Paf-acether-induced death in mice: involvement of arachidonate metabolites and β-adrenoceptors

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Abstract
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 LD20 of Paf dose-dependently, while the β1-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 LD80 of Paf. 3 High doses of indomethacin, aspirin, benoxaprofen and FPL 55712 given i.p. failed to inhibit the effects of an LD80 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 β2-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.