Platelets from type IIa hypercholesterolemic subjects have been previously shown to be less sensitive than normal platelets to the antiaggregatory effect of PGI2. We demonstrate here that these platelets display a reduced response to iloprost, a chemically stable analogue of PGI2, as well. In fact, the concentration of iloprost yielding 50% inhibition of PRP aggregation was higher in type IIa patients (0.77 +/- 0.08 nM) than in controls (0.51 +/- 0.06 nM, P less than 0.01). In addition, an inverse relationship existed between the threshold aggregatory concentration for collagen and the concentration of iloprost yielding 50% inhibition of PRP aggregation, both in type IIa and normal individuals. In order to elucidate the mechanism of the different sensitivity of platelets to prostacyclin and its analogue, we characterized the binding of 3H-iloprost to platelet rich plasma from single individuals. The binding was rapid, reversible, inhibited by iloprost, PGI2 and PGE1 (Kd = 50.7; 346.2 and 7500 nM, respectively); no heterogeneity of sites could be demonstrated in the PRP from a single individual. When binding studies were carried out in PRP of type IIa patients and controls, it appeared that the amount of 3H-iloprost bound at a fixed (300 nM) concentration was significantly lower in platelets from type IIa individuals (0.94 +/- 0.17 vs. 1.77 +/- 0.27 fmol/10(6) platelets, for patients and controls, respectively). It is concluded that such difference in binding might represent the mechanism underlying the reduced response to PGI2 and iloprost observed in platelets from type IIa patients.