bluuebunny/crossref_metadata_2025_split huggingface dataset:
Indirect inhibitory effect of succinylcholine on acetylcholine‐activated channel activities and its modulation by external Ca2+ in mouse skeletal muscles
Authors: Nojima Hiroshi , Muroi Masashi , Kimura Masayasu 
Published: July 2012

The effect of extracellular calcium on single acetylcholine (ACh)‐activated channel activities when desensitizing concentrations of succinylcholine (SuCh) were applied to the surrounding endplate membrane was investigated by the cell‐attached patch‐clamp technique at endplates of single skeletal muscle (flexor digitorum brevis) fibres of adult mice.
Bath‐applied SuCh (0.1–3 μm, in 2.5 mm Ca2+) increased in a concentration‐dependent manner the mean open time of ACh‐activated channel currents recorded at membrane potentials which cancelled the SuCh‐induced depolarizations.
In the presence of 0.5 and 2.5 mm external Ca2+, SuCh (3 μm) applied outside the patch pipette prolonged the mean open time of ACh‐activated channel currents in a time‐dependent manner (by 45% and 52%, respectively), and simultaneously significantly decreased the single channel conductance (by 14% and 10%, respectively). These SuCh‐induced effects did not occur in a nominally Ca2+‐free extracellular medium.
Under the same conditions, SuCh (3 μm) augmented the time‐dependent decline in the opening frequency of ACh‐activated channel currents obtained in nominally Ca2+‐free medium.
These results suggest that external calcium ions act to modulate nicotinic ACh receptor channel activity, and accelerate desensitization of the receptor.
Pharmacological characterization of RP 62203, a novel 5‐hydroxytryptamine 5‐HT2 receptor antagonist
Authors: Doble A. , Girdlestone D. , Piot O. , Allam D. , Betschart J. , Boireau A. , Dupuy A. , Guérémy C. , Ménager J. , Zundel J.L. , Blanchard J.C. 
Published: July 2012

RP 62203 (2‐[3‐(4‐(4‐fluorophenyl)‐piperazinyl)propyl]naphto[1,8‐cd]isothiazole‐1,1‐dioxide) is a novel naphtosultam derivative which shows very high affinity for 5‐HT2 receptors in the rat cerebral cortex (Ki = 50.0 pm).
RP 62203 is relatively selective for this sub‐type of 5‐hydroxytryptamine (5‐HT) receptor, having lower affinity for the 5‐HT1A receptor and very low affinity for the 5‐HT3 receptor. RP 62203 displayed low to moderate affinity for α1‐adrenoceptors, dopamine D2 receptors and histamine H1 receptors.
In vivo binding experiments demonstrated that oral administration of low doses of RP 62203 led to a long‐lasting (> 6 h) occupation of cortical 5‐HT2 receptors (ID50 = 0.39 mg kg−1).
In cortical slices from the neonatal rat, RP 62203 potently inhibited inositol phosphate formation evoked by 5‐HT, with an IC50 of 7.76 nm.
The activity of neurones in the raphé and their responses to microiontophoretically applied 5‐HT were studied with extracellular recording electrodes in the anaesthetized rat. RP 62203 potently and dose‐dependently blocked excitations evoked by 5‐HT when administered at doses of 0.5–4.0 mg kg−1, i.p. In contrast, neither 5‐HT‐evoked depressions nor glutamate‐evoked excitations of raphé neuronal firing were blocked by RP 62203 at doses as high as 8.0 mg kg−1 i.p.
Head twitches induced by 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI) could be abolished by low doses of RP 62203 in mice (ED50 = 0.44 mg kg−1, p.o.) and in rats (ED50 = 1.54 p.o.). Similar results were obtained with mescaline and 5‐hydroxytryptophan (5‐HTP).
The potency of RP 62203 was compared with that of three other 5‐HT2 receptor antagonists, ritanserin, ICI 169,369 and ICI 170,809. In all models, RP 62203 showed similar activity to ritanserin, whilst either ICI 169,369 or ICI 170,809 was several fold less active.
It is concluded that RP 62203 is a potent and selective antagonist at 5‐HT2 receptors in the rodent central nervous system.
Changes in adrenoceptors and monoamine metabolism in neonatal and adult rat brain after postnatal exposure to the antihypertensive labetalol
Authors: Erdtsieck‐Ernste E.B.H.W. , Feenstra M.G.P. , Botterblom M.H.A. , DE Barrios J. , Boer G.J. 
Published: July 2012

The purpose of the present study was to investigate the acute (single injection), direct (chronic treatment) and the long‐lasting effects after exposure to the α1/β‐adrenoceptor antagonist labetalol during rat brain development on adrenoceptors and monoamine metabolism.
In 10‐day‐old rat pups, subcutaneously administered labetalol (10 mg kg−1) passed the blood‐brain barrier, reaching a level of 2.1 μg g−1 tissue in the brain 90 min after injection.
Chronic labetalol treatment (10 mg kg−1, s.c., twice daily) during the first 10 days of life significantly increased α1‐adrenoceptor binding in the hypothalamus (+39%), but not in the occipital cortex.
This chronic postnatal labetalol treatment did not result in long‐lasting changes in α1 and β‐receptors measured on day 60.
A single labetalol injection (10 mg kg−1, s.c.) on postnatal day 10 significantly increased noradrenaline (NA) metabolism in all brain regions tested (+25 to 105%), but had no effects on 5‐hydroxytryptamine (5‐HT) or dopamine metabolism.
Chronic labetalol treatment between postnatal (PN) days 1 and 10 also increased NA metabolism on PN 10 (3‐methoxy‐4‐hydroxyphenylglycol (MHPG)/NA, +20 to 100%), suggesting that tolerance to the acute effect of labetalol did not occur. A slight increase in 5‐HT metabolism (20%) was induced by the chronic labetalol treatment in the hippocampus and meso‐limbic system.
In general, long‐lasting effects on NA metabolism could not be detected on day 60, more than one month after the treatment. However, 5‐HT metabolism was significantly increased in all four brain regions measured (+20 to 70%).
We conclude that chronic labetalol exposure during early postnatal rat brain development does not cause long‐lasting changes in β‐receptor number or NA metabolism, but appears to be critical for the rate of 5‐HT metabolism in later life.
Characterization of vascular neuropeptide Y receptors
Authors: Grundemar Lars , Jonas S.E. , Mörner N. , Högestätt Edward D. , Wahlestedt Claes , Håkanson Rolf 
Published: July 2012

In the present study we compared neuropeptide Y (NPY) and NPY‐related analogues for their ability to activate or bind to vascular NPY receptors in four experimental set‐ups. Previous results have suggested the existence of different receptor subtypes, Y1 receptors requiring full‐length NPY (1–36) or [Pro34]‐NPY, and Y2 receptors recognizing also N‐terminally truncated forms of NPY but not [Pro34]‐NPY.
NPY 1–36 and [Pro34]‐NPY dose‐dependently increased arterial pressure in the anaesthetized rat with a similar magnitude and potency. NPY 2–36 was much less potent than NPY 1–36. NPY 4–36 and NPY 11–36 were inactive even at a dose as high as 10 nmol kg−1.
NPY 1–36, [Pro34]‐NPY, NPY 2–36 and NPY 5–36 concentration‐dependently increased the coronary resistance in the Langendorff preparation of the rat. NPY 1–36 and [Pro34]‐NPY were equipotent, while NPY 2–36 and NPY 5–36 were about 7 and 20 times less potent. At 0.3 μm, NPY 11–36, NPY 20–36 and NPY 22–36 induced a slight contraction while NPY 23–36 was inactive.
NPY 1–36, [Pro34]‐NPY, NPY 2–36, NPY 4–36, NPY 5–36 and NPY 11–36 evoked concentration‐dependent contractions in the isolated inferior caval vein of the rat and guinea‐pig. [Pro34]‐NPY was more potent than NPY 1–36. NPY 2–36 was equipotent with NPY 1–36, while NPY 4–36, NPY 5–36 and NPY 11–36 were approximately 30 times less potent.
[Pro34]‐NPY was equipotent with NPY 1–36 in displacing the 125I‐labelled gut hormone peptide ([125I]‐PYY) from rat aortic smooth muscle cells, while NPY 2–36 and shorter forms of NPY were much less potent or inactive.
In caval vein smooth muscle cells of the rat, the displacement pattern was more complex than in aortic smooth muscle cells, in that both [Pro34]‐NPY and NPY 13–36 effectively displaced the radioligand, albeit none of them completely.
In conclusion, the NPY‐evoked pressor response in the whole rat and coronary vessels seems to be mediated by vascular Y1 receptors and the binding characteristics of the NPY‐related peptides in the aortic smooth muscle cells correspond to a population of such receptors. In the caval vein, the profile of the bioactivity and the binding affinity of the NPY‐related peptides suggest a mixed population of Y1/Y2 receptors.
The resistance of some rat cerebral arteries to the vasorelaxant effect of cromakalim and other K+ channel openers
Authors: McPherson Grant A. , Stork Andrew P. 
Published: July 2012

Cromakalim (0.01–30 μm) and sodium nitroprusside (SNP, 0.01–100 μm) were tested for their ability to relax a number of pre‐contracted small arteries (approximate diameter 200–700 μm at 100 mmHg) from the rat, rabbit and guinea‐pig.
In the rat, SNP (0.01–100 μm) caused near maximal relaxation in all vessels studied including the middle cerebral, anterior cerebellar, basilar, mesenteric and renal arteries. Cromakalim (0.01–30 μm) relaxed pre‐contracted mesenteric and renal arteries but was only a weak relaxant of all the rat cerebral arteries with the exception of the basilar artery. Similar experiments using mesenteric and cerebral vessels from the rabbit and guinea‐pig showed cromakalim could relax pre‐contracted vessels in a concentration‐dependent manner.
Two other K+ channel openers, nicorandil and pinacidil, were also tested for their ability to relax rat cerebral arteries. Nicorandil (0.01–100 μm) was ineffective in the rat anterior cerebellar artery at concentrations up to 100 μm. Pinacidil (0.01–100 μm) caused significant vasorelaxation, although high concentrations were required (> 10 μm) and the response was insensitive to the effects of glibenclamide (3 μm).
Electrophysiological experiments with the rat anterior cerebellar artery showed that cromakalim (up to 30 μm) failed to influence the resting membrane potential of impaled single smooth muscle cells.
The results showed that some rat small cerebral arteries were resistant to the effects of K+ channel openers including cromakalim, pinacidil and nicorandil. This is peculiar to this vascular tree since the same vessels from other species do not exhibit the same behaviour. Such a phenomenon could result from a lack of K+ channels opened by cromakalim in rat cerebral arteries.
Platelet‐activating factor synthesis by peritoneal mast cells and its inhibition by two quinoline‐based compounds
Authors: Hogaboam Cory M. , Donigi‐Gale Donna , Shoupe T. Scott , Bissonnette Elyse Y. , Befus A. Dean , Wallace John L. 
Published: July 2012

Peritoneal mast cells from rat were co‐incubated in vitro in a platelet aggregometer cuvette with washed rabbit platelets. In response to stimulation with calcium ionophore (A23187; 1–5 μm), the mast cells released a substance which stimulated the platelets to aggregate. These concentrations of ionophore did not stimulate platelet aggregation in the absence of mast cells, nor affect the responsiveness of the platelets to aggregation induced by thrombin or PAF. Release of a PAF‐like substance was also observed in response to stimulation of the mast cells with antigen.
This pro‐aggregatory activity is attributable to the release of PAF by the mast cells, since the activity could be abolished by preincubating the platelets with a specific PAF receptor antagonist (WEB 2086; 10 μm). Furthermore, the platelet‐aggregating factor co‐migrated with PAF on thin‐layer chromatographs and could be abolished by incubation with phospholipase A2 (20 μg ml−1) or a specific antibody directed against PAF.
The release of PAF by peritoneal mast cells could be inhibited, in a concentration‐dependent manner, by PF‐5901 (IC50 of 3.9μm) or Wy‐50,295 (IC50 of 1.2μm), two structurally similar compounds with inhibitory effects on leukotriene synthesis, as well as leukotriene D4 (LTD4) receptor antagonist properties.
Inhibition of PAF synthesis was not observed when the mast cells were incubated with a structurally unrelated 5‐lipoxygenase inhibitor (A‐64077), a structurally dissimilar inhibitor of 5‐lipoxygenase activating protein (MK‐886) or with a structurally related LTD4 receptor antagonist (MK‐571) which lacks inhibitory effects on leukotriene synthesis, each at concentrations of up to 100 μm.
Neither PF‐5901 nor Wy‐50,295 (1 or 10 μm) significantly affected histamine release or prostaglandin D2 synthesis by peritoneal mast cells in response to calcium ionophore stimulation.
These results demonstrate the ability of a class of quinoline‐based compounds to inhibit PAF synthesis by peritoneal mast cells. This activity does not appear to be related to effects of these compounds on leukotriene synthesis or LTD4 receptors. The ability of these compounds to inhibit PAF synthesis may contribute to their anti‐inflammatory properties.
Binding properties of nine 4‐diphenyl‐acetoxy‐N‐methyl‐piperidine (4‐DAMP) analogues to M1, M2, M3 and putative M4 muscarinic receptor subtypes
Authors: Waelbroeck M. , Camus J. , Tastenoy M. , Christophe J. 
Published: July 2012

We compared the binding properties of 4‐diphenyl‐acetoxy‐N‐methyl‐piperidine methiodide (4‐DAMP) and nine analogues of this compound on muscarinic receptors of human neuroblastoma NB‐OK1 cells (M1 subtype), rat heart (M2 subtype), rat pancreas (M3 subtype) and to the putative M4 subtype in striatum.
The requirements for high affinity binding were somewhat different for the four receptor subtypes. In general, the requirements of M3 receptors were more stringent than for M1, M2 or putative M4 receptors.
The abilities of the compounds to discriminate muscarinic receptor subtypes were not correlated with their affinities at any subtype.
The temperature‐dependence of binding of 4‐DAMP analogues to M2 receptors varied with the drug structure. In particular, the increased affinity of the α‐methyl derivative of 4‐DAMP could be ascribed to van der Waals interactions.
The affinities of most 4‐DAMP analogues for M2 and M3 receptors were similar to their pharmacological potencies on atrial and ileum preparations, respectively.
At concentrations above 1 μm, all 4‐DAMP analogues as well as atropine, reduced the [3H]‐N‐methyl scopolamine ([3H]‐NMS) dissociation rate from cardiac muscarinic receptors, with no obvious structure‐activity relationship.
The effects of vesamicol on trains of endplate currents and on focally recorded nerve terminal currents at mammalian neuromuscular junctions
Authors: Pemberton Karen E. , Prior Chris , Marshall Ian G. 
Published: July 2012

The effects of vesamicol, an inhibitor of vesicular acetylcholine (ACh) storage, were studied on trains of endplate currents (e.p.cs) in the cut rat hemidiaphragm nerve‐muscle preparation and on trains of focally recorded nerve terminal current waveforms in the mouse triangularis sterni nerve‐muscle preparation.
In the rat, 0.1 and 1 μm (−)‐vesamicol produced an enhancement of the rundown of e.p.c. amplitudes during trains of high frequency (50 Hz) nerve stimulation. However, 1 μm (+)‐vesamicol had no effect on the rundown of e.p.c. amplitudes.
In the mouse, high concentrations of (−)‐vesamicol (10–100 μm) produced a concentration‐ and stimulation‐dependent decrease in the amplitude of the second negative‐going deflection of focally recorded nerve terminal current waveforms.
At 1 mm, (−)‐vesamicol produced a stimulation‐independent decrease in the amplitude of the first negative‐going deflection of the nerve terminal current waveforms, an increase in signal delay and evidence of nerve conduction failure. These all indicate a local anaesthetic‐like block of nodal Na+‐channels.
In contrast to its effects on trains of e.p.cs, the effects of vesamicol on the nerve terminal current waveforms were not stereoselective, the (+)‐isomer being equipotent with the (−)‐isomer.
Low concentrations of the Na+‐channel blocking toxin, tetrodotoxin (15–60 nm), produced similar changes in the focally recorded nerve terminal current waveforms to those seen with vesamicol.
It is concluded that the stereoselective rundown of e.p.c. amplitudes produced by (−)‐vesamicol is due to an effect, either direct or indirect, on ACh mobilization within motor nerve terminals. Furthermore, in mammalian species, the inhibitory effects of vesamicol on nodal Na+‐channels which are seen at high concentrations do not contribute to the principal neuromuscular effects of the compound.
X‐irradiation attenuates relaxant responses in the rabbit ear artery
Authors: Maynard Kenneth I. , Stewart‐Lee Anne L. , Milner Pam , Burnstock Geoffrey 
Published: July 2012

The relaxant actions of acetylcholine, substance P and calcitonin gene‐related peptide, and the levels of neuropeptide Y and calcitonin gene‐related peptide were assessed in the rabbit central ear artery 1, 4 and 6 weeks after a single dose of 45 Gy X‐irradiation, a dose similar to that used clinically in intraoperative radiotherapy.
Relaxant responses induced by acetylcholine and substance P (both endothelium‐dependent) and calcitonin gene‐related peptide (endothelium‐independent) were reduced, and endogenous neuropeptide Y and calcitonin gene‐related peptide levels were unaffected after X‐irradiation.
The mechanism(s) by which a single dose of 45 Gy X‐irradiation may selectively damage relaxant, but not direct, contractile responses of the smooth muscle (as we have shown previously) of the rabbit central ear artery are discussed.
Differences in intrinsic efficacy of benzodiazepines are reflected in their concentration‐EEG effect relationship
Authors: Mandema Jaap W. , Kuck Maarten T. , Danhof Meindert 
Published: July 2012

The relevance of EEG effect parameters as a measure of the central nervous system effects of benzodiazepines was evaluated. The concentration‐EEG effect relationships of the benzodiazepine agonist midazolam, partial agonist bretazenil, antagonist flumazenil and inverse agonist Ro 19–4603 were quantified and compared with the intrinsic efficacy and affinity of these compounds at the γ‐aminobutyric acid (GABA)‐benzodiazepine receptor complex.
The pharmacokinetics and pharmacodynamics of the compounds were determined after a single intravenous bolus administration of 5 mg kg−1 midazolam, 2.5 mg kg−1 bretazenil, 10 mg kg−1 flumazenil or 2.5 mg kg−1 Ro 19–4603 to male Wistar derived rats. In a separate experiment the distribution between blood, cerebrospinal fluid and brain concentrations of these compounds was determined. A sensitive assay was developed to measure bretazenil and Ro 19–4603 concentrations in small samples of biological fluids.
The benzodiazepine‐induced changes in amplitudes in the 11.5–30 Hz frequency band, as determined by aperiodic analysis, was used as EEG effect measure. Concentration‐EEG effect relationships were derived by a pharmacokinetic‐pharmacodynamic modelling procedure and in the case of midazolam, bretazenil and Ro 19–4603 successfully quantified by the sigmoidal Emax model. Large differences in maximal effect of midazolam (Emax = 73 ± 2 μVs−1), bretazenil (Emax = 19 ± 1 μVs−1) and Ro 19–4603 (Emax = −6.5 ± 0.4 μVs−1) were observed, reflecting their differences in intrinsic efficacy. A close correlation was found between the EC50 values based on free drug concentration and receptor affinity as determined by displacement of [3H]‐flumazenil in a washed brain homogenate at 37°C. In the concentration range of receptor saturation flumazenil did not produce any changes in the EEG effect measure.
The study demonstrated that the change in amplitudes in the 11.5–30 Hz frequency band of the EEG is a relevant measure of the pharmacological effect intensity of benzodiazepines, because it seems to reflect their affinity and intrinsic efficacy at the central GABA‐benzodiazepine receptor complex.
Endogenous nitric oxide and sensory neuropeptides interact in the modulation of the rat gastric microcirculation
Authors: Tepperman B.L. , Whittle B.J.R. 
Published: July 2012

The effects of depletion of sensory neuropeptides from primary afferent neurones by capsaicin pretreatment, on the changes in resting gastric mucosal blood flow following administration of inhibitors of nitric oxide biosynthesis have been investigated in the pentobarbitone‐anaesthetized rat.
Bolus administration of the NO‐synthase inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME; 0.8–12.5 mg kg−1 i.v.), induced a dose‐dependent increase in systemic arterial blood pressure (BP) and a reduction in resting mucosal blood flow, as determined by laser Doppler flowmetry.
Concurrent administration of l‐arginine (300 mg kg−1 i.v.) attenuated the effects of l‐NAME (6.25 mg kg−1) on resting mucosal blood flow and BP. The enantiomer, d‐NAME (50 mg kg−1 i.v.), which does not inhibit NO biosynthesis, had no effect on either parameter.
The fall in mucosal blood flow induced by submaximal doses of l‐NAME (0.8–3.2 mg kg−1) was substantially augmented in rats pretreated 2 weeks earlier with capsaicin.
The fall in resting mucosal blood flow induced by the less potent NO‐synthase inhibitor, NG‐monomethyl‐l‐arginine (l‐NMMA; 1.6–25 mg kg−1 i.v.) was likewise significantly augmented in capsaicin‐pretreated rats.
Pretreatment (15 min) with indomethacin (5 mg kg−1 i.v.) did not augment further the microvascular actions of l‐NAME or l‐NMMA in capsaicin‐pretreated rats, suggesting the lack of interaction of endogenous prostanoids with these other mediators in regulating local blood flow. The effects of l‐NAME on BP were not altered by capsaicin and indomethacin administration.
These findings indicate that endogenous sensory neuropeptides and NO can interact in the regulation of the gastric microcirculation.
Imidazoline antagonists of α2‐adrenoceptors increase insulin release in vitro by inhibiting ATP‐sensitive K+ channels in pancreatic β‐cells
Authors: Jonas J.C. , Plant T.D. , Henquin J.C. 
Published: July 2012

Islets from normal mice were used to study the mechanisms by which imidazoline antagonists of α2‐adrenoceptors increase insulin release in vitro.
Alinidine, antazoline, phentolamine and tolazoline inhibited 86Rb efflux from islets perifused with a medium containing 3 mm glucose, i.e. under conditions where many adenosine 5′‐triphosphate (ATP)‐sensitive K+ channels are open in the β‐cell membrane. They also reduced the acceleration of 86Rb efflux caused by diazoxide, an opener of ATP‐sensitive K+ channels.
ATP‐sensitive and voltage‐sensitive K+ currents were measured in single β‐cells by the whole‐cell mode of the patch‐clamp technique. Antazoline more markedly inhibited the ATP‐sensitive than the voltage‐sensitive current, an effect previously observed with phentolamine. Alinidine and tolazoline partially decreased the ATP‐sensitive K+ current.
The four imidazolines reversed the inhibition of insulin release caused by diazoxide (through opening of ATP‐sensitive K+ channels) or by clonidine (through activation of α2‐adrenoceptors) in a concentration‐dependent manner. Only the former effect correlated with the ability of each drug to increase control insulin release stimulated by 15 mm glucose alone.
It is concluded that the ability of imidazoline antagonists of α2‐adrenoceptors to increase insulin release in vitro can be ascribed to their blockade of ATP‐sensitive K+ channels in β‐cells rather than to their interaction with the adrenoceptor.