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Paf‐acether‐induced death in mice: involvement of arachidonate metabolites and β‐adrenoceptors
Author(s) -
Criscuoli Marco,
Subissi Alessandro
Publication year - 1987
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1987.tb16841.x
Subject(s) - bronchoconstriction , nordihydroguaiaretic acid , salbutamol , pharmacology , lipoxygenase , antagonist , platelet activating factor , chemistry , propranolol , cyclooxygenase , medicine , endocrinology , receptor , asthma , enzyme , biochemistry
1 Intravenous Paf‐acether (Paf, 15–80 μg kg −1 ) killed conscious Swiss mice in a dose‐dependent manner, without causing platelet aggregation in the lung micro vasculature, or pulmonary oedema. 2 Propranolol (0.01–10 mg kg −1 , i.p.) potentiated the effects of an LD 20 of Paf dose‐dependently, while the β 1 ‐adrenoceptor selective antagonist, metoprolol, was three orders of magnitude less potent in this respect. Salbutamol (1 mg kg −1 , i.p.) provided complete protection against an LD 80 of Paf. 3 High doses of indomethacin, aspirin, benoxaprofen and FPL 55712 given i.p. failed to inhibit the effects of an LD 80 of Paf, while BW 755C (50–100 mg kg −1 ) exerted a dose‐dependent protection and benzydamine (50 mg kg −1 ) and nordihydroguaiaretic acid (200 mg kg −1 ) were partially active. Dexamethasone (1–5 mg kg −1 , s.c.) exerted a dose‐dependent protection, when administered at least 4h before Paf. 4 In mice anaesthetized with urethane, Paf (1–30 μg kg −1 ) produced hypotension which was not clearly dose‐related. The effects of the highest dose were also tested on the resistance of the lungs to inflation and found to produce bronchoconstriction. 5 It may be concluded that pharmacological manipulation of β 2 ‐adrenoceptors modulates Paf‐induced death in mice, while arachidonate metabolites of the cyclo‐oxygenase pathway and peptidoleukotrienes do not appear to be involved. However, lipoxygenase products, distinct from peptidoleukotrienes, may play a role in this phenomenon. It is suggested that bronchoconstriction, probably associated with cardiovascular effects, is a major determinant of the acute toxicity of Paf in mice.