Similar effects of ether phospholipids, PAF and lyso-PAF on the Ca(2+)-ATPase activity of rat brain synaptosomes and leukocyte membranes.
The present study is an extension of our previous work with the antineoplastic ether phospholipid ET-18-OCH3 (edelfosine), which was shown to affect the activity of the Ca(2+)-ATPase of rat brain synaptosomes and peritoneal leukocyte membranes. The effect of ET-18-OCH3 was compared with that of the 16-carbon chain analogue ET-16-OCH3 as well as with the structurally related 16- and 18-carbon PAFs (platelet-activating factors) and lyso-PAFs. In addition, the two alkylphosphocholines D-20166 and D-21266 (perifosine) were included in the investigation. The influence of all of the compounds followed the same pattern, i.e., the Ca(2+)-ATPase activity of the synaptosomes was increased over a relatively narrow concentration range (peak at 20-30 microM) and that of the leukocyte membranes was inhibited in a concentration-dependent manner by 10-50 microM concentrations of the drugs. Ether phospholipids with an 18-carbon chain at C-1 were more potent than those with a 16-carbon chain. All of the compounds increased the activity of the synaptosomal ATPase to the same extend (ca. 50%). With the exception of lyso-PAF, all inhibited the enzyme activity of leukocyte membranes by 60-70%, whereas lyso-PAF was less effective (ca. 50% inhibition). The concentration range of activity for PAF and lyso-PAF indicates that their effect on the enzyme activity was caused by receptor-independent mechanisms. The ether phospholipids and alkylphosphocholines are suggested to act by accumulating in the membranes and thereby altering the character of the lipid environment of the enzyme rather than by a direct interaction with the Ca(2+)-ATPase.
Grosman
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Department of Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. fipe@farmakol.ku.dk
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D008566:Membranes / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010742:Phospholipid Ethers / Q000494:pharmacology; D010743:Phospholipids / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology*
D018836:Inflammation Mediators; C029271:O-deacetyl platelet activating factor; D010726:Phosphodiesterase Inhibitors; D010742:Phospholipid Ethers; D010743:Phospholipids; D010972:Platelet Activating Factor; C026659:edelfosine; D000252:Calcium-Transporting ATPases