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

Abstract

Summary1. 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 10-3M 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 10-3M.7. Further evidence for intracellular penetration was obtained because quinidine released endogenous 5-HT and ATP, and also 14C-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.

Effect of Quinidine on Platelets

“…The drug caused considerable ultrastructural changes such as swelling of platelets and loss of agranules, mitochondria and microtubules, confirming the findings of two previous studies [6,7]. There was a slight but definite release of l4C-serotonin after incubation of platelets with 1 or 1.5 mM quinidine, sug gesting platelet injury or activation by the drug.…”

“…There was a slight but definite release of l4C-serotonin after incubation of platelets with 1 or 1.5 mM quinidine, sug gesting platelet injury or activation by the drug. However, quinidine at concentrations as high as 1.5 mM did not induce platelet lysis as there was no significant release of LDH, even though it was suggested in a pre vious report [6] that the drug might cause disruption of the platelet membrane. In ad dition, this study found that these high con centrations of quinidine caused marked in hibition of platelet aggregation induced by ADP, adrenaline, collagen and arachidonate.…”

“…At very high nonpharmacological levels of the drug, quinidine has been reported pre viously to cause profound ultrastructural changes [6,7] and impaired serotonin up take [8,9]. However, it is not known whether quinidine in concentrations within the thera peutic range has any effect on platelets or would impair platelet function, thus contrib uting to a bleeding tendency.…”

The Assessment of Drug-Dependent and Isoimmune Antiplatelet Antibodies by the Use of Platelet Aggregometry

“…Therefore, precise enumeration of the platelets was not critical. Boullin and O'Brien (18) have shown that the platelet uptake of quinidine from plasma reaches a peak value at quinidine concentrations between 10' and 2 X 10' M. Below 10' M quinidine uptake by platelets falls off sharply. These data correlate well with the effects of changing quinidine concentration in our system (Fig.…”