Differential inhibition of the platelet activation sequence: shape change, micro- and macro-aggregation, by a stable prostacyclin analogue (Iloprost).
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).
Pedvis
L G
LG
Dept. of Physiology, McGill University, Montreal, Quebec, Canada.
Wong
T
T
Frojmovic
M M
MM
D000244:Adenosine Diphosphate / Q000008:administration & dosage / Q000494:pharmacology; D000328:Adult; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016285:Iloprost; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects
D000244:Adenosine Diphosphate; D011464:Epoprostenol; D016285:Iloprost