Vinblastine inhibits platelet aggregation by a microtubule-independent mechanism, probably by its perturbing action on the plasma membrane.
Inhibitory mechanism of vinblastine on platelet activation was examined with respect to its effect on disassembly of the microtubule system. Vinblastine at 10 microM concentration caused washed platelets to become sphere with disorganized microtubule system, but did not affect aggregation induced by collagen, arachidonic acid or thrombin. Collagen-induced aggregation was inhibited by 50-100 microM of vinblastine and much higher concentration was required to inhibit arachidonic acid- and thrombin-induced aggregation. When the vinblastine (100 microM)-treated platelets were washed with albumin medium, the impaired aggregability was well recovered in response to collagen. In this case, however, both the vinblastine-induced sphered shape and disappeared microtubule system were not recovered to the normal states. Within the concentration ranges that inhibited collagen-induced aggregation, vinblastine also suppressed reversibly Ca2+ influx and arachidonic acid liberation from membrane phospholipids by phospholipase A2. Conversion of added arachidonic acid to thromboxane A2 was not inhibited even by such concentration. These results suggest that vinblastine interacts non-specifically with the cell membrane to cause reversible inhibition of arachidonic acid liberation by phospholipase A2 and Ca2+ influx and thereby aggregation through physical perturbation of membrane lipid bilayer, independent of the activity to disassemble platelet microtubule system.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D066298:In Vitro Techniques; D008855:Microscopy, Electron, Scanning; D008870:Microtubules / Q000187:drug effects*; D010743:Phospholipids / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D013929:Thromboxane B2 / Q000096:biosynthesis; D014747:Vinblastine / Q000494:pharmacology*
D001095:Arachidonic Acids; D010743:Phospholipids; D016718:Arachidonic Acid; D013929:Thromboxane B2; D014747:Vinblastine; D000255:Adenosine Triphosphate; D002118:Calcium