Activation of guinea pig peritoneal macrophages by platelet activating factor (PAF) and its agonists.
The platelet activating factor (PAF: 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine) and its analogs were examined to determine their effects on guinea pig peritoneal macrophages. PAF activated macrophages, but its effect on macrophages was much weaker than that observed on platelets: the concentration required for 50% maximum activation was 8.5 X 10(-6) M for macrophages and 2.9 X 10(-10) M for platelets. Three PAF agonists, 1-O-octadecyl-2-O-(N,N-dimethylcarbamoyl)-glycero-3-phosphocholine (Compound I), 1-O-octadecyl-2-acetamido-2-deoxy-glycero-3-phosphocholine (Compound II), and 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine (Compound III), showed higher activity in stimulating macrophage function than PAF. The abilities of these non-metabolizable PAF agonists to activate macrophage paralleled their relative potency to induce platelet activation. The sn-3 enantiomers of PAF and Compound III exhibited activity, while the sn-1 did not. By comparing the activities of derivatives of Compound III, it was shown that the long-chain alkyl-ether group in the glycerol-1 position, a relatively small size of the substituent on the hydroxy group at the sn-2 position, and the choline moiety in the glycerol-3 position must play critical roles in the process of macrophage activation. A specific PAF antagonist, CV3988, which inhibits PAF-induced platelet activation and hypotension, inhibited the activation of macrophages caused by PAF and its agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Hayashi
H
H
Kudo
I
I
Inoue
K
K
Onozaki
K
K
Tsushima
S
S
Nomura
H
H
Nojima
S
S
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects*; D010529:Peritoneal Cavity; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology
D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; C039351:platelet activating factor receptor; C037913:CV 3988