Effect of PF 10040 on PAF-induced airway responses in neonatally immunized rabbits.
1. PF 10040 displaced [3H]-PAF from binding sites on rabbit platelets with an IC50 = 1.07 x 10(-5) M, which was approximately three orders of magnitude below that of a standard PAF antagonist WEB 2086 (IC50 = 4.23 x 10(-9) M). 2. PF 10040 at doses of 5 and 10 mg (direct intratracheal administration) had no effect on the acute bronchoconstriction induced by PAF in neonatally immunized rabbits (airway resistance RL or dynamic compliance Cdyn). However, the PAF-induced increase in airway responsiveness to inhaled histamine was significantly inhibited (RL and Cdyn) by both doses of PF 10040. 3. PF 10040 (5 and 10 mg) significantly inhibited the total pulmonary cell infiltration and neutrophil influx induced by PAF as assessed by bronchoalveolar lavage. PAF-induced eosinophil infiltration into the airways was significantly inhibited in rabbits that received only 10 mg PF 10040. 4. We suggest from the results of the present study that PF 10040 does not exert an inhibitory effect on PAF-induced airway responses solely via antagonism of the PAF receptor located on platelets, as PF 10040 significantly inhibited PAF-induced airway hyperresponsiveness in the absence of an effect on the acute bronchospasm induced by PAF. 5. We provide further evidence that pulmonary eosinophil infiltration and the development of airway hyperresponsiveness are not causally related events as the lower dose of PF 10040 (5 mg) significantly inhibited PAF-induced airway hyperresponsiveness yet was without effect on the eosinophil influx.
Department of Pharmacology, Kings College London.
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D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects; D016535:Bronchial Hyperreactivity / Q000139:chemically induced*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects; D005260:Female; D006632:Histamine; D007114:Immunization; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits
D007546:Isoquinolines; D010972:Platelet Activating Factor; C077682:PF 10040; D006632:Histamine