The peripheral serotonergic system and platelet aggregation in cyclosporin A-induced hypertensive rats.
Cyclosporin A plays an important role in preventing rejection in allograft transplant recipients. However, the therapeutic use of cyclosporin A is associated with increased incidence of thromboembolic complications and drug-related hypertension. In order to study the mechanisms by which cyclosporin A induces these abnormal pathophysiological situations, we have assessed the platelet serotonin contents and whole blood platelet aggregation in control rats as well as in rats treated (orally) with 30 and 5 mg/kg/day of cyclosporin A, after 2 and 7 weeks of treatment. These doses correspond respectively to CsA "peak" and "trough" concentrations achieved in human blood in clinical practice (immediately following an intake of a daily dose of CsA and when the blood concentration stabilizes, respectively). Both trough and peak doses caused an increase in blood pressure after 2 and 7 weeks. Platelet serotonin content decreased in the cyclosporin-treated groups, in contrast with the control. Collagen-induced whole blood platelet aggregation increased drastically for the peak concentration-treated group, while adenosine 5'-diphosphate-induced platelet aggregation did not reach statistical significance. Finally, in vitro platelet thromboxane A2 generation increased in cyclosporin A concentrations when platelets were stimulated with either collagen or adenosine 5'-diphosphate. In conclusion, both tested cyclosporin A concentrations induced important changes in platelet serotonin and thromboxane content and aggregation, factors which may play a decisive role in the development and/or maintenance of hypertension and thrombotic complications.
Reis
F
F
Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Universidade de Coimbra, Portugal.
Tavares
P
P
Fontes Ribeiro
C A
CA
Antunes
F
F
Teixeira
F
F
D000818:Animals; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010976:Platelet Count / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000097:blood*; D013928:Thromboxane A2 / Q000096:biosynthesis / Q000097:blood; D013929:Thromboxane B2 / Q000378:metabolism; D013997:Time Factors
D012701:Serotonin; D013929:Thromboxane B2; D013928:Thromboxane A2; D016572:Cyclosporine; D003094:Collagen