title: Desensitization of platelet thromboxane A2/prostaglandin H2 receptors by the mimetic U46619.
abstract: Thromboxane A2 (TXA2) and prostaglandin H2 (PGH2) activate platelets through membrane receptors. This study sought to determine if changes occur in the TXA2/PGH2 receptor during its desensitization induced by exposure to its agonist 11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619). Washed human platelets were incubated for 30 min with U46619 in the presence of an antiaggregatory agent, Iloprost. The platelets were washed and the aggregation response to U46619 was determined. The EC50 increased from 372 +/- 94 nM in the control group to 826 +/- 143 nM for the U46619-pretreated group (n = 7). This desensitization was specific inasmuch as the aggregation responses to thrombin and the calcium ionophore A23187 were not affected by U46619 pretreatment. Desensitization was accompanied by a decrease in the number of binding sites for [3H]U46619 from 789 +/- 189 in the control to 386 +/- 120 sites per platelet in the U46619-treated group (n = 5) and a decrease in the number of binding sites for the TXA2/PGH2 receptor antagonist, [125I]9,11-dimethylmethano-11,12-methano-16(3-iodo-4-hydroxyphenyl )-13,14- dihydro-13-aza-15-alpha beta-omega-tetranor-TXA2 from 3988 +/- 957 to 2443 +/- 553 (n = 8). The Kd for U46619 was 37 +/- 10 nM in the control group and 23 +/- 11 nM for the U46619-treated group (n = 5). The Kd for I-9,11-dimethylmethano-11,12-methano-16(3-iodo-4-hydroxyphenyl)-13 ,14-dihydro- 13-aza-15-alpha beta-omega-tetranor-TXA2 changed from 58 +/- 12 nM in the control to 44 +/- 9 nM in the U46619-treated group (n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston.
authors.forename: N
authors.initials: N
authors.lastname: Liel
authors.forename: D E
authors.initials: DE
authors.lastname: Mais
authors.forename: P V
authors.initials: PV
authors.lastname: Halushka
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001792:Blood Platelets / Q000187:drug effects*; D003988:Dibenzothiepins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D003988:Dibenzothiepins; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C047685:L 636499; C046957:I-PTA-OH