Reduction in the number of thromboxane receptors on human platelets after exposure to GR32191

Abstract

1 Exposure of human resuspended platelets in vitro for 30 min to the potent thromboxane A₂ (TP)-receptor blocking drug GR32191, followed by its removal by dilution-dissociation, reduced the degree of subsequent binding to 2 nm [³H]-GR32191 by almost 50%. Exposure for longer periods (60 min) led to a further reduction. However, no change in the K_d of the radioligand was observed. 2 This effect of GR32191 could not be explained by persistent binding of drug to platelets since a dilution-dissociation stage, designed to remove all drug, was included prior to measurement of binding. 3 Using an alternative TP-receptor radioligand, [³H]-SQ29,548, to monitor receptor number, a reduction in B_max was observed after GR32191 pre-treatment; the K_d value of the radioligand remained unchanged. 4 The effect was not a common property of TP-receptor blocking drugs since pre-exposure of platelets in vitro for 30 min to BM13.177 or SQ29,548 did not produce a fall in subsequent B_max to [³H]-SQ29,548. 5 While the mechanism behind this apparent down-regulation of platelet TP-receptor is unknown, it may explain the long duration of action of GR32191 upon platelets in man which persists in the absence of detectable drug in the plasma.