title: 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 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.
authors.affiliation: Department of Pharmacology, University of Edinburgh Medical School.
authors.forename: R A
authors.initials: RA
authors.lastname: Armstrong
authors.forename: P P
authors.initials: PP
authors.lastname: Humphrey
authors.forename: P
authors.initials: P
authors.lastname: Lumley
mesh_terms: 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
chemical_list: 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