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D I Kerr

Publications and source records attributed to D I Kerr.

At least 55 records · Page 3Linked to original sources
PubMed1990

GABA-receptors in peripheral tissues.

Gamma-aminobutyric acid (GABA) and its receptors are found in a wide range of peripheral tissues, including parts of the peripheral nervous system, endocrines, and non-neural tissues such as smooth muscle and the female reproductive system. In all these, both GABAA- and GABAB-receptor types are found, with good evidence for a physiological role in the gut, pancreatic islets and the urinary bladder. In some tissues, the pharmacology of GABA-induced actions is quite atypical and should be further explored with the newer ligands and modulators for GABAA- and GABAB-receptors.

Animals↗
PubMed1990

Antagonism of GABAB-receptor-mediated responses in the guinea-pig isolated ileum and vas deferens by phosphono-analogues of GABA.

1. The phosphono-analogues of gamma-aminobutyric acid (GABA), 4-amino-butylphosphonic acid (4-ABPA), 3-amino-2-(4-chlorophenyl)-propylphosphonic acid (phaclofen) and 3-amino-2-cyclohexylpropyl-phosphonic acid, each antagonized the GABA- and baclofen-induced GABAB-receptor-mediated depression of twitch responses to transmural stimulation in the guinea-pig isolated ileum, in a concentration-dependent, reversible and surmountable manner (apparent pA2 = 4.0 +/- 0.1, 4 +/- 0.2 and 3.7 +/- 0.2 respectively, compared with 3.9 +/- 0.1 for delta-aminovaleric acid). No such activity was found in a variety of related analogues. 2. By contrast, 3-amino-propylphosphonic acid (3-APPA) behaved as a partial agonist, itself partly depressing ileal twitch contractions in a manner sensitive to 4-ABPA and phaclofen, as well as antagonizing the depression of the ileal twitch by GABA and baclofen (apparent pA2 = 4.0 +/- 0.2). 3. Both 4-ABPA and phaclofen also antagonized the baclofen-induced depression of the twitch in the guinea-pig isolated vas deferens (apparent pA2 = 4.0 +/- 0.1 for each), whilst 3-APPA behaved as a partial agonist, slightly depressing the vas twitch, and antagonised the baclofen-induced depression of the twitch (apparent pA2 = 3.9 +/- 0.1). 4. None of these phosphono-analogues exhibited any action at ileal GABAA-receptors, nor influenced the ileal twitch depression with morphine, adenosine or noradrenaline, suggesting their selectivity as antagonists at GABAB-receptors.

Adenosine↗
PubMed1990

Cortisone: a potent GABAA antagonist in the guinea-pig isolated ileum.

In the guinea-pig isolated ileum, cortisone at 0.001-10 nM induced a non-competitive, dose-dependent antagonism of GABAA-receptor-mediated contractile responses to applied GABA, depressing the maximum contractile response to GABA (100 microM), without affecting contractile responses to acetylcholine or cholinergic twitch contractions. At higher concentrations (greater than 10 nM), cortisone depressed contractile responses to acetylcholine (10-100 nM) and cholinergic twitch responses to transmural stimulation. Cortisone is thus the most potent non-competitive antagonist at GABAA-receptor complexes in the guinea-pig ileum. From molecular modelling, sterically there appeared little difference between cortisone and cortisol, the latter being an enhancer of GABAA-receptor-mediated action in the ileum. However, there were significant differences in electrostatic potentials between the two steroids, due to the different levels of oxidation at C11 which may contribute to such opposing actions.

Androstanes↗
PubMed1989

Blockade of the late IPSP in rat CA1 hippocampal neurons by 2-hydroxy-saclofen.

The effects of the GABAB receptor antagonist 2-hydroxy-saclofen were studied using intracellular recording of synaptic potential from CA1 hippocampal neurons. 2-Hydroxy-saclofen (50-200 microM) reversibly blocked the late, GABAB receptor-mediated inhibitory postsynaptic potential (IPSP) but not the early, GABAA receptor-mediated IPSP. In addition, the hyperpolarizing response to baclofen was reduced by similar concentrations of 2-hydroxy-saclofen. This suggests that 2-hydroxy-saclofen is a potent antagonist at postsynaptic GABAB receptors on hippocampal neurons.

Action Potentials↗
PubMed1989

Antagonism at GABAB receptors by saclofen and related sulphonic analogues of baclofen and GABA.

Saclofen (the direct sulphonic analogue of baclofen) is a competitive antagonist of baclofen at GABAB receptors in guinea pig ileum and rat cortical slices (estimated pA2 = 5.3), at least twice as potent as 2-hydroxy-saclofen (pA2 = 5). A series of related sulphonic analogues also antagonised baclofen in the guinea pig ileum, including 2-hydroxy-saclofen amide (pA2 = 3.3), 3-amino-2-hydroxy-2-phenyl-propylsulphonic acid (pA2 = 3.5), 3-amino-2-(benzo-(b)-furan-2-yl)-propylsulphonic acid (pA2 = 4.3), and 3-amino-2-(4-chlorophenyl)-prop-1-enesulphonic acid (pA2 = 2.5-3), but none were more active than saclofen which is the most potent specific GABAB antagonist yet found.

Animals↗
PubMed1989

Modulation of spontaneous motility by GABAA receptor antagonism in the guinea pig isolated ileum.

Rhythmic neurally mediated spontaneous contractions of the longitudinal muscle in the isolated ileum of the guinea pig, sensitive to tetrodotoxin and atropine, were depressed and most often abolished by the GABAA receptor antagonists, bicuculline methiodide, RU 5135, and picrotoxin, a Cl- -ionophore blocker, as well as by GABA desensitization. 3-Mercaptopropionic acid, known to prevent GABA release, also reduced these naturally occurring spontaneous contractions. All these strongly indicate a physiological involvement of endogenous GABA in the control of spontaneous rhythmic activity in the intestine.

3-Mercaptopropionic Acid↗
PubMed1989

Benzofuran analogues of baclofen: a new class of central and peripheral GABAB-receptor antagonists.

Two novel beta-(benzo[b]furan) analogues of baclofen (4-amino-3-benzo[b]furan-2-ylbutanoic acid, 9G, and 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid, 9H) antagonised the baclofen-induced depression of twitch contractions in the guinea-pig isolated ileum (estimated apparent pA2 3.9 and 4.1 respectively); both 9G and 9H also antagonised in a dose-dependent manner the baclofen-induced reduction of repetitive paroxysmal discharges in rat neo-cortical slice preparations maintained in Mg2+-free Krebs solution. These benzofurans evidently represents a new class of GABAB-receptor antagonist.

Animals↗
PubMed1989

GABAB-receptor-mediated actions of baclofen in rat isolated neocortical slice preparations: antagonism by phosphono-analogues of GABA.

Baclofen, 3-amino-propylphosphonic acid (3-APPA), and beta-phenyl-GABA (BPG), each reduced the frequency of spontaneous paroxysmal discharges in rat neocortical slices maintained in Mg2+-free medium, reversibly antagonised by phaclofen and 4-amino-butylphosphonic acid (4-ABPA). At lower concentrations, not influencing the discharges, both 3-APPA and BPG also reversibly antagonised this action of baclofen. However, des-chloro-phaclofen was inactive. Thus, phaclofen and 4-ABPA are GABAB-receptor antagonists in neocortex, whereas both 3-APPA and BPG have partial agonist/antagonist activity at cortical GABAB-receptors.

Animals↗
PubMed1988

2-Hydroxy-saclofen: an improved antagonist at central and peripheral GABAB receptors.

2-hydroxy-saclofen (2-OH-S), a sulphonic analogue of baclofen, slightly increased the twitch height and reversibly antagonised the GABA- and baclofen-induced depression of twitch contractions in the guinea pig vas deferens and isolated ileum, causing a parallel dextral shift in the baclofen dose-response curve in a competitive manner (pA2 = 5.0) in the latter tissue. 2-OH-S (10-50 microM) reversibly elevated the spike height and antagonised the baclofen (8-20 microM)-induced suppression of ictal discharges in rat cortical slices superfused in Mg2+-free Krebs solution, the spike height declining to control level within 15 min of washout. The antagonism by 2-OH-S on GABAB receptor-mediated actions is selective, as 2-OH-S did not affect depressive responses to adenosine or morphine, or contractile responses to GABA (GABAA receptor-mediated), acetylcholine and carbachol in the ileum. Compared to phaclofen, 2-OH-S is a more potent competitive antagonist of GABAB receptor-mediated actions in the central and peripheral nervous system.

Action Potentials↗
PubMed1988

Baclofen antagonism by 2-hydroxy-saclofen in the cat spinal cord.

When administered microelectrophoretically, a sulphonic acid derivative of baclofen, 3-amino-2-(4-chlorophenyl)-2-hydroxy-propylsulphonic acid, reversibly reduced the presynaptic reduction by (-)-baclofen of the monosynaptic excitation of spinal interneurones by impulses in low threshold primary afferent fibres of the cat as well as the postsynaptic depression by (-)-baclofen of the firing of these neurones. This compound, 2-hydroxy-saclofen, may be useful in assessing the physiological significance of central baclofen receptors.

Action Potentials↗
PubMed1988

Alfaxalone potentiates and mimics GABA-induced contractile responses in the guinea-pig isolated ileum.

1. Alfaxalone (1-100 nM) potentiated gamma-aminobutyric acidA (GABAA)-receptor-mediated contractile responses in the guinea-pig isolated ileum, with a leftward shift of the GABA concentration-response curve, and a significant potentiation of the GABA-induced contractions over the lower concentration-range for GABA (3-30 microM). Alfadalone on the other hand, did not affect contractile responses to GABA. 2. Picrotoxinin (10 microM) induced a non-parallel rightward shift of the GABA concentration-response curve, with a 50% depression of the maximum response to GABA. Alfaxalone (100 nM) potentiated the responses to GABA in the presence of picrotoxinin (10 microM) over the GABA concentration-range of 10-100 microM, causing a leftward shift of the concentration-response curve, but without affecting the depression of the maximum response by picrotoxinin. 3. Bicuculline methochloride (10 microM) caused a parallel rightward shift of the GABA concentration-response-curve; the ratio of this shift was unchanged in the presence of alfaxalone (100 microM), although the latter itself displaced the curve leftwards. 4. Alfaxalone (1-100 mM) also induced a similar potentiation of contractile responses to 3-amino-1-propanesulphonic acid (3-APS), a GABA agonist not subject to uptake. Such concentrations of alfaxalone were ineffective against contractile responses to exogenous acetylcholine. 5. Higher concentrations of alfaxalone (1 microM and above), however, elicited a GABA-like ileal contraction, sensitive to both picrotoxinin (10 microM) and bicuculline (10 microM). 6. In conclusion, alfaxalone potentiated GABAA-receptor-mediated contractile responses in the guinea-pig isolated ileum by acting at a modulatory site on GABAA-receptor-chloride-ionophore complexes of GABA-sensitive myenteric neurones, whilst high concentrations of alfaxalone exhibited a GABA-mimetic action at GABAA-receptors in the ileum. It is suggested that more than one site may exist where steroids interact with the GABAA-receptor-ionophore complexes.

Anesthetics↗
PubMed1987

Cortisol: a potent biphasic modulator at GABAA-receptor complexes in the guinea pig isolated ileum.

Cortisol had a biphasic action on GABAA-receptor-mediated contractile responses, enhancing at picomolar concentrations (1-10 pM) and inhibiting at higher concentrations (10-1000 nM). There was a sinistral shift of the GABA dose-response curve in the presence of 10 pM cortisol, with a significant potentiation of the GABA-induced contractions over the lower dose range of GABA (3-30 microM), whereas 100 nM cortisol caused a non-parallel dextral shift of the GABA dose-response curve, with a depression of the maximum GABA response indicative of non-competitive antagonism. Cortisol at various concentrations did not affect GABAB-receptor-mediated ileal relaxations, or the baclofen-induced depression of twitch contractions to transmural stimulation. Such concentrations of cortisol also did not affect ileal responses to exogenously applied acetylcholine or cholinergic twitch contractions themselves. These results suggest that cortisol is a specific, and very potent modulator at GABAA-receptor complexes in the guinea pig ileum.

Animals↗
PubMed1987

Pregnenolone and its sulphate modulate GABAA-receptor-mediated contractile responses in the guinea-pig isolated ileum.

Pregnenolone and its sulphate had concentration-dependent dual actions on gamma-aminobutyric acid (GABAA)-receptor-mediated ileal contractile responses, enhancing at 0.001-1 microM but inhibiting at 10 microM. There was a sinistral shift of the GABA dose-response curve in the presence of 0.01 microM pregnenolone, with a significant potentiation over the lower concentration range of GABA (3-30 microM), whilst 10 microM pregnenolone depressed the curve by 50% without a significant change in the EC50, in a manner resembling non-competitive inhibition with picrotoxin. Pregnenolone and its sulphate evidently have modulatory actions at ileal GABAA-receptor complexes in keeping with those seen using neurochemical studies in the central nervous system.

Animals↗
PubMed1987

The influence of temperature upon depolarizing responses of rat isolated vagal nerve to 5-hydroxytryptamine.

In isolated cervical segments of rat vagus nerve, over the temperature range 5-45 degrees C, reversible depolarizations to 5-hydroxytryptamine (5-HT) were maximal at 10 degrees C and negligible at 45 degrees C. Dose-response curves for this depolarization were compared at 20 degrees C and 37 degrees C, with a similar sensitivity but marked proportionate reduction at 37 degrees C vs 20 degrees C, whilst the 5-HT-induced depression of vagal compound action potentials seen at 20 degrees C was abolished at 37 degrees C; such changes at 20 degrees C or 37 degrees C were insensitive to inhibitors of 5-HT-uptake (zimelidine) or MAO (pargyline). 5-HT may participate in presynaptic inhibition of C-fibre afferents.

Action Potentials↗
PubMed1987

Differing actions of beta-phenyl-GABA and baclofen in the guinea pig isolated ileum.

In the guinea-pig isolated ileum, both gamma-aminobutyric acid (GABA) and baclofen induced a dose-dependent depression of cholinergic twitch contractions to transmural stimulation, sensitive to delta-aminovaleric acid (DAVA) and phosphonobaclofen (phaclofen). beta-Phenyl-GABA (BPG) antagonised this depressant action of baclofen and GABA, whilst itself weakly depressing ileal twitch contractions, an effect insensitive to DAVA or phaclofen, and thus unrelated to any GABAB-receptor-mediated effects. These results suggest that the baclofen receptors in the ileum that are antagonised by BPG differ from either of baclofen receptors in the spinal cord, where the presynaptic receptors are blocked by phaclofen and the postsynaptic receptors are insensitive to phaclofen, with BPG having baclofen-like actions at both sites. Interaction of BPG and baclofen with different receptor populations may explain the differing therapeutic actions of these compounds.

Amino Acids↗
PubMed1987

Phaclofen: a peripheral and central baclofen antagonist.

Phaclofen, the phosphonic acid derivative of baclofen, reversibly antagonized the depression of the cholinergic twitch response of the guinea pig ileum and distal colon by either baclofen or GABA. When administered microelectrophoretically, phaclofen reversibly blocked the presumed presynaptic reduction by baclofen of the monosynaptic excitation of spinal interneurones by impulses in primary afferent fibres of the cat but did not block the postsynaptic depressant action of baclofen on these neurones. Phaclofen may thus be useful in determining the physiological significance of central and peripheral bicuculline-insensitive receptors with which GABA and (-)-baclofen interact.

Animals↗
PubMed1987

Comparison of GABA-induced responses in various segments of the guinea-pig intestine.

In preloaded, isolated segments of duodenum, jejunum, ileum and colon, ethylenediamine (EDA) caused a 3-mercaptopropionic acid (3-MPA)-sensitive release of [3H]GABA. Both EDA and GABA caused a contraction and a delayed 'after-relaxation' in the ileum, but only a delta-aminovaleric acid (DAVA)-sensitive relaxation in other intestinal segments; these actions of EDA were reduced by 3-MPA and therefore due to release of endogenous GABA. Baclofen induced a DAVA-sensitive relaxation in all tissues. Evidently, GABA modulates cholinergic excitation of the smooth muscle at all levels of the intestine.

Animals↗