Tatsuzo Fujii

Effect of some amphiphilic drugs on the membrane morphology and aggregation of rabbit platelets.

Abstract Treatment of normal, disc-shaped rabbit platelets with lysophosphatidylcholine and chlorpromazine induced respectively spine formation and spherical transformation. In similar concentration ranges to those in which they induced these morphological changes, the drugs suppressed a series of events triggered by thrombin: pseudopod formation, arachidonate release from the membrane phospholipids, and aggregation. Washing the drug-treated platelets reversed the morphological changes and abolished the inhibitory effect on aggregation. These observations suggest that amphiphilic drugs perturb the plasma membrane structure of platelets, inducing the membrane shape change and inhibiting the stimulus-induced aggregation.

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.