Inactivation of GABA receptors by phenoxybenzamine: Effects on GABA-stimulated benzodiazepine binding in the central nervous system

Smokcum, Roger W.J.

doi:10.1016/0014-2999(82)90323-5

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…The use of phenoxybenzamine to characterise a-adrenoceptors poses some specificity problems. Indeed, this drug can act as an antagonist at some other types of receptors, namely dopamine (Lehmann & Langer, 1981), acetylcholine (Blazso & Minker, 1980), GABA (Smockum, 1983) and opioid (Robson & Kosterlitz, 1979) receptors. However, it is, to our knowledge, the only a-adrenoceptor antagonist that easily crosses the blood±brain barrier, therefore allowing us to compare its actions with the other intravenously administered drugs.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of experimental vasogenic brain oedema in the rat: changes induced by adrenergic drugs

Borges¹,

Sarmento²,

Azevedo³

1999

Journal of Autonomic Pharmacology

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The effects of adrenergic drugs on the formation and resolution of cerebral oedema in a rat model of cold-induced vasogenic brain oedema were studied. Evans blue dye extravasation, water content and ultrastructural alterations (pinocytotic vesicle formation in capillary endothelial cells and apparent water accumulation in the brain parenchyma) were evaluated in parietal cortex. Previous administration of the alpha-adrenoceptor antagonist phenoxybenzamine produced a reduction of Evans blue extravasation and water content, diminished vesicle formation and reduced water accumulation. Previous administration of the beta2-adrenoceptor agonist clenbuterol reduced Evans blue extravasation and water content, but did not change vesicle frequency. The effects of clenbuterol on Evans blue passage to the brain were blocked by timolol (beta-adrenoceptor antagonist) but not by metoprolol (selective beta1-adrenoceptor antagonist). When given after the application of cold, clenbuterol was also able to reduce Evans blue and water content in the brain. Isoprenaline (beta-adrenoceptor agonist that does not cross the blood-brain barrier) showed a reduction in Evans blue extravasation only when given intracerebroventricularly. Vinblastine (a drug that prevents vesicle formation) produced a reduction of the amount of pinocytotic vesicles. We conclude that there is an influence of the central adrenergic nervous system on the formation and/or resolution of vasogenic brain oedema and that the alterations on water movement and Evans blue transport mediated by adrenergic drugs seem to be due, at least in part, to alterations of pinocytotic activity in capillary endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Dynamics of experimental vasogenic brain oedema in the rat: changes induced by adrenergic drugs

Borges¹,

Sarmento²,

Azevedo³

1999

Journal of Autonomic Pharmacology

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“…Our results, taken together, suggest the presence of a tyrosine residue in low-affinity GABA receptors, which is responsible for the enhancing effect of GABA agonists on r3H]diazepam binding. This tyrosine may also be responsible for the reported alkylating effect of phenoxybenzamine a t the GABA receptors (Smokcum, 1983), which also eliminated the GABA enhancement of t3H Jdiazepam binding. On the basis of the electrophysiological analysis of the chloride conductance in Onchidium neurons and on the N-acetylimidazole and tyrosinase effect on it, the involvement of tyrosine residues was speculated at the GABA site (Oomura et al, 1982).…”

Section: Gaba Receptormentioning

confidence: 93%

Characterization of γ‐Aminobutyric Acid‐Benzodiazepine Receptor Complexes by Protection Against Inactivation by Group‐Specific Reagents

Maksay

Ticku

1984

Journal of Neurochemistry

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The chemical topography of the gamma-aminobutyric acid (GABA) and benzodiazepine (BZ) receptors was investigated in a thoroughly washed cortical membrane preparation of the rat. Chemical modification by several amino- and tyrosyl-selective reagents and the protection from it by direct and allosteric ligands of the GABA-BZ receptor complex were used to identify the residues at the binding sites. Inhibition of specific GABA binding by p-diazobenzenesulfonic acid (DSA), tetranitromethane (TNM), and N-acetylimidazole and the selective and complete protection from it by GABA and muscimol suggest the presence of a tyrosine residue at the GABAA site. TNM, like DSA, selectively decreased the number of the low-affinity GABA receptors, and this could be completely protected only by GABA concentrations that can saturate the low-affinity sites. TNM pretreatment also abolished the muscimol enhancement of [3H]diazepam binding, which suggests that the low-affinity GABA receptor sites are responsible for this enhancement. Inhibition of GABA binding by pyridoxal-5-phosphate (PLP) and the selective protection by GABA and muscimol support the presence of a lysine residue at the GABAA receptor site. Complete and selective protection from diethylpyrocarbonate (DEP) inhibition of [3H]diazepam binding by flurazepam suggests the presence of a histidine residue at the BZ site. Flurazepam selectively protected from inhibition of [3H]diazepam binding by N-bromosuccinimide and N-acetylimidazole, but not that by DSA and TNM, which does not allow a unanimous conclusion regarding the presence of tyrosine or tryptophan residues at the BZ site.

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“…A series of protein modification reagents have also been used to probe the GABA binding site. As such, phenoxybenzamine has been shown to inhibit specific [ 3H]muscimol binding in a dosedependent manner (Smokcum, 1983). A time-and concentration-dependent loss of [3H]muscimol binding activity is described with 2,3-butadione, an arginine-specific reagent (Widdows et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

m‐Sulfonate Benzene Diazonium Chloride: A Powerful Affinity Label for the γ‐Aminobutyric Acid Binding Site from Rat Brain

Bouchet

Jacques

Ilien

et al. 1992

Journal of Neurochemistry

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m-Sulfonate benzene diazonium chloride (MSBD) was used to affinity-label the gamma-aminobutyric acid (GABA) binding site from rat brain membranes. To assess the irreversibility of the labeling reaction, we used an efficient ligand dissociation procedure combined to a rapid [3H]muscimol binding assay, both steps being performed on filter-adsorbed membranes. Inactivation of specific [3H]-muscimol binding sites by MSBD and its prevention by GABA were both time- and concentration-dependent. The time course of MSBD labeling was shortened as the pH of the incubation medium was increased from 6.2 to 8. These data suggest that MSBD can efficiently label the GABA binding site through alkylation of a residue having an apparent dissociation constant around neutrality.

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Inactivation of GABA receptors by phenoxybenzamine: Effects on GABA-stimulated benzodiazepine binding in the central nervous system

Cited by 6 publications

References 13 publications

Dynamics of experimental vasogenic brain oedema in the rat: changes induced by adrenergic drugs

Dynamics of experimental vasogenic brain oedema in the rat: changes induced by adrenergic drugs

Characterization of γ‐Aminobutyric Acid‐Benzodiazepine Receptor Complexes by Protection Against Inactivation by Group‐Specific Reagents

m‐Sulfonate Benzene Diazonium Chloride: A Powerful Affinity Label for the γ‐Aminobutyric Acid Binding Site from Rat Brain

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