Influence of selective thromboxane synthetase blocker CGS-13080 on thromboxane and prostacyclin biosynthesis in whole blood: evidence for synthesis of prostacyclin by leukocytes from platelet-derived endoperoxides.
Increase in thromboxane A2 (TXA2) generation has been proposed as a mechanism of dynamic vaso-occlusion and in vivo platelet thrombus formation. We have examined the effects of CGS-13080, an imidazole derivative, on rabbit and human TXA2-prostacyclin (PGI2) "balance." In rabbits given CGS-13080, serum levels of TXB2 (stable metabolite of TXA2) were inhibited 81% at 2 hours and 56% at 24 hours (both P less than or equal to 0.01). Collagen-induced platelet aggregation was inhibited at 2 hours after CGS-13080 administration. In contrast, serum levels of 6-keto-PGF1 alpha (stable hydrolysis product of PGI2) increased 587% compared with control values at 2 hours (P less than or equal to 0.01). Platelet and white blood cell counts were not significantly altered. In human blood incubated in vitro with CGS-13080, serum TXB2 was completely inhibited, whereas PGI2 generation was stimulated (both P less than or equal to 0.001). In other experiments, we demonstrated uptake of platelet-generated cyclic endoperoxides by leukocytes and generation of PGI2 in the presence of CGS-13080 but not indomethacin. Thus, CGS-13080 inhibits TXA2 and stimulates PGI2 production in rabbit and human blood. Increase in PGI2 generation with TXA2 inhibition may be of potential benefit in conditions characterized by platelet hyperactivity.
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002122:Calcium Chloride / Q000494:pharmacology; D003094:Collagen; D011464:Epoprostenol / Q000096:biosynthesis*; D007093:Imidazoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007962:Leukocytes / Q000378:metabolism*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000096:biosynthesis*
D007093:Imidazoles; D011725:Pyridines; D013931:Thromboxanes; D000001:Calcimycin; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D003094:Collagen; C037787:pirmagrel; D011464:Epoprostenol; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase; D002122:Calcium Chloride; D007213:Indomethacin