Platelet aggregation and intracellular calcium mobilisation responses are enhanced by cyclosporin A but not by pimecrolimus (SDZ ASM 981).
It has been shown previously that cyclosporin A enhances platelet aggregation responses, particularly to adenosine diphosphate (ADP). In this investigation platelet responses to ADP in the presence of cyclosporin A and pimecrolimus (SDZ ASM 981), a new cell selective inhibitor of inflammatory cytokines, were determined. Measurements were performed in whole blood using a sensitive platelet counting method and in platelet-rich plasma (PRP) using a Biola laser aggregometer. The latter monitors both aggregate formation and aggregate size. In vitro studies were performed using recombinant hirudin as anticoagulant in order that physiological concentrations of divalent cation concentrations were maintained. Studies using both methods confirmed an enhanced aggregation response to ADP in the presence of cyclosporin A. In contrast, aggregation responses were not enhanced in the presence of pimecrolimus, either in PRP or in whole blood where a slight reduction of ADP-induced aggregation was seen at concentrations of pimecrolimus >10(-6) M. The effects of cyclosporin A and pimecrolimus on ADP-induced calcium mobilisation in platelets were determined using a flow cytometric method. A significant increase in intracellular calcium mobilisation was seen in the presence of cyclosporin A but not in the presence of pimecrolimus. Enhanced platelet aggregation responses to ADP observed in the presence of cyclosporin A may be a consequence of enhanced ADP-induced calcium mobilisation.
Centre for Vascular Research, University of Nottingham, Cardiovascular Medicine, Queen's Medical Centre, Nottingham NG7 2UH, UK. sue.fox@nottingham.ac.uk
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Fox
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Judge
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Allen
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Heptinstall
D000244:Adenosine Diphosphate / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D009391:Nephelometry and Turbidimetry; D010974:Platelet Aggregation / Q000187:drug effects*; D010976:Platelet Count / Q000295:instrumentation; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D000244:Adenosine Diphosphate; C117268:pimecrolimus; D016572:Cyclosporine; D016559:Tacrolimus