Mechanism of inhibitory effect of some amphiphilic drugs on platelet aggregation induced by collagen, thrombin or arachidonic acid.
The effects of two representative groups of amphiphilic drugs, lysophosphatidylcholine species (myristoyl, palmitoyl and stearoyl) and phenothiazine neuroleptics (promethazine, chlorpromazine and trifluoperazine), on the morphology of intact rabbit platelets, arachidonate release from membrane phospholipids, pseudopod formation and the resulting aggregation of stimulated platelets were examined and compared with those of two known cycloxygenase inhibitors, aspirin and indomethacin. Collagen-induced aggregation was inhibited by relatively low concentrations of amphiphilic drugs in parallel with the prevention of arachidonate release from the membrane phospholipids. Thrombin-and arachidonate-induced aggregations were inhibited by these drugs at higher concentrations, at which they transform intact platelets from discoid to spiny and spherical shape, respectively, and consequently suppress formation of native pseudopods induced by these stimuli. Washing the drug-treated platelets with BSA-Tyrode solution abolished all the effects of drugs. In contrast, the cycloxygenase inhibitors blocked both collagen- and arachidonate-induced aggregations without causing membrane shape change of the intact platelets, although they inhibited thrombin-induced aggregation at extremely high concentrations, at which they did elicit membrane shape change. These observations suggest that these amphiphilic drugs act on the plasma membrane of platelets and impair membrane-linked functions. At lower concentrations they specifically inhibit the arachidonate release from the membrane phospholipids under collagen stimulation; at higher concentrations they drastically perturb the plasma membrane structure, inducing the membrane shape change, and suppressing the native pseudopod formation under thrombin or arachidonate stimulation. The impairment of membrane-linked functions by these amphiphilic drugs is thought to account for their inhibition of stimulus-induced aggregation.
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001792:Blood Platelets / Q000648:ultrastructure; D002462:Cell Membrane / Q000187:drug effects; D003094:Collagen / Q000037:antagonists & inhibitors; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D010640:Phenothiazines; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D013917:Thrombin / Q000037:antagonists & inhibitors
D014150:Antipsychotic Agents; D001095:Arachidonic Acids; D008244:Lysophosphatidylcholines; D010640:Phenothiazines; D003094:Collagen; D013917:Thrombin