Aprotinin decreases release of 6-keto-prostaglandin F1 alpha and increases release of thromboxane B2 in cultured human umbilical vein endothelial cells.
Use of the proteinase inhibitor aprotinin significantly improves hemostasis and reduces bleeding after operations in which extracorporeal circulation is used. The mechanism of action, however, has been only partially clarified. In this work we investigated whether aprotinin influenced the production and release of the eicosanoids prostacyclin, measured as the stable metabolite 6-keto-prostaglandin F1 alpha, and thromboxane A2, measured as the stable metabolite thromboxane B2, from endothelial cells. Human umbilical vein endothelial cells were incubated with different concentrations of aprotinin (5.5, 20, 55, and 100 mumol/L). The levels of 6-keto-prostaglandin F1 alpha and thromboxane B2 were measured at baseline and after thrombin stimulation. A concentration-dependent effect of aprotinin on 6-keto-prostaglandin F1 alpha synthesis was demonstrated. After incubation with 100 mumol/L of aprotinin, a 90% reduction in 6-keto-prostaglandin F1 alpha production was seen (31.69 versus 307.44 picograms per million cells; p less than 0.001). Conversely, thromboxane B2 production showed a 345% increase after incubation with aprotinin (287.80 versus 83.82 picograms per million cells; p less than 0.0001). Since 6-keto-prostaglandin F1 alpha inhibits and thromboxane B2 strongly enhances platelet aggregation, it appears that one mechanism of the clinically observed effectiveness of aprotinin lies in the altered ratio of 6-keto-prostaglandin F1 alpha: thromboxane B2 in endothelial cells, which leads to enhanced platelet aggregation and improved vessel sealing.
Havel
M P
MP
Second Surgical Clinic, University of Vienna, Austria.
Griesmacher
A
A
Weigel
G
G
Owen
A
A
Simon
P
P
Müller
M M
MM
Wolner
E
E
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis / Q000096:biosynthesis*; D007611:Aprotinin / Q000494:pharmacology*; D002452:Cell Count; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis; D004727:Endothelium / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D010974:Platelet Aggregation; D011863:Radioimmunoassay; D013929:Thromboxane B2 / Q000032:analysis / Q000096:biosynthesis*; D014471:Umbilical Veins
D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D007611:Aprotinin; D000242:Cyclic AMP