Suppression of PAF-induced bronchoconstriction in the guinea-pig by oxatomide: mechanism of action.
Oxatomide potently (ED50 0.9 mg/kg orally, -2 h) attenuates the reduction of pulmonary tidal volume elicited by PAF (250 ng/kg i.v.) in anaesthetized, ventilated and propranolol-treated guinea-pigs. The increase of the pulmonary inflation pressure elicited by PAF (40 ng/kg i.v.) in such animals, ventilated at a fixed tidal volume, is also significantly reduced by the compound, but substantially higher doses (5 mg/kg i.v., -15 min) are required. The potency of oxatomide in the latter respect (50.4% reduction) is equivalent to that of ketotifen at 5 mg/kg i.v. (55% reduction). In spontaneously breathing, anaesthetized guinea-pigs, oxatomide (5 mg/kg i.p., -1 h) significantly reduces the increase in pulmonary resistance, but not the reduction in dynamic compliance, elicited by PAF (30, 60, 90 ng/kg i.v.), suggesting a pharmacological interference mainly with PAF-induced processes in the larger airways. Changes in arterial blood pressure, haemoconcentration, thrombocytopenia and leukopenia induced by PAF in vivo, contraction of guinea-pig lung parenchymal strips, production of superoxide anion by alveolar macrophages, aggregation and release of ATP by platelets challenged with PAF in vitro are not affected by the compound. These observations suggest that oxatomide attenuates the PAF-induced pulmonary reactions by inhibiting the release and/or the effect of allergic mediators elicited by the phospholipid rather than by a direct antagonism at the PAF receptors.
Nijkamp
F P
FP
Department of Veterinary Pharmacology, University of Utrecht, The Netherlands.
Folkerts
G
G
Beetens
J R
JR
De Clerck
F
F
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood / Q000378:metabolism; D001772:Blood Cell Count; D001792:Blood Platelets / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001980:Bronchi / Q000187:drug effects*; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000166:cytology; D012129:Respiratory Function Tests; D013481:Superoxides / Q000378:metabolism
D001095:Arachidonic Acids; D006634:Histamine H1 Antagonists; D010879:Piperazines; D010972:Platelet Activating Factor; D013481:Superoxides; D016718:Arachidonic Acid; D000255:Adenosine Triphosphate; C015408:oxatomide