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Involvement of nitric oxide and eicosanoids in platelet‐activating factor‐induced haemodynamic and haematological effects in dogs
Author(s) -
Noguchi Katsuhiko,
Matsuzaki Toshihiro,
Shiroma Noboru,
Ojiri Yoshihiko,
Sakanashi Matao
Publication year - 1996
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.1476-5381.1996.tb15490.x
Subject(s) - autacoid , platelet activating factor , vascular resistance , nitric oxide , thromboxane a2 , thromboxane , pharmacology , medicine , contractility , eicosanoid , endocrinology , nitric oxide synthase , platelet , hemodynamics , chemistry , arachidonic acid , receptor , biochemistry , enzyme
1 Platelet‐activating factor (PAF) is a phospholipid mediator with potent cardiovascular and haematological actions. But its mechanisms of action in vivo have not been fully elucidated, probably due to difficulties arising from previous findings that the effects of PAF are largely mediated by the release of a variety of other autacoids. In the present study, the roles of nitric oxide and eicosanoids in the effects of PAF (0.01‐0.25 μg kg −1 i.v.) on systemic and pulmonary vasculatures and circulating blood cell count were pharmacologically evaluated in anaesthetized dogs. 2 Higher doses of PAF (>0.1 μg kg −1 ) produced a biphasic systemic hypotension. The first hypotension seen 30 s after the injection was accompanied by a decrease in systemic vascular resistance, thrombocytopenia and leukopenia, while the second hypotension seen 1–2 min after PAF was accompanied by a marked rise in pulmonary vascular resistance and decreases in aortic blood flow and cardiac contractility. Lower doses of PAF (0.01‐0.05 μg kg −1 ) caused only the first responses in a dose‐dependent manner. 3 Pretreatment with indomethacin inhibited the second responses to PAF without affecting the first responses. The thromboxane A 2 /prostaglandin H 2 (TP)‐receptor antagonist vapiprost blocked the PAF‐induced rise in pulmonary vascular resistance. AA‐861, a 5‐lipoxygenase inhibitor, attenuated the PAF‐induced cardiac depression. The nitric oxide synthase inhibitor N G ‐nitro‐ l ‐arginine methyl ester inhibited the PAF‐induced early decrease in systemic vascular resistance. 4 All observed changes in haemodynamics and blood cell count after PAF were almost abolished by TCV‐309, a PAF‐receptor antagonist. 5 Reproducible hypotension and thrombocytopenia produced by a lower dose of PAF (0.05 μg kg −1 ) were respectively attenuated and potentiated by pretreatment with N G ‐nitro‐ l ‐arginine, another nitric oxide synthase inhibitor. Administration of l ‐arginine reversed the effects of the nitric oxide synthase inhibitor. 6 These results indicate that PAF‐receptor‐mediated production of not only eicosanoids but also nitric oxide may contribute to the cardiovascular and haematological responses to PAF in the dog.