Differential inhibition of the platelet activation sequence: shape change, micro- and macro-aggregation, by a stable...

The relative sensitivities of adenosine diphosphate (ADP)-induced activation, and of prostaglandin-mediated inhibition, were determined for rates of platelet shape change (SC [Vs]), early platelet recruitment measured by electronic platelet counting (PA [PA3]), and turbidometrically-measured aggregation (TA [Va]). Studies were performed on stirred citrated platelet-rich plasma from 9 healthy human donors. The [ADP]1/2, [( ADP] giving half maximal rate) was determined for the sequence of activation steps: unactivated platelets----SC----PA----TA. Distinct ADP sensitivities were obtained from log dose-response studies, with a relative dose dependency for rates of change in the order of [ADP]1/2 TA greater than [ADP]1/2 PA greater than [ADP]1/2 SC of approximately 4:3:1. Differential inhibition of the above activation scheme was evaluated from log dose-response curves for Iloprost (ZK 36374), a stable carbacyclin analogue of prostacyclin (PGI2), with greater potency than PGI2 for the same platelet receptors. IC50 values corresponding to Iloprost concentrations causing 50% inhibition of rates of TA (Va), PA (PA3) and SC (Vs) were found in the relative ratios of 1: approximately 3: approximately 5, when measured at a common ADP concentration for all three parameters, or 1: approximately 2: approximately 3 when determined at respective [ADP]1/2 values for each parameter. Thus, about 3-5 times more Iloprost is required to respectively inhibit the rates of shape change (Vs) and early platelet recruitment (PA3), than that needed to inhibit the rate of turbidometrically-measured aggregation (Va).