Metabolism of Cysteinyl Leukotrienes to Novel Polar Metabolites in the Rat and Endogenous Formation of Leukotriene D<sub>4</sub> during Systemic Anaphylaxis in the Guinea Piga

Hammarström, Sven; Örning, Lars; Keppler, Andrea

doi:10.1111/j.1749-6632.1988.tb38530.x

Cited by 8 publications

(5 citation statements)

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“…Measurement of biliary cysteinyl LTs is a convenient method to evaluate the synthesis of these substances in vivo (17). The biliary recovery of radioactivity after intratracheal instillation of [ 3 H]LTC 4 was ,23% in 4 h. Although this value is substantially less than the recovery of intravenously injected [ 3 H]LTC 4 , which has been reported to be 60% over 6 h, it is similar to the recovery of the intratracheally instilled label in rats (29).…”

Section: Discussionmentioning

confidence: 76%

“…We hypothesized that cysteinyl LTs mediate HIB and that their release is stimulated by the action of tachykinins on effector cells in the airways. To investigate the role of cysteinyl LTs in HIB, we took advantage of the fact that the bile is the major route for their excretion in the guinea pig (17,26). Biliary cysteinyl LT levels were quantitated before and after hyperpnea challenge, and the effects of selective NK antagonists on cysteinyl LT levels were determined.…”

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confidence: 99%

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Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis

Yang

Powell

Hojo

et al. 1997

Journal of Applied Physiology

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The purpose of the study was to test the hypothesis that tachykinins mediate hyperpnea-induced induced bronchoconstriction indirectly by triggering cysteinyl leukotriene (LT) synthesis in the airways. Guinea pigs (350-600 g) were anesthetized with xylazine and pentobarbital sodium and received hyperpnea challenge (tidal volume 3.5-4.0 ml, frequency 150 breaths/min) with either humidified isocapnic gas (n = 6) or dry gas (n = 7). Dry gas challenge was performed on animals that received MK-571 (LTD4 antagonist; 2 mg/kg i.v.; n = 5), capsaicin (n = 4), neurokinin (NK) antagonists [NK1 (CP-99994) + NK2 (SR-48968) (1 mg/kg i.v.); n = 6], or the H1 antihistamine pyrilamine (2 mg/kg i.v.; n = 5). We measured the tracheal pressure and collected bile for 1 h before and 2 h after hyperpnea challenge. We examined the biliary excretion of cysteinyl LTs; the recovery of radioactivity in bile after instillation of 1 microCi [3H]LTC4 intratracheally averaged 24% within 4 h (n = 2). The major cysteinyl LT identified was LTD4 (32% recovery of radioactivity). Cysteinyl LTs were purified from bile of animals undergoing hyperpnea challenge by using reverse-phase high-pressure liquid chromatography and quantified by radioimmunoassay. There was a significant increase in the peak value of tracheal pressure after challenge, indicating bronchoconstriction in dry gas-challenged animals but not after humidified gas challenge. MK-571, capsaicin, and NK antagonists prevented the bronchoconstriction; pyrilamine did not. Cysteinyl LT levels in the bile after challenge were significantly increased from baseline in dry gas-challenged animals (P < 0.05) and were higher than in the animals challenged with humidified gas or dry gas-challenged animals treated with capsaicin or NK antagonists (P < 0.01). The results indicate that isocapnic dry gas hyperpnea-induced bronchoconstriction is LT mediated and the role of tachykinins in the response is indirect through release of LTs. Endogenous histamine does not contribute to the response.

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Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis

Yang

Powell

Hojo

et al. 1997

Journal of Applied Physiology

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“…1991), guinea pig (Foster ut ak. 1989), domestic pig (Ezra et al 1989), and rat ( (Hammarstrom et al 1988). Rats eliminated 25% of the injected radioactivity into bile after 30 min and 50% after 90 min (Hammarstrom et a!.…”

Section: Discussionmentioning

confidence: 95%

“…However, it was not possible to obtain recovery information for polar metabolites in urine as a result of interfering absorbance of coeluting material. Enzymes for o-oxidation of LTE4 or N-acetyl-LTE4 to 20-hydroxy-LTE4 and 28-carboxy-LTE4 (or N-acetyl-LTE4 metabolites) have been found in rat kidney tissue (Hammarstrom et al 1988). The occurrence of o-oxidation metabolites in toad urine suggests that the toad kidney also has a-oxidation enzymes.…”

Section: Discussionmentioning

confidence: 97%

Tissue distribution, elimination, and metabolism of [³H]leukotriene C₄ by the conscious marine toad, Bufo marinus

Pfeifer¹,

Furilla²,

Gronert³

et al. 1992

Can. J. Physiol. Pharmacol.

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Tissue distribution, elimination, and metabolism of 3H-labelled leukotriene (LT) C4 were studied in ureter-catheterized conscious marine toads, Bufo marinus. Six and 24 h after injection, organs containing the highest percent of injected radioactivity were small intestine, liver, and kidney. Radioactivity declined in these organs at 24 h by approximately threefold. Peak elimination time for radioactivity in the urine was between 2 and 4 h after the injection. During the 24-h collection period, 55.2 +/- 0.2% of the injected radioactivity was eliminated in the urine. Polar metabolites represented 40.3 +/- 1.1, 57.3 +/- 5.6, and 62.8 +/- 1.6% of the radioactivity at 2, 4, and 6 h, respectively. The primary urinary polar metabolite was 20-carboxy-LTE4, with 18-carboxydinor-LTE4 and 20-hydroxy-LTE4 also present. [3H]LTE4 decreased from 37.2 +/- 1.8% at 2 h to 15.8 +/- 3.3 and 15.0 +/- 2.1% of the radioactivity at 4 and 6 h, respectively. Bile radioactivity was low. N-Acetyl-LTE4 was not detected in urine or bile samples. Radioactivity in the pan water was 14.3 +/- 2.4 and 15.8 +/- 2.5% of the injected radioactivity, at 6 and 24 h, respectively, suggesting that the skin was a route for excretion of leukotrienes. The marine toad is an interesting model demonstrating both similarities and differences from mammals in distribution, elimination, and metabolism of peptide leukotrienes.

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“…Leukotrienes have been recovered from biological fluids during spontaneous or induced asthmatic episodes. Two general strategies have been used with respect to leukotriene recovery; these include recovery of authentic LTE 4 from urine (66–72) or recovery from the blood, serum, or plasma. The latter measurements have been technically difficult and fraught with artifacts (73), but recent techniques have ostensibly allowed the quantitative recovery of leukotrienes from blood (74).…”

Section: Leukotriene Production In Asthmamentioning

confidence: 99%

Asthma Therapy with Agents Preventing Leukotriene Synthesis or Action

Drazen

1999

Proc Assoc American Phys

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Elucidation of the biochemistry of leukotriene production and the pharmacology of its actions has led to the development of a number of therapeutic agents shown to be of value in the treatment of asthma. These agents either prevent the synthesis of the leukotrienes, by preventing the action of the 5-lipoxygenase-activating protein or the catalytic action of the 5-lipoxygenase, or by inhibiting the action of leukotrienes at the CysLT1 receptor. Numerous clinical trials in exercise-induced asthma, allergen-induced asthma, aspirin-induced asthma, and spontaneously occurring asthmatic episodes have indicated that these agents are safe and effective asthma treatments.

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Metabolism of Cysteinyl Leukotrienes to Novel Polar Metabolites in the Rat and Endogenous Formation of Leukotriene D₄ during Systemic Anaphylaxis in the Guinea Piga

Cited by 8 publications

References 55 publications

Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis

Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis

Tissue distribution, elimination, and metabolism of [³H]leukotriene C₄ by the conscious marine toad, Bufo marinus

Asthma Therapy with Agents Preventing Leukotriene Synthesis or Action

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Metabolism of Cysteinyl Leukotrienes to Novel Polar Metabolites in the Rat and Endogenous Formation of Leukotriene D4 during Systemic Anaphylaxis in the Guinea Piga

Cited by 8 publications

References 55 publications

Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis

Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis

Tissue distribution, elimination, and metabolism of [3H]leukotriene C4 by the conscious marine toad, Bufo marinus

Asthma Therapy with Agents Preventing Leukotriene Synthesis or Action

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Metabolism of Cysteinyl Leukotrienes to Novel Polar Metabolites in the Rat and Endogenous Formation of Leukotriene D₄ during Systemic Anaphylaxis in the Guinea Piga

Tissue distribution, elimination, and metabolism of [³H]leukotriene C₄ by the conscious marine toad, Bufo marinus