CV 6209 is a non-competitive antagonist of platelet-activating factor receptors on guinea-pig resident peritoneal macrophages.
1. The characteristics of antagonism of platelet-activating factor (Paf) receptors by the phospholipid Paf analogue, CV 6209, were studied in rabbit platelets and polymorphonuclear leucocytes (PMN) and in guinea-pig macrophages. 2. Paf-induced aggregation of PMN or platelets was antagonized in a competitive and specific manner by CV 6209 with no detectable difference between the pA2 values (approximately 9.5). 3. The specificity of CV 6209 (1-100 nmol/L) for Paf receptors in platelets and PMN was indicated by a lack of effect on A23187 (10 mumols/L) or fMLP (1 mumol/L) induced aggregation, respectively. 4. CV 6209 (1-100 nmol/L) was also a potent antagonist of Paf-induced prostacyclin (PGI2) generation by guinea-pig peritoneal macrophages. However, CV 6209 caused significant depression of the maximum response to Paf and a non-parallel shift in the concentration-response curve indicating a non-competitive type antagonism. 5. PGI2 generation induced by the ionophore A23187 was unaffected by CV 6209 (up to 100 nmol/L) whereas basal PGI2 production by macrophages was reduced by lower concentrations (10-100 nmol/L). These observations are not consistent with a direct effect of CV 6209 on the enzymes involved in PGI2 synthesis but do suggest that endogenous Paf regulates basal PGI2 generation. 6. The non-competitive antagonism of guinea-pig macrophage Paf receptors gives further support to the contention that these receptors are distinct from those mediating aggregation of platelets and PMN.
Stewart
A G
AG
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D011464:Epoprostenol / Q000097:blood; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010529:Peritoneal Cavity / Q000166:cytology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled
D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011726:Pyridinium Compounds; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C053321:CV 6209; D000001:Calcimycin; D015121:6-Ketoprostaglandin F1 alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011464:Epoprostenol