Accumulation of quinidine by human blood platelets: effects on platelet ultrastructure and 5-hydroxytryptamine.

1. We have studied the mechanism of quinidine uptake by normal human blood platelets.2. Platelets in plasma or Krebs solution took up quinidine extremely rapidly, the maximal drug concentration ratio of platelet to medium being 24 to 1 after 1 minute.3. The effects of metabolic inhibitors on uptake were equivocal. Ouabain had no effect but iodoacetate and dinitrophenol were effective. However, as accumulation was not inhibited by low temperature, it was probably not energy dependent.4. Interactions between quinidine and 5-HT were also investigated.5. Quinidine blocked 5-HT uptake, but conversely, neither 5-HT itself nor 5-HT uptake inhibitors, such as cocaine, dexamphetamine, and desipramine interfered with quinidine accumulation.6. Electronmicrographs of platelets incubated with 10(-5), 10(-4) or 2 x 10(-3)M quinidine in Krebs solution for 2 h showed no changes at the lower concentrations, but gross ultastructural damage, including disintegration of the plasma membrane, at 2 x 10(-3)M.7. Further evidence for intracellular penetration was obtained because quinidine released endogenous 5-HT and ATP, and also (14)C-5-HT from loaded cells.8. We conclude that quinidine is taken up by the platelet by a passive process, unrelated to the 5-HT transport mechanism. It is probably accumulated largely in the plasma membrane and outer protein layer, but intracellular penetration and ultrastructural damage may occur.9. Although the effects on 5-HT and ATP were not due to platelet damage, this may occur in vivo and be the cause of quinidine induced thrombocytopenic purpura.