Retinoic acid enhances fibrinolytic activity in-vivo by enhancing tissue type plasminogen activator (t-PA) activity and inhibits venous thrombosis.
We studied the profibrinolytic effect and the anti-thrombotic potential of retinoic acid in-vivo. Male Wistar rats were treated with retinoic acid either acutely or twice daily for a period of 5 consecutive days in a dose range of 0.01 to 3.0 mg/kg. Fibrinolytic activity was measured ex-vivo using the diluted blood clot lysis test and net t-PA activity in tissue extracts was measured in a spectrophotometric rate assay. Clot lysis was dose dependently increased by retinoic acid up to about 170% (relative to vehicle treated rats) at a dose of 3 mg/kg. No tachyphylaxis could be detected. Ex-vivo measured fibrinolytic activity after single administration of 1 mg/kg of retinoic acid peaked at 3 h after ingestion. Even after 18 h a significantly higher clot lysis rate was measured. Lysis of blood clots from vehicle and retinoic acid treated rats could be completely blocked by addition of tranexamic acid or antibodies against rat t-PA before clot formation. t-PA activity in plasma was slightly increased after retinoic acid treatment; no effects were measured on plasma PAI-1, u-PA, plasminogen, and alpha 2-antiplasmin levels. t-PA activity in lung and kidney was marginally enhanced by retinoic acid but in heart and aortic tissue extracts t-PA activity was increased by about 50%. We confirmed this potential anti-thrombotic property in an in-vivo venous thrombosis model. A reduced clot size was observed after retinoic acid administration (35% reduction at a dose of 1 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Solvay Duphar B. V., Dept. of Vascular Pharmacology, Weesp, The Netherlands.
J J
JJ
van Giezen
G I
GI
Boon
J W
JW
Jansen
B N
BN
Bouma
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D010960:Plasminogen Activators / Q000032:analysis; D010974:Platelet Aggregation; D051381:Rats; D017208:Rats, Wistar; D013924:Thrombophlebitis / Q000517:prevention & control*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D000979:alpha-2-Antiplasmin / Q000032:analysis
D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D000979:alpha-2-Antiplasmin; D014212:Tretinoin; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator