Pathophysiological mechanisms of sudden death induced by platelet activating factor.
Platelet activating factor (Paf) (15-40 micrograms-1) kills male rabbits within 3 to 5 min. Intravenous injection of Paf at a dose of 15 micrograms kg-1 is uniformly lethal, and the rabbits died within 4.5 +/- 0.4 min. The sudden death is characterized by cessation of respiration, a marked decrease in mean arterial blood pressure (M.A.B.P.), and 8 fold increases in plasma thromboxane B2 (TxB2) concentrations with only modest elevation in plasma 6 keto-prostaglandin F1 alpha (6-keto PGF1 alpha) concentrations. Pretreatment with the cyclo-oxygenase inhibitor, ibuprofen (6.25 mg kg-1), or with the thromboxane synthetase inhibitors dazoxiben (2.5 mg kg-1), CGS-13080, or OKY-046 1 mg kg-1) increased survival rates to 83-100%. Protected rabbits showed only modest changes in M.A.B.P. and no significant increase in plasma TxB2 concentrations. The protective drugs showed a dose-related action on M.A.B.P., plasma TxB2 concentration and mortality rate in Paf-induced sudden death. The mechanisms of the protection appeared to be prevention of platelet aggregation (leading to pulmonary thrombosis) and pulmonary and coronary vasoconstriction. However, Paf does not appear to exert direct vasoconstrictor effects in isolated coronary or pulmonary arteries. The effects of Paf in vivo appear to be mediated by TxA2 released by activated platelets in the absence of the protective effects of prostacyclin. Inhibition of thromboxane synthesis effectively prevents the Paf-induced sudden death.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors; D003645:Death, Sudden / Q000209:etiology*; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011651:Pulmonary Artery / Q000187:drug effects; D011817:Rabbits; D012119:Respiration / Q000187:drug effects; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D010972:Platelet Activating Factor; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase