Pharmacologic and pharmacokinetic profile of SK&amp;F S-106203, a potent, orally active peptidoleukotriene receptor antagonist, in guinea-pig

Hay, Douglas W. P.; Muccitelli, Roseanna M.; Vickery-Clark, Lynne M.; Novák, L; Osborn, Ruth R.; Gleason, John G.; Yodis, Lee Ann P.; Saverino, C.M.; Eckardt, R.D.; Sarau, Henry M.; Wasserman, Martin A.; Torphy, Theodore J.; Newton, John F.

doi:10.1016/0952-0600(91)90009-r

Cited by 41 publications

(51 citation statements)

References 27 publications

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“…Employing p-LT antagonists including FPL 55712, previous studies have shown similar results that p-LTs play a considerable role in antigen-induced contractions of isolated human bronchi (8,12,19,20). However, according to our present results, p-LTs must play a more significant role than indicated in the previous stud ies, which may be due to the inherently weak potency of the antagonists used in those studies or short time observation during anaphylaxis in their experiments.…”

Section: Discussionsupporting

confidence: 54%

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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Section: Discussionsupporting

confidence: 54%

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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“…Previous studies in our laboratory have indicated that SK&F 104353 or mepyramine generally had minor effects on antigen-induced contraction of guinea-pig trachea or human bronchus, whereas the combination of the antagonists essentially abolished the response (Hay et al, 1987). In this experi- ment the combination of SK&F 104353 (10 gLM) and mepyramine (10 gM) had no effect on contraction elicited by ET-1 (Figure 3a).…”

Section: Contractile Studiesmentioning

confidence: 63%

“…The functional data from the present study also demonstrate that the contractile response to ET-1 in human bronchus does not appear to involve the release of significant amounts of acetylcholine, histamine, leukotrienes, PAF or thromboxane. Thus, atropine, the classical muscarinic receptor antagonist, WEB 2086, the PAF receptor antagonist (Casals-Stenzel, 1987a,b), SQ 29,548, the thromboxane receptor antagonist (Ogletree et al, 1985), or the combination of mepyramine, the HI-histamine receptor antagonist, and SK&F 104353, the leukotriene receptor antagonist (Hay et al, 1987), were without marked effect on ET-1 concentration-response curves. The concentrations of these receptor antagonists employed in this study were those which had been observed to inhibit markedly contractions produced by the natural ligands in human bronchus and/or guinea-pig trachea (see above).…”

Section: Mediator Releasementioning

confidence: 99%

“…A preliminary account of the results has been presented by Hay et al (1992 CasalsStenzel, 1987a,b). The concentration of SK&F 104353 used has been observed previously to produce marked, competitive antagonism of leukotriene-induced contraction in human bronchus (pKB>8), and, in combination with 1OiLM mepyramine, to abolish antigen-induced contraction in this tissue (Hay et al, 1987 added for 15 min. After this time the supernatant was taken to assay histamine and eicosanoid release.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Endothelin‐induced contraction and mediator release in human bronchus

Hay

Hubbard

Undem

1993

British J Pharmacology

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1 To elucidate the role of acetylcholine and various autacoids in endothelin-I (ET-l)-induced contraction in human bronchus, the effects of various receptor antagonists were examined. In addition, the ability of ET-1 to stimulate the release of histamine, peptidoleukotrienes and prostanoids was determined. 2 ET-1 was a potent and effective contractile agonist in human bronchus, possessing similar potency and efficacy to leukotriene D4 (LTD4); EC50 (-log M): ET-1 = 7.76 ± 0.09, n = 7; LTD4 = 8.46 ± 0.53, n = 7; P>0.2; maximum response (% 10PiM pre-carbachol): ET-1 = 103.8 ± 17.4, n = 7; LTD4=95.5±9.3, n=7; P>0.6.3 The cyclo-oxygenase inhibitor, sodium meclofenamate (1 pM) or the potent and selective thromboxane receptor antagonist, SQ 29,548 (1 pLM) were without significant effect on ET-1 concentrationresponse curves. 4 In the presence of sodium meclofenamate (1 I1M), the muscarinic receptor antagonist, atropine(1 fLM), the platelet activating factor (PAF) receptor antagonist, WEB 2086 (1 jiM) or the combination of the Hi-histamine receptor antagonist, mepyramine (10#iM) and the leukotriene receptor antagonist, SK&F 104353 (10 pM), were without marked effect on ET-1 concentration-response curves. In addition, the combination of all four receptor antagonists did not antagonize ET-1-induced contraction.5 ET-1 (0.3 pM) did not stimulate the release of histamine or immunoreactive leukotrienes from human bronchus.6 ET-1 (0.3 f4M) significantly stimulated the release of prostaglandin D2 (PGD2), 9a, 11p PGF2 (PGD2 metabolite), PGE2, 6-keto PGF1, (PGI2 metabolite), PGF2,, and thromboxane B2 (TxB2) a lower concentration, 10 nM, was without effect on prostanoid release. The production of PGD2 was increased 7.5 fold, whereas the release of the other prostanoids was stimulated only about 1.6 to 2.7 fold. 7 These data provide evidence that ET-1 elicits contraction of human isolated bronchus predominantly via a direct mechanism with no significant involvement of the release of acetylcholine, leukotrienes, histamine or PAF. Although IntroductionYanagisawa and co-workers described the isolation, purification, cloning and pharmacological characterization of a potent vasoconstrictor peptide, designated endothelin, which was released from porcine aortic endothelial cells (Yanagisawa et al., 1988). Endothelin is a 21-amino acid peptide, with two sets of intrachain disulphide bridges, which bears a close structural homology with the sarafotoxins, a group of snake venom toxins (Lee & Chiappinelli, 1988;Kloog et al., 1988). Subsequent research indicated that endothelin, named endothelin-1 (ET-1), is only one member of a family of mammalian endothelins; Thus, Inoue and co-workers cloned three distinct ET-related genes by screening a human genomic DNA library (Inoue et al., 1989). These three 21-amino acid peptides, which have only minor differences in amino acid sequence, were designated ET-1 (the orginal porcine/human ET), ET-2 (two amino acid substitution from ET-1) and ET-3 (six amino acid substitution from ET-1) (Yanagisawa & Ma...

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“…Combined antagonists to histamine H1, 5-hydroxytryptamine (5-HT), aand f-adrenoceptors, and muscarinic receptors (Piper & Vane, 1969). In addition, the substance P antagonist spantide (Folkers et al, 1984), TXA2 antagonist GR 3219B (Lumley et al, 1989) and the leukotriene antagonist SK&F 104353 (Hay et al, 1987b) were also used in some of the experiments.…”

Section: Administration Ofdrugsmentioning

confidence: 99%

The role of the epithelium in modulating the responses of guinea‐pig trachea induced by bradykinin in vitro

Bramley

Samhoun

Piper

1990

British J Pharmacology

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The effect of removing the epithelium on the responses of the guinea‐pig isolated trachea (GPT) to bradykinin (BK) and prostaglandin E2 (PGE2) was investigated. BK (3 pmol–10 nmol) induced dose‐related relaxations of the intact (with epithelium), and contracted the rubbed (without epithelium) preparation of GPT. Similar responses were also obtained with PGE2 (0.3–3.0 nmol). Indomethacin (1.4 μm) modified the BK‐induced response of intact GPT, from a relaxation to a contraction, but inhibited the BK‐induced contraction of the rubbed GPT. There was a significant increase in PGE2 release from the intact GPT following stimulation with BK. Removal of the epithelium from the GPT significantly reduced both basal and BK‐induced generation of PGE2. The induction of tone in the rubbed GPT by addition of acetylcholine (ACh) caused BK and PGE2 (0.3 nmol–3 nmol) to produce relaxations of the tissue. Salbutamol (10−8 m‐10−6 m) reduced the relaxations induced by BK on intact GPT, in a concentration‐dependent manner. These results suggest that both tone and an epithelial‐dependent cyclo‐oxygenase mechanism are important in modulating BK‐induced responses of GPT.

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Pharmacologic and pharmacokinetic profile of SK&F S-106203, a potent, orally active peptidoleukotriene receptor antagonist, in guinea-pig

Cited by 41 publications

References 27 publications

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.

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.

Endothelin‐induced contraction and mediator release in human bronchus

The role of the epithelium in modulating the responses of guinea‐pig trachea induced by bradykinin in vitro

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