Platelet activation is increased in cyclosporin A-induced hypertensive rats

One of the most severe side effects of the immunosuppressive agent, cyclosp orin A (CsA), is increased risk of thromboembolic complications and drug-re lated hypertension. Because platelets might be involved in these processes, we rested the possibility of CsA affecting platelet activation, which migh t contribute to these adverse drug reactions. The experiments were done usi ng. Wistar rats, treated or not (control) with CsA (Sandimmun Necoral). 5 a nd 30 mg/kg/day, for 7 weeks. Systolic. diastolic, and mean blood pressures . intracellular free calcium concentration ([Ca2+](i)). platelet serotonin (5-HT) contents. and aggregation were determined, at weeks 0, 2, and 7 of t reatment. Inositol phosphates (InsP) production. platelet thromboxane A(2) (TXA(2)) generation, and morphology of plate lets, through electron microsc opy studies, also were compared. it was demonstrated that blood pressures i ncreased in the CsA treated groups, when compared with the control group, a fter 2 and 7 weeks of administration. CsA at both "attack" and "maintenance " doses increased basal, 5-HT, and thrombin-evoked [Ca2+](i) after 7 and 7 weeks versus the control group. However. basal and evoked InsP production w as stimulated by 5 mg/kg of CsA, but inhibited by 30 mg/kg, when compared w ith the control. Platelet 5-HT contents decreased significantly after 2 and 7 weeks in the CsA-treated groups, when compared with the control group. C ollagen-induced whole brood platelet aggregation increased drastically in t he "attack" CsA-treated group, whereas adenosine diphosphate (ADP)-induced platelet aggregation did not reach statistical significance. Finally, in vi tro basal, collagen-, and ADP-evoked platelet TXA(2) generation increased i n both CsA concentrations, versus the control. In conclusion, our study dem onstrates that both CsA doses alter platelet calcium homeostasis (even affe cting the calcium fluxes differently), 5-HT and TXA(2) contents and aggrega tion; which might contribute to the development and/or maintenance of high blood pressures and increased risk of thromboembolic complications.