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1‐ O ‐hexadecyl‐2‐acetyl‐ sn ‐glycero‐3‐phospho (N,N,N trimethyl) hexanolamine: an analogue of platelet‐activating factor with partial agonist activity
Author(s) -
Grigoriadis George,
Stewart Alastair G.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12403.x
Subject(s) - platelet activating factor , chemistry , agonist , platelet , antagonist , bovine serum albumin , stimulation , superoxide , endocrinology , receptor , medicine , biochemistry , biology , enzyme
1 During studies of the role of platelet‐activating factor (PAF) in macrophage superoxide anion generation (O 2 −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 (O 2 − 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 [Ca 2+ ] i , whereas the aggregation response to PAF was preceded by a large rise in [Ca 2+ ] i . 5 Hexanolamine PAF induced O 2 − generation in adherent macrophages, with a maximum response 45% of that to PAF. Hexanolamine PAF (100 n m ), at a concentration equi‐effective with PAF (1 n m ) for stimulation of O 2 − generation in macrophages, induced an increase in [Ca 2+ ] 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 μ m ). 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 O 2 − 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 [Ca 2+ ] i in platelets suggests that PAF receptors may be coupled to platelet aggregation by both Ca 2+ ‐dependent and ‐independent pathways.