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Pharmacological characterization of the sulphonylurea receptor in rat isolated aorta.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 1997 Feb; Vol. 120 (3), pp. 476-80. - Publication Year :
- 1997
-
Abstract
- 1. The binding of the sulphonylurea [3H]-glibenclamide, a blocker of adenosine 5'-triphosphate (ATP)-sensitive K+ channels (KATP channels), was studied in endothelium-denuded rings from rat aorta. 2. [3H]-glibenclamide labelled two classes of binding sites with KD values of 20 +/- 5 nM and 32 +/- 1 microM. The high affinity component, which comprised 17% of total binding at 1 nM [3H]-glibenclamide, had an estimated binding capacity of 150 fmol mg-1 wet weight. 3. Other sulphonylureas such as glipizide and glibornuride and the sulphonylurea-related carboxylate, AZ-DF 265, inhibited high affinity [3H]-glibenclamide binding with the potencies expected from their K+ channel activity. At very high concentrations, AZ-DF 265 and glipizide started to interact also with the low affinity component of [3H]-glibenclamide binding. 4. Openers of the ATP-sensitive K+ channel belonging to different structural groups inhibited only the high affinity [3H]-glibenclamide binding; the potencies in this assay were similar to those obtained in functional (i.e. vasorelaxation) studies. 5. High affinity [3H]-glibenclamide binding was abolished by prolonged hypoxia combined with metabolic inhibition. 6. The data indicate that the high affinity component of [3H]-glibenclamide binding mediates the block of the KATP channel by the sulphonylureas in rat aorta; hence, it represents the sulphonylurea receptor in this vessel. The pharmacological properties of this binding site resemble those of the binding site for the openers of the KATP channel; present evidence suggests that these two classes of sites are negatively allosterically coupled.
- Subjects :
- Adenosine Triphosphate physiology
Animals
Aorta, Thoracic drug effects
Binding, Competitive drug effects
Glyburide metabolism
Glyburide pharmacology
Hypoglycemic Agents metabolism
Hypoglycemic Agents pharmacology
In Vitro Techniques
Kinetics
Male
Muscle, Smooth, Vascular drug effects
Potassium Channels drug effects
Potassium Channels metabolism
Rats
Rats, Sprague-Dawley
Receptors, Drug drug effects
Sulfonylurea Compounds pharmacology
Aorta, Thoracic metabolism
Muscle, Smooth, Vascular metabolism
Receptors, Drug metabolism
Sulfonylurea Compounds metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 120
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 9031752
- Full Text :
- https://doi.org/10.1038/sj.bjp.0700919