Differential Inhibition of Vascular Prostacyclin and Platelet Thromboxane Synthesis by Different Doses Aspirin and by the Thromboxane Inhibitor Ridogrel (R 68070)

Abstract

The present study has examined the effect of different doses of aspirin and of ridogrel, a compound combining specific TXA₂-synthetase and TXA₂-prostaglandin endoperoxide receptor blockade in one molecule, on prostacyclin (PGI2) and thromboxane A₂ (TXA₂)-production in a rat model. Prostaglandin-production by incubated vascular rings and in serum were evaluated. The equivalent of a daily 60 mg aspirin-dose in an adult person, significantly inhibited both serum PGI₂-concentration (-44 %) and direct vascular PGI₂-production (-50 %). No significant effect on PGI₂-formation was seen with a 20 mg aspirin equivalent. There was on the other hand no significant difference in the degree of TXA₂-inhibition obtained with the higher (76 %) and lower dose (62 %), so that a more interesting PGI₂-TXA₂ ratio was obtained with the latter. With ridogrel however a nearly complete (99 %) TXA₂-inhibition was acquired with no effect on PGI₂. The differences in PGI₂-TXA₂ balance after intraperitoneally or intramuscularly administered low dose aspirin were compatible with presystemic hydrolysis of acetylsalicylic acid.

These data suggest that a more selective TXA₂-inhibition, than the one obtained with the currently used aspirin doses, must be possible and that the results of the current trials still might be ameliorated.

Key Words:

• low-dose aspirin
• ridogrel
• prostacyclin
• thromboxane
• differential inhibition