BN 52021 and related compounds: A new series of highly specific PAF-acether receptor antagonists isolated from Ginkgo biloba L.

1The aim of the present experiments was to study the possible involvement of known bronchoconstrictor substances in mediating the myotropic action of endothelin-l (ET-1, human-porcine endothelin) in guinea-pig isolated airways. 2 ET-1 (1-100nm) caused a dose-dependent contraction of guinea-pig trachea, upper bronchus and parenchyma. The contractions developed slowly, reaching maximal values 4-6 min after addition of the peptide. 3 The contractile action of ET-1 was significantly attenuated by indomethacin (10uM), a cyclo-oxygenase blocker, BM 13505 (5,UM), a thromboxane receptor antagonist, FPL 55712 (19 pM) and YM 16638 (1pM), antagonists of the sulphidopeptide leukotrienes, BN 52021 (10pM) and WEB 2086 (1 pM), plateletactivating factor receptor antagonists in all three tissue preparations studied.4 Pretreatment of the airway tissues with compound U 75302 (3 guM), a selective leukotriene B4 receptor antagonist, or with a mixture of antagonists containing methysergide (0.75,UM), phentolamine (0.4UM), propranolol (13juM), atropine (0.4 pM) and diphenhydramine (0.45 pM) did not modify the myotropic action of ET-1. 5 ET-1, 10 and lOOnM induced three, and nine fold increases in thromboxane A2 release from lung parenchymal strips. 6 ET-1-induced thromboxane A2 release was completely abolished by indomethacin, and was significantly attenuated by BN 52021, WEB 2086 and FPL 55712. Neither BM 13505 nor YM 16638 exerted a significant effect on thromboxane release. 7 The present findings show that contraction of guinea-pig airway smooth muscle by ET-1 is mediated, in part, by the release of thromboxane A2, sulphidopeptide leukotrienes and platelet-activating factor, and suggest that the increased thromboxane A2 release following ET-1 is partly a consequence of enhanced synthesis of sulphidopeptide leukotrienes and platelet-activating factor.

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Experimental Protocolmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological modulation of endothelin‐induced contraction of guinea‐pig isolated airways and thromboxane release

Filep

Battistini

Sirois

1991

“…(Casals-Stenzel et al, 1987) or BN 52021 (10mgkg-1, i.v.) (Braquet et al, 1985;Foldes-Filep et al, 1987), for 10min before injection of endothelin-1 (1 nmol kg-1) or PAF (1.9 nmol kg-1). Ten min after the injection of endothelin-1 or PAF, the animals were stunned, then decapitated and exsanguinated.…”

Section: Experimental Protocolsmentioning

confidence: 99%

Effects of endothelin‐1 on vascular permeability in the conscious rat: interactions with platelet‐activating factor

Filep¹,

Sirois

Rousseau

et al. 1991

106

The objectives of the present experiments were to assess the effects of endothelin‐1 on the macrovascular permeability in selected vascular beds, to study the involvement of platelet‐activating factor (PAF) in vascular responses to endothelin‐1 and to examine the vascular effects of combined administration of endothelin‐1 and PAF in conscious rats. Intravenous bolus injection of endothelin‐1 (0.1–2 nmol kg−1) resulted in a dose‐dependent biphasic change in mean arterial blood pressure (MABP) with initial transient hypotension followed by a prolonged pressor action. These changes were accompanied by a dose‐dependent increase in haematocrit values. Endothelin‐1 (0.1 and 1 nmol kg−1) increased dose‐dependently the vascular permeability of the trachea, upper and lower bronchi, stomach, duodenum, spleen and kidney (up to 240%) as measured by the extravasation of Evans blue dye. The permeability of pulmonary parenchyma, liver and pancreas was not affected significantly by endothelin‐1 treatment. Pretreatment of animals with the specific PAF receptor antagonist, WEB 2086 (1 mg kg−1, i.v.) or BN 52021 (10 mg kg−1, i.v.) reduced the endothelin‐1 (1 nmol kg−1)‐induced rise in haematocrit by about 50 and 30%, respectively. Both antagonists were highly effective at inhibiting protein extravasation in the stomach, duodenum and kidney. On the other hand, BN 52021, but not WEB 2086, significantly attenuated the effect of endothelin‐1 on permeability in the lower bronchi and spleen. Neither WEB 2086 nor BN 52021 modified the changes in MABP evoked by endothelin‐1. When low doses of endothelin‐1 (0.1 nmol kg−1) and PAF (0.19 nmol kg−1) were administered simultaneously, enhanced protein extravasation was detected in the upper and lower bronchi, whereas neither endothelin‐1 nor PAF by themselves affected vascular permeability in these tissues. These changes occurred in the absence of significant changes in MABP. Combined administration of higher doses of endothelin‐1 (1 nmol kg−1) and PAF (1.9 nmol kg−1) resulted in marked increases (up to 530%) in protein extravasation in the airways, pancreas, stomach and duodenum. The effect of endothelin‐1 on permeability was not affected by PAF in the spleen, whereas it was completely inhibited by PAF in the kidney. Combined injection of endothelin‐1 and PAF resulted in a slight, but significant increase in MABP. The present findings show that endothelin‐1 is capable of increasing vascular permeability in selected vascular beds including the airways, gastrointestinal tract and kidney, and suggest that PAF may mediate, in part, its action on permeability, but not its hypotensive action. The present data also suggest that endothelin‐1 and PAF can act in concert to increase vascular permeability in rat airways and gastrointestinal tract.

“…Furthermore, a critical point of our adhesion assay using platelets labelled with [3H]-adenine might be the slight release of radioactivity in response to PAF, although our technique has some advantages compared with those using 51Cr or "'Inoxine (Curwen et al, 1982;Heaton et al, 1989). Although Curwen et al (1982) (Miyamoto et al, 1985) and BN 52021 (Braquet et al, 1985), dose-dependently suppressed the platelet adhesion. PAF also activated PMNs, resulting in the stimulation of PMN adhesion to endothelial cell monolayer.…”

Section: Discussionmentioning

confidence: 99%

Platelet‐leukocyte interaction in adhesion to endothelial cells induced by platelet‐activating factor in vitro

Hirafuji

Satoh

1991

1 Platelet-activating factor (PAF, 10 nM) did not induce platelet adhesion to endothelial cells cultured in monolayer but it induced their adhesion to protein-coated plastic. However, PAF induced a marked platelet adhesion to endothelial cells when polymorphonuclear leukocytes (PMNs) were present. Lyso-PAF had no effect. 2 Phase-contrast microscopic examination showed that single platelets rather than their aggregates adhered to the endothelial cell surface around aggregating and adhering PMNs. 3 Significant platelet adhesion was induced by PAF at concentrations higher than 0.01 nm with the maximal response at 10nm. Platelet adhesion occurred within minutes after PAF addition, reaching a maximum approximately after 30 min. Platelet adhesion also occurred significantly at a PMN : platelet ratio of 1: 800, and linearly up to 1: 50. 4 The PAF-induced platelet adhesion was suppressed by three structurally unrelated PAF antagonists, WEB 2086, ONO 6240 and BN 52021, in a concentration-dependent manner. 5 PAF also increased PMN adhesion to endothelial cell monolayers, which was further augmented by the presence of platelets. 6 The present study demonstrates that PAF induces platelet adhesion to endothelial cells in vitro when PMNs are present and that there is a close interaction between platelets and PMNs in their adhesion to endothelial cells. The present study further suggests that PMNs could play a central role in platelet adhesion to vascular endothlium in certain pathological conditions.