F. Reis et al., The peripheral serotonergic system and platelet aggregation in cyclosporinA-induced hypertensive rats, THROMB RES, 96(5), 1999, pp. 365-372
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.