Manipulation of the local thromboxane and prostacyclin balance in vivo by the antithrombotic compounds dazoxiben, acetylsalicylic acid and nafazatrom.
We have developed an experimental model for the study of local prostaglandin production by platelets and the vessel wall following stimulation 'in vivo'. A nylon thread was inserted into the external jugular vein of rabbits; its presence did not induce an occluding thrombus. Thromboxane (TXB2) values in the blood, sampled through the facial vein, immediately distal to the stimulus, rose and remained high for at least 4 hr, while 6-keto prostaglandin (PG) F1 alpha levels, after a first increase, gradually returned to normal ('exhaustion' of the endothelial cells?). No changes were observed in the contralateral jugular vein without thread. After infusion via the femoral vein of 10 mg/kg dazoxiben, a thromboxane synthetase inhibitor, local TXB2 production was completely abolished, whereas 6-keto PGF1 alpha formation no longer returned to basal values, but tended to increase. This leads to the conclusion that upon inhibition of TXB2 formation endoperoxide metabolism is reoriented 'in vivo' towards prostacyclin, and this mainly at the site where platelets are activated. Injection of 100 mg/kg lysine acetylsalicylic acid resulted in complete inhibition of TXB2 and 6-keto PGF1 alpha formation, the latter, however, slowly recovering with time. The administration of nafazatrom to the animals did not influence the local TXB2 changes, but partially prevented the decline of 6-keto PGF1 alpha with time. The antithrombotic properties of this drug thus could be related to protection of the endothelial cells from 'exhaustion'.
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D015237:Dinoprost; D004347:Drug Interactions; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007839:Functional Laterality; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D011460:Prostaglandins F / Q000097:blood*; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones; D011817:Rabbits; D013929:Thromboxane B2 / Q000097:blood*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000097:blood*
D005343:Fibrinolytic Agents; D007093:Imidazoles; D011460:Prostaglandins F; D011720:Pyrazoles; D047069:Pyrazolones; D013931:Thromboxanes; C029166:dazoxiben; D013929:Thromboxane B2; D015237:Dinoprost; D013930:Thromboxane-A Synthase; C018845:nafazatrom; D001241:Aspirin