Leukotriene C4 stimulates TXA2 formation in isolated sensitized guinea pig lungs

Folco, G.C.; Hansson, Göran; Graström, Elisabeth

doi:10.1016/0006-2952(81)90349-x

Cited by 108 publications

(20 citation statements)

References 11 publications

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“…As there existed ONO-1078-sensitive or -less sensitive LTD4 receptors, it is suggested that LTD4 receptors in guinea pig lung parenchymal strips may differ from those present in guinea pig trachea. LTC4 and LTD4 have been shown to produce throm boxane A2 and PGs from guinea pig lung (13,34) and to induce the contraction of guinea pig parenchymal strips mediated by thromboxane A2 (35). ONO-1078 antagonized the LTC4 and LTD4-induced contractions of guinea pig lung in the presence of indomethacin and moreover, ONO-1078 had little or no effect on cyclo oxygenase and thromboxane synthetase activities.…”

Section: Specificity Of the Action Of Ono-1078mentioning

confidence: 99%

In Vitro Antagonism of ONO-1078, a Newly Developed Anti-Asthma Agent, against Peptide Leukotrienes in Isolated Guinea Pig Tissues.

et al. 1992

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ABSTRACT-We evaluated the antagonist activity of ONO-1078 against peptide leukotrienes (LTs) by a radioligand binding assay and functional experiments in guinea pigs. In the radioligand binding assay, ONO-1078 inhibited [3H]LTD4 and [3H]LTE4 bindings to lung membranes (K; = 0.99 and 0.63 nM, re spectively) and was 2,000 to 3,000-fold more potent than FPL55712. Antagonism of ONO-1078 against [3H]LTC4 binding (K; = 5640 nM) was approximately twofold more potent than that of FPL55712. The antagonism of ONO-1078 against [3H]LTD4 binding was competitive. In functional experiments, ONO 1078 showed competitive antagonism against the LTC4 and LTD4-induced contractions of guinea pig trachea and lung parenchymal strips with a pA2 range of 7.70 to 10.71 and was approximately 400 to 3,300-fold more potent than FPL55712. Interestingly, in the presence of an inhibitor of the bioconver sion of LTC4 to LTD4, ONO-1078 also antagonized the LTC4-induced contraction of guinea pig trachea (pA2 = 7.78). ONO-1078 significantly reversed the LTD4-induced prolonged contraction without effect on the KCl and BaC12-induced contractions of guinea pig trachea. Furthermore, ONO-1078 antago nized the antigen-induced SRS-A mediated contraction of guinea pig trachea. On the other hand, ONO-1078 showed no antagonism against histamine, acetylcholine, 5-hydroxytryptamine, prostaglandin D2 and U-46619. In addition, ONO-1078 showed little or no effect on the activities of cyclooxygenase, 5-lipoxygenase and thromboxane synthetase. These in vitro studies indicate that ONO-1078 is a highly potent, selective and competitive antagonist of peptide leukotrienes that acts with higher affinity at LTD4 and LTE4 receptors than LTC4 receptors.

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Section: Specificity Of the Action Of Ono-1078mentioning

confidence: 99%

In Vitro Antagonism of ONO-1078, a Newly Developed Anti-Asthma Agent, against Peptide Leukotrienes in Isolated Guinea Pig Tissues.

et al. 1992

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“…Unlike human bronchi and lung parenchymas, the guinea pig lung parenchyma preferentially forms TXA2 by stimulation of p-LTs (26,27). Thus, the inhibitory mechanism of the drug-induced contraction of the tissue can be ex plained as follows: p-LTs released during immunologi cal reaction indirectly induce the additional contraction of airway smooth muscle through the action of TXA2 formed by their stimulation.…”

Section: Discussionmentioning

confidence: 99%

Significant Role of Peptide Leukotrienes (p-LTs) in the Antigen-Induced Contractions of Human and Guinea Pig Lung Parenchymas and Bronchi or Tracheas In Vitro.

et al. 1992

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Chemical mediators responsible for the antigen-induced contractions of isolated, passive ly sensitized human and guinea pig lung parenchymas and bronchi or tracheas were evaluated by sev eral antagonists and enzyme inhibitors, with emphasis on the effects of the potent and selective peptide leukotriene (p-LT) antagonist MCI-826. All of these preparations showed long-lasting contractions in response to an antigen challenge which lasted for more than 60 min. In either the human lung paren chyma and bronchus or guinea pig lung parenchyma, pretreatment with 10-6 g/ml (2.4 X 10-6 M) MCI-826 significantly inhibited the late phase at 10 to 60 min after the challenge of the contraction fol lowing slight suppression of the early phase. The early phase contractions of these preparations were moderately antagonized by 10-6 g/ml mepyramine, but the late phases were not influenced or even rather enhanced. The combination treatment of MCI-826 with mepyramine additionally and markedly inhibited both phases of these preparations. On the other hand, although mepyramine apparently inhib ited the early phase of the guinea pig tracheal contraction but not the late phase, no synergistic inhibi tions of the contraction were observed when it was combined with MCI-826. The p-LT antagonist FPL 55712, atropine and indomethacin at 10-6 g/ml either slightly inhibited or enhanced the contractions of human lung parenchymas, guinea pig tracheas and lung parenchymas, but the effects were not signifi cant. From these results, it should be emphasized that p-LTs largely contribute to induction of the anaphylactic contractions of human lung parenchymas as well as human bronchi and guinea pig lung parenchymas but not guinea pig tracheas.

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“…It was reported that pre treatment with cyclooxygenase inhibitors modified the vasoactive effects of LTs in guinea pigs (18,19), and LTs stimulated the release of PG12 and/or TXA2 (20,21). Thus, in guinea pigs, the actions of LTs seem likely to depend on cyclooxygenase products (22).…”

Section: Discussionmentioning

confidence: 99%

Renal effects of leukotrienes C4 and D4 in anesthetized dogs.

et al. 1988

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Abstract-We investigated the effects of leukotrienes (LTs) C4 and D4 on renal function and hemodynamics of dogs. LTC4 (0.5 itg/min, infused into the renal artery), but not LTD4 (1 ug/min), caused an increase in renal blood flow, urine flow, urinary excretion of sodium and potassium, and rate of free water reabsorption, with a concomitant rise in systemic blood pressure. Intrarenal infusion of LTC4 under conditions of constant renal perfusion pressure induced no significant effect on renal blood flow or urine formation.Infusions or LTC4 and LTD4 into the renal artery induced no change in the release of prostaglandins, PGE2, PGF2a, 6-keto PGF1a or thromboxane B2 into renal venous blood. From these findings, we concluded that the renal effects of LTC4 were secondary responses to a rise in systemic blood pressure.

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Leukotriene C4 stimulates TXA2 formation in isolated sensitized guinea pig lungs

Cited by 108 publications

References 11 publications

In Vitro Antagonism of ONO-1078, a Newly Developed Anti-Asthma Agent, against Peptide Leukotrienes in Isolated Guinea Pig Tissues.

In Vitro Antagonism of ONO-1078, a Newly Developed Anti-Asthma Agent, against Peptide Leukotrienes in Isolated Guinea Pig Tissues.

Significant Role of Peptide Leukotrienes (p-LTs) in the Antigen-Induced Contractions of Human and Guinea Pig Lung Parenchymas and Bronchi or Tracheas In Vitro.

Renal effects of leukotrienes C4 and D4 in anesthetized dogs.

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