- Email: [email protected]
Inhibition of in vivo and in vitro pulmonary effects of paf-acether by BN 52021
PROSTAGLANDINS
INHIBITION
OF IN V/V0 AND IN V/TRO PULMONARY OF PAF-ACETHER BY BN 52021
EFFECTS
Paf-acether is now known to accompanychemical or immune activation of several cell types such as basophils, neutrophils, vascular endothelial cells, IgE-sensitized macrophages exposed to specific antigens and thrombinstimulated platelets. These cells are thus potential sources for the formation of paf-acether in pathophysiological conditions and indeed paf-acether is released into the rabbit circulation during anaphylacticshock. A role for paf-acether in immediate hypersensitivity, late asthma and shock is supported by evidence that it induces bronchoconstriction when injected i.v. to the guinea-pig accompanied by thrombocytopenia and leukopenia. The effects of BN 52021 were investigated on two experimental models of asthma in guinea-pigs: (i) BN 52021 (i.v., 5 min before or per OS 1 hour before paf-acether ) greatly inhibited paf-acether (60 or 100 ng/k$; i.v.) induced bronchospasm (- 88.8 k 6.4%, n = 10 at 1 mg/k$; i.v. and - 74.4 k 8.4% n = 6 at 10 mg/k$; per OS) (ii) BN 52021 was also a vet-y potent inhibitor of anaphylactic bronchospasm (IgG-dependent) induced by antigen (ovalbumin, 1 mgikg; i.v.) in passive/y sensitized guinea-pig. The sensitization was performed by i.v. injection of anti-ovalbumin rabbit serum 18 h before challenge. Given 5 min before ovalbumin (0.1 mgikg; i.v.), BN 52021 totallysuppressed the immunological response. In comparison, the inhibitory effect of FPL 55712! a leukotriene-receptor antagonist, was only -48% (2 mg/k$; i.v.) and no significant inhibition was observed with a lower dose (1 mg/k$; i.v.). In order to ascertain the specific paf-acether-antagonistic activity of BN 52021 on the lung, the effects of this compound were also studied in vitro on superfused guinea-pig lung parenchymal strips (GLPS) contracted by paf-acether (1O-‘9 + 1O-9 mole), leukotrienes (LT) 8, and D, (lo-” + 10-pmole) and histamine (lO_” ~+ 10e5 mole). BN 52021 competitively inhibitedpaf-acelher-induced contraction at O-5 and 1 &ml. At higher doses (3 and 30 &ml), the inhibition appeared to be non competitive. Kadsurenone, an other paf-acether antagonist also inhibited paf-acether-induced contraction. BN 52021 was without effect on histamine but it slightly affected LTD,-induced contraction. This effect was dose-dependent. These findings confirm that BN 52021 is a specific paf-acether receptor antagonist and suggest that paf-acether might play a role in an anaphylacticbronchospasm.
OCTOBER 1985 VOL. 30 NO. 4
719
INHIBITION
OF IN V/V0 AND IN V/TRO PULMONARY OF PAF-ACETHER BY BN 52021
EFFECTS
Paf-acether is now known to accompanychemical or immune activation of several cell types such as basophils, neutrophils, vascular endothelial cells, IgE-sensitized macrophages exposed to specific antigens and thrombinstimulated platelets. These cells are thus potential sources for the formation of paf-acether in pathophysiological conditions and indeed paf-acether is released into the rabbit circulation during anaphylacticshock. A role for paf-acether in immediate hypersensitivity, late asthma and shock is supported by evidence that it induces bronchoconstriction when injected i.v. to the guinea-pig accompanied by thrombocytopenia and leukopenia. The effects of BN 52021 were investigated on two experimental models of asthma in guinea-pigs: (i) BN 52021 (i.v., 5 min before or per OS 1 hour before paf-acether ) greatly inhibited paf-acether (60 or 100 ng/k$; i.v.) induced bronchospasm (- 88.8 k 6.4%, n = 10 at 1 mg/k$; i.v. and - 74.4 k 8.4% n = 6 at 10 mg/k$; per OS) (ii) BN 52021 was also a vet-y potent inhibitor of anaphylactic bronchospasm (IgG-dependent) induced by antigen (ovalbumin, 1 mgikg; i.v.) in passive/y sensitized guinea-pig. The sensitization was performed by i.v. injection of anti-ovalbumin rabbit serum 18 h before challenge. Given 5 min before ovalbumin (0.1 mgikg; i.v.), BN 52021 totallysuppressed the immunological response. In comparison, the inhibitory effect of FPL 55712! a leukotriene-receptor antagonist, was only -48% (2 mg/k$; i.v.) and no significant inhibition was observed with a lower dose (1 mg/k$; i.v.). In order to ascertain the specific paf-acether-antagonistic activity of BN 52021 on the lung, the effects of this compound were also studied in vitro on superfused guinea-pig lung parenchymal strips (GLPS) contracted by paf-acether (1O-‘9 + 1O-9 mole), leukotrienes (LT) 8, and D, (lo-” + 10-pmole) and histamine (lO_” ~+ 10e5 mole). BN 52021 competitively inhibitedpaf-acelher-induced contraction at O-5 and 1 &ml. At higher doses (3 and 30 &ml), the inhibition appeared to be non competitive. Kadsurenone, an other paf-acether antagonist also inhibited paf-acether-induced contraction. BN 52021 was without effect on histamine but it slightly affected LTD,-induced contraction. This effect was dose-dependent. These findings confirm that BN 52021 is a specific paf-acether receptor antagonist and suggest that paf-acether might play a role in an anaphylacticbronchospasm.
OCTOBER 1985 VOL. 30 NO. 4
719