Recovery of Thromboxane A2 and Prostacyclin Production in Vivo Following Single-Dose Aspirin Treatment

Abstract

In recent years considerable attention has focused on the potential usefulness of aspirin (ASA) in the prevention of thromboembolism. Based on the inability of blood platelets to produce new cyclooxygenase enzyme, it has been suggested that low-dose ASA therapy may afford selective inhibition of thromboxane A2 (TxA2) biosynthesis. Thus, it was proposed that endothelial production of prostacyclin (PGI2) may recover more rapidly than platelet production of TxA2 following low-dose ASA treatment. The present study investigated the relative rates of TxA2 cyclooxygenase (CO) and PGI2 CO recovery following ASA inhibition in an in vitro animal model. In this model, measurable and reproducible plasma levels of TxB2 and 6-keto-PGFlα were achieved by the infusion of arachidonic acid (AA), and the effects of ASA on these levels were determined over a period of time. Specifically, 1 mg/kg ASA (or ASA vehicle) was administered to anesthetized Swiss Webster mice (25 g) via cardiac puncture. At various time intervals subsequent to ASA treatment (i.e., 2 to 144 hr), AA (50 mg/kg) was infused, and TxB2/6-keto-PGF1α plasma levels were determined by radioimmunoassay. In animals not treated with ASA, the infusion of AA resulted in an increase in TxB2 from <0.1 ng/ml to 69.8 ± 5.6 ng/ml and an increase in 6-keto-PGF1α from 0.080 ± 0.017 ng/ml to 1214.9 ± 85.9 ng/ml. These values are comparable to our previous results, which demonstrated a dose-response relationship for TxB2/6-keto-PGF1α over the AA concentration range of 5-50 mg/kg infused AA. In animals pretreated with ASA, there was a rapid and marked decrease in TxB2/6-keto-PGF1α production. In this connection it was found that at 2 hr post-ASA, TxB2/6-keto-PGF1α production were inhibited by 77.4 ± 3.9% and 73.4 ± 3.1%, respectively. At 24, 48, and 72 hr post-ASA treatment, there was an equal recovery of TxB2/6-keto-PGF1α production. Only at 96 hr and 144 hr post-ASA did the PGI2 CO appeared to recover at a more rapid rate. Thus, 96 hr following ASA, 6-keto-PGF1α had returned to control levels, whereas TxB2 production remained inhibited. Furthermore, selective inhibition of the TxA2 CO was still evident 144 hr post-ASA, i.e., 76.0 ± 9.3% of preaspirin levels forTxB2 versus 121.5 ± 10.5% of preaspirin levels for 6-keto-PGF1α. These findings indicate that in response to 1 mg/kg ASA there is a gradual and parallel recovery of TxB2/6-keto-PGF1α over 3 days. On the other hand, at 4 and 6 days post-ASA, a divergence in the rates of recovery of these CO products becomes apparent. In summary, the present results suggest that although PGI2 CO appears to recover more rapidly than TxA2 CO, the observed differences in these rates of recovery may not be substantial enough to serve as the basis for selective inhibition of TxA2 production by ASA therapy.