INHIBITION OF HUMAN PLATELET AGGREGATION BY THE THROMBOXANE MIMETIC, U46619

Recent publications suggest that high concentrations (10-100μM) of the stable analogues of PGH2, U46619 and U44069 stimulate adenylate cyclase (Avdonin et al.. 1985) and cause an elevation in cAMP in intact platelets (Best et al., 1979). The effect of high concentrations of U46619 on responses to ADP [1.0-30μM] and vasopressin [1-10nM] was investigated in human platelet rich plasma preincubated with the thromboxane antagonist, GR32191, [10μM] (Lumley et al., this meeting) and aspirin [0.1mM]. Concentration-effect curves to ADP were not affected by preincubation with O.lmM U46619 in the presence of GR32191 [10μM]. Under the same conditions, aggregation to vasopressin was inhibited. U46619 at 30μM had no effect on the vasopressin concentration-effect curve, but at 0.1mM, it resulted in an eight-fold rightwards shift and also reduced the maximum response by 30%. This was equivalent to the inhibition of vasopressin-induced aggregation achieved with prostacyclin at a concentration of 1nM in the same experiments. At 0.3mM, U46619 caused total inhibition of aggregation to vasopressin, equivalent to that seen with prostacyclin at 3nM. The failure of U44619 to inhibit ADP-induced aggregation may reflect inhibition of adenylate cyclase by ADP (Cusack et al. 1982). Aggregation induced by vasopressin is independent of inhibition of adenylate cyclase (Thomas et al.. 1983) and under these conditions, U46619 may induce increases in cAMP which exert an inhibitory action on platelet function. These results indicate that experiments using U44619 as an aggregating agent should be interpreted with caution. The high concentrations of U46619 required to induce aggregation in the presence of thromboxane antagonists may also cause stimulation of adenylate cyclase, thereby making an additional contribution to the inhibition observed. Avdonin P.V. et al.f Thromb. Res., 40, 101-112, 1985.

Best L.C. et al.. Biochim, Biophys. Acta, 583. 344-351, 1979.

Thomas M.E. et al.. Thromb. Res., 32, 557-566, 1983.

Cusack et al.. Br. J. Pharmac., 76, 221-227, 1982.