1-O-hexadecyl-2-acetyl-sn-glycero-3-phospho (N,N,N trimethyl) hexanolamine: an analogue of platelet-activating factor with partial agonist activity

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Abstract
1 During studies of the role of platelet-activating factor (PAF) in macrophage superoxide anion generation (O2−1), we identified an agonist action of the putative PAF receptor antagonist 1-O-hexadecyl-2-acetyl-sn-glycero-3-phospho (N,N,N-trimethyl) hexanolamine (hexanolamine PAF) in guinea-pig macrophages. The 1-O-octadecyl form of this compound has specific antagonist actions at PAF receptors. 2 The agonist properties of hexanolamine PAF were examined in rabbit washed platelets (aggregation) and in guinea-pig peritoneal macrophages (O2−generation). 3 Hexanolamine PAF induced significant platelet aggregation (50% of the PAF maximum). However, the omission of bovine serum albumin (BSA) from the Tyrode buffer resulted in a diminution of the response of washed platelets during storage for 24 h at 4°C (7% of PAF maximum), whereas the maximum response to PAF was unaffected by storage for this period, irrespective of the presence of BSA. 4 Platelet aggregation induced by hexanolamine PAF was not accompanied by a detectable increase in intracellular calcium [Ca2+]i, whereas the aggregation response to PAF was preceded by a large rise in [Ca2+]i. 5 Hexanolamine PAF induced O2−generation in adherent macrophages, with a maximum response 45% of that to PAF. Hexanolamine PAF (100 nm), at a concentration equi-effective with PAF (1 nm) for stimulation of O2−generation in macrophages, induced an increase in [Ca2+]i which was significantly less than that induced by PAF. 6 PAF concentration-response curves were constructed in platelets or macrophages following pretreatment with hexanolamine PAF (0.1 and 1 μm). The interaction between PAF and the putative partial agonist (hexanolamine PAF) had the characteristics expected of a partial agonist interacting with a full agonist. 7 Platelet aggregation induced by hexanolamine PAF was antagonized non-competitively by the PAF receptor antagonist, WEB 2086, whereas antagonism of PAF-induced aggregation by WEB 2086 was competitive. Macrophage O2−generation induced by hexanolamine PAF or PAF was antagonized by WEB 2086. 8 These data indicate that hexanolamine PAF is a partial agonist at PAF receptors in macrophages and platelets. The inability of hexanolamine PAF to increase [Ca2+]i in platelets suggests that PAF receptors may be coupled to platelet aggregation by both Ca2+-dependent and -independent pathways.