The peripheral serotonergic system and platelet aggregation in cyclosporinA-induced hypertensive rats

Cyclosporin A plays an important role in preventing rejection in allograft transplant recipients. However, the therapeutic use of cyclosporin A is ass ociated with increased incidence of thromboembolic complications and drug-r elated hypertension. In order-to study the mechanisms by which cyclosporin A induces these abnormal pathophysiological situations, we have assessed th e platelet serotonin contents and whole blood platelet aggregation in contr ol rats as well as in rats treated (orally) with 30 and 5 mg/kg/day of cycl osporin A, after 2 and 7 weeks of treatment. These doses correspond respect ively to CsA "peak" and "trough" concentrations achieved in human blood in clinical practice (immediately following an intake of a daily dose of CsA a nd when the blood concentration stabilizes, respectively). Both trough and peak doses caused an increase in blood pressure after 2 and 7 weeks. Platel et serotonin content decreased in the cyclosporin-treated groups, in contra st with the control. Collagen-induced whole blood platelet aggregation incr eased drastically for the peak concentration-treated group, while adenosine 5'-diphosphate-induced platelet aggregation did not reach statistical sign ificance. Finally, in vitro platelet thromboxane Az generation increased in cyclosporin A concentrations when platelets were stimulated with either co llagen or adenosine 5'-diphosphate, In conclusion, both tested cyclosporin A concentrations induced important changes in platelet serotonin and thromb oxane content and aggregation, factors which may play a decisive role in th e development and/or maintenance of hypertension and thrombotic complicatio ns. (C) 1999 Elsevier Science Ltd. All rights reserved.