In vitro characterization of a novel TXA2/PGH2 receptor ligand (S-145) in platelets and vascular and airway smooth muscle
| Autor: | G P, Dubé, D E, Mais, J A, Jakubowski, K A, Brune, B G, Utterback, T A, True, L E, Rinkema, W L, Kurtz |
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| Rok vydání: | 1992 |
| Předmět: |
Male
Dose-Response Relationship Drug Platelet Aggregation Guinea Pigs Receptors Prostaglandin Receptors Thromboxane Muscle Smooth Stereoisomerism In Vitro Techniques Bridged Bicyclo Compounds Heterocyclic Muscle Smooth Vascular Receptors Thromboxane A2 Prostaglandin H2 Prostaglandin Endoperoxides Synthetic Fatty Acids Monounsaturated Trachea Bridged Bicyclo Compounds Hydrazines Fatty Acids Unsaturated Animals |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 262(2) |
| ISSN: | 0022-3565 |
| Popis: | The stereoisomers of S-145, a novel thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor ligand, were compared to TXA2/PGH2 receptor antagonists, SQ29548 and BM13505 in guinea pig platelets, aortas and trachea. Equilibrium binding assays in platelets yielded Kd values (nanomolar) for (+)-S-145 (0.57 +/- 0.04), (-)-S-145 (9.2 +/- 1.3), SQ29548 (11.1 +/- 0.70) and BM13505 (118 +/- 16). In aortas, the corresponding Kb values (nanomolar) were (0.014 +/- 0.002), (1.90 +/- 0.31), (16.8 +/- 3.3) and (142 +/- 29), respectively, whereas in trachea, the Kd values (nanomolar) were (0.019 +/- 0.004), (1.12 +/- 0.18), (1.94 +/- 0.30) and (18.99 +/- 2.59), respectively. S-145 stereoisomers elicited platelet shape change stereoselectively that was characterized by EC50 values 8 to 16-fold higher than the EC50 values for these ligands to block aggregation induced by TXA2/PGH2 mimetic, U44069. S-145 (+)- and (-)-isomers stereoselectively induced transient aortic contraction at concentrations 214,000- and 16,000-fold higher, respectively, than the corresponding Kb values in this tissue. S-145-induced platelet shape change and aortic contraction were inhibitable by low concentrations of SQ29548. We postulate that S-145 may elicit partial agonist activity in platelets and aorta via lower affinity for the active than inactive state of the TXA2/PGH2 receptor in those tissues. S-145 had no agonist activity in isolated trachea possibly indicating different TXA2/PGH2 recognition sites in aorta and trachea or a smaller preligand ratio of active to inactive TXA2/PGH2 receptors in trachea than in aorta. |
| Databáze: | OpenAIRE |
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