxane A2 Receptor

Do inhibitors of lipoxygenase and cyclooxygenase block neonatal hypoxic pulmonary vasoconstriction?

1989 ◽  
Vol 66 (4) ◽  
pp. 1779-1784 ◽  
Author(s):  
S. Cassin ◽  
G. Gause ◽  
T. Davis ◽  
M. ter Riet ◽  
R. Baker
Keyword(s):  
Receptor Antagonist ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Leukotriene D4 ◽  
Thromboxane Receptor ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Leukotriene Receptor ◽  
Thromboxane Receptor Antagonist ◽  
Muscle Relaxant Activity

Lipoxygenase products have been suggested as mediators of the hypoxic pulmonary pressor response in newborn animals. Data supporting this suggestion are equivocal, since lipoxygenase and leukotriene receptor antagonists that have been used may produce vasodilation because of phosphodiesterase inhibition. We used a leukotriene receptor antagonist L 649923, which appears not to have smooth muscle relaxant activity. L 649923 blocks pressor responses to leukotriene D4 (LTD4) without diminishing the pressor response to hypoxia. Also, BW 755C did not block the pressor response to hypoxia in newborn sheep and goats, whereas the pressor response to LTD4 (75 ng/kg) was depressed significantly. In newborn sheep there was an augmented response to hypoxia with BW 755C, which is consistent with cyclooxygenase inhibition. Finally, the thromboxane receptor antagonist SQ 29548 was investigated in both species. With this agent the pressor response to LTD4 in contrast to that of hypoxia was completely inhibited. We conclude that thromboxanes are involved in the pressor response to LTD4 in newborn lambs and goats. These data do not support the view that leukotrienes are involved in the ovine or caprine neonatal pulmonary pressor response to hypoxia.

scholarly journals Effect of pranlukast, an oral leukotriene receptor antagonist, on leukotriene D4 (LTD4) challenge in normal volunteers

Thorax ◽  
1997 ◽  
Vol 52 (6) ◽  
pp. 519-522 ◽  
Author(s):  
T. C. O'Shaughnessy ◽  
P. Georgiou ◽  
K. Howland ◽  
M. Dennis ◽  
C. H. Compton ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Leukotriene Receptor Antagonist ◽  
Leukotriene D4 ◽  
Normal Volunteers ◽  
Leukotriene Receptor

Zafirlukast: The First Leukotreene-Receptor Antagonist Approved for the Treatment of Asthma

1997 ◽  
Vol 31 (9) ◽  
pp. 1012-1021 ◽  
Author(s):  
Judy Shepard Kelloway
Keyword(s):  
Clinical Trials ◽  
Receptor Antagonist ◽  
Patient Adherence ◽  
Statistical Significance ◽  
Oral Dosage ◽  
Atopic Asthma ◽  
Leukotriene Receptor Antagonist ◽  
Leukotriene D4 ◽  
Safety And Efficacy ◽  
Leukotriene Receptor

Objective To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of zafirlukast. Therapeutic issues regarding the use of a leukotriene-receptor antagonist as prophylactic antiinflammatory therapy for asthma are also discussed. Data Sources A MEDLINE search was conducted to identify pertinent literature, including preclinical trials, clinical trials, and reviews. Pharmacokinetic and dosing information were abstracted from the product labeling. Study Selection All available published articles describing double-blind, placebo-controlled trials of both oral and aerosol zafirlukast in patients with asthma or rhinitis were reviewed. These included single-dose studies with zafirlukast against exercise, allergen, leukotriene D4 (LTD4), and platelet-activating factor (PAF) challenges, and 6- and 13-week trials in patients with asthma. Studies describing clinical trials with long-term use or comparisons with other asthma medications as reported in abstracts are also included. Data Extraction Information on the safety and efficacy of zafirlukast from single- and multiple-dose studies was evaluated on the basis of statistical significance relative to placebo treatment. Data Synthesis Zafirlukast, a potent and selective antagonist of the cysteinyl leukotriene receptor, blocks leukotriene-mediated pathologic events in both experimental animal and clinical disease models. Zafirlukast antagonizes LTD4-, PAF-, and exercise-induced bronchoconstriction, and blocks both early- and late-phase responses following allergen provocation in patients with atopic asthma. Greater efficacy is noted following oral administration than with aerosol dosing, presumably because of the enhanced delivery of drug when ingested rather than inhaled. Conclusions Zafirlukast is the first orally active leukotriene-receptor antagonist approved by the Food and Drug Administration for the prophylactic and chronic treatment of asthma. Since the leukotrienes play an important role in the underlying inflammatory processes of asthma, zafirlukast represents a new antiinflammatory option available in an oral dosage form. It is clear that this agent has therapeutic activity in patients with asthma, but its effectiveness relative to other antiasthma medications still needs confirmation. Data from clinical studies support the use of zafirlukast as first-line therapy in patients with mild-to-moderate asthma. Further research is needed to establish its role as an add-on agent for patients with severe asthma, aspirin-sensitive asthma, and both allergies and asthma. In addition to having a favorable safety and efficacy profile, zafirlukast has the advantage of being an oral agent with twice-daily dosing; these attributes offer the potential for greater patient adherence to pharmacotherapy and, thereby, improved control of asthma symptoms.

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