Effect of cyclosporin A on platelet aggregation and thromboxane/prostacyclin balance in a model of extrahepatic cholestasis in the rat.
Cyclosporin A (CsA), a potent immunosuppressor used in organ transplants and autoimmune diseases, is associated with adverse effects in the kidney, liver, and nervous system. This drug was recently shown to stimulate platelet aggregation, to increase thromboxane synthesis, and to decrease vascular prostacyclin synthesis. In experimental cholestasis, thrombocyte function is altered. The present study was designed to assess the effects of CsA on platelet function in extrahepatic biliary obstruction (EBO) in rats. Cyclosporin or its excipient (Cremaphore El, polyethoxylated castor oil) did not modify collagen-induced platelet aggregation. In animals with EBO, platelet aggregation decreased by 50%. The administration of CsA (5 or 10 mg/kg) or Cremaphore El increased aggregation by 163%, 253% and 123% respectively. Thromboxane production increased by 119% after Cremaphore El was administered, but was not significantly modified by CsA. Cholestasis increased thromboxane synthesis by 48.4%, whereas CsA showed a direct dose-dependent effect, and excipient had no significant effect. Excipient inhibited the vascular synthesis of 6-keto-PFG1 alpha by 67.2%, as did 5 mg/kg (56.8%) and 10 mg/kg CsA (27.6%). EBO led to a nonsignificant increase in the vascular synthesis of 6-keto-PFG1 alpha. Cremaphore EI inhibited prostacyclin synthesis by 79%; inhibition by CsA was dose-dependent (31% at 5 mg/kg, 60% at 10 mg/kg). Our findings show that cholestasis enhances the effects of CsA on platelet aggregation and thromboxane/prostacyclin balance. These results may reflect the vascular effects of CsA, which in turn may be enhanced by cholestasis.
González-Correa
J A
JA
Department of Pharmacology and Therapeutics, School of Medicine, University of Málaga, Spain.
De La Cruz
J P
JP
Lucena
M I
MI
Sánchez de la Cuesta
F
F
D000818:Animals; D002368:Castor Oil / Q000031:analogs & derivatives / Q000494:pharmacology; D001651:Cholestasis, Extrahepatic / Q000097:blood* / Q000601:surgery; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000096:biosynthesis*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013931:Thromboxanes / Q000096:biosynthesis*
D007166:Immunosuppressive Agents; D013931:Thromboxanes; C023040:polyethoxylated castor oil; D002368:Castor Oil; D016572:Cyclosporine; D011464:Epoprostenol