The influence of cyclandelate on Ca++ translocation in human platelets.
A major event in signal transduction in platelets is the mobilisation of Ca++ ions by 2 mechanisms: influx of Ca++ from the extracellular medium and release from intracellular storage sites. The calcium modulating drug cyclandelate is known to inhibit platelet aggregation induced by various agonists. Thus, by studying the effects of cyclandelate on cytosolic Ca++ concentrations in gel-filtered human platelets, an explanation was sought of the mechanism which couples receptor stimulation with the processes that execute aggregation and secretion. Cyclandelate in concentrations between 10 and 50 mumol/L induced a dose-dependent increase in the basal level of cytosolic Ca++ of unstimulated platelets. In platelets stimulated with thrombin (5 U/ml) or platelet activating factor (1 mumol/L), cyclandelate strongly inhibited the increase of cystolic Ca++ in the presence of extracellular Ca++, but in the absence of extracellular Ca++ only a weak inhibition was observed. This inhibition was dose dependent and optimal at about 50 mumol/L, the concentration at which Ca++ mobilisation was suppressed to about 10% of control values, and at which cyclandelate inhibits platelet aggregation. In contrast, the metabolites cyclandelate alcohol and cyclandelate acid were without effect at the same concentrations (50 mumol/L). Concentrations of cyclandelate greater than 50 mumol/L were found to further increase the concentration of Ca++ in the unstimulated platelet, an effect which interfered with the stimulus-induced Ca++ translocation. Thus, at concentrations which inhibit platelet aggregation, cyclandelate prevents the mobilisation of Ca++ ions induced by such agonists as thrombin and platelet activating factor. Further study is required to determine the mechanism by which cyclandelate inhibits these platelet responses.[1]References
- The influence of cyclandelate on Ca++ translocation in human platelets. Akkerman, J.W., van den Hoven, W.E. Drugs (1987) [Pubmed]
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