Reduction in the number of thromboxane receptors on human platelets after exposure to GR32191.
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 Kd 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 Bmax was observed after GR32191 pre-treatment; the Kd 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 Bmax 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.
Armstrong
R A
RA
Department of Pharmacology, University of Edinburgh Medical School.
Humphrey
P P
PP
Lumley
P
P
D001667:Binding, Competitive / Q000187:drug effects; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015536:Down-Regulation / Q000187:drug effects; D005231:Fatty Acids, Unsaturated; D006538:Heptanoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011869:Radioligand Assay; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology
D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006538:Heptanoic Acids; D006834:Hydrazines; D008024:Ligands; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013449:Sulfonamides; C040624:sulotroban; C045749:SQ 29548; C060013:vapiprost