Inhibition of uptake of adenosine into human blood platelets

Abstract

Adenosine transport into human blood platelets is mediated by two independent systems with different affinities. Both systems transport only purine nucleosides and no pyrimidine nucleosides. In experiments with differently substituted purine nucleosides, purines and analogues, differences in carrier specificity could be shown. For both uptake systems an intact purine ring system is required. Substituents at position 6 are of importance for the low affinity carrier. The more bulky this substituent. the less is the affinity. Double substitution, position 2 being an amino group and position 6 either being an amino, hydroxyl or mercapto group gave opposite effects for both carriers: the high affinity system being less inhibited, the low affinity system being more inhibited in changing from amino to mercapto. The 2' and 3' position of the ribose ring appeared to he of importance for both high and low affinity carriers. The requirement of a 2' hydroxyl group oriented opposite the purine ring with respect to the ribose ring is suggested for the low affinity system. This, together with an appropriate substituent at position 6 of the ring system, is typical for a substance being a substrate for the low affinity carrier. On the other hand, the presence of a hydroxyl group at the 2' position is of less importance for the high affinity carrier: here the 3' position appears to be the more important one. The effects of dipyridamole (RA 8) and some related drugs (RA 233, RA 433, VK 744 and VK 774) upon adenosine uptake were investigated. Only the pyrimido pyrimidine compounds RA 8, RA 233 and RA 433 had an effect upon adenosine transported through the high affinity system. RA 8 appeared to be a competitive inhibitor of adenosine uptake by the high affinity system.