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.