bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential role of extra‐ and intracellular calcium in the release of EDRF and prostacyclin from cultured endothelial cells
Authors: Lückhoff Andreas , Pohl Ulrich , Mülsch Alexander , Busse Rudi 
Published: July 2012

The effects of extracellular Ca2+ on the release of endothelium‐derived relaxing factor (EDRF) and prostacyclin (PGI2), and on the intracellular free calcium concentration ([Ca2+]i), were studied in cultured bovine aortic endothelial cells.
Receptor‐mediated stimulation of endothelial cells with bradykinin (10 nM) elicited a transient release of EDRF (assayed by its stimulant effect on purified soluble guanylate cyclase) and of PGI2 (measured by radioimmunoassay for 6‐keto prostaglandin F1α).
Bradykinin (10 nM) also increased [Ca2+]i (measured with the fluorescent probe indo‐1) from 125 ± 11 nM to 631 ±59 nM, with the same time course as for autacoid release.
In Ca2+‐free medium, [Ca2+]i was still increased by bradykinin but declined faster (within 1 min) to resting levels than in the presence of extracellular Ca2+.
PGI2 release was almost completely abolished in Ca2+‐free medium. The intracellular calcium antagonist TMB‐8 evoked a similar inhibition of PGI2 release.
In contrast, bradykinin‐induced EDRF release was not significantly affected by TMB‐8 but was completely abolished in Ca2+‐free medium.
When endothelial cells were stimulated with the receptor‐independent drug thimerosal (an inhibitor of the enzyme acyl‐CoA‐lysolecithin‐acyl‐transferase; 5 μM), a long‐lasting release of EDRF (>90 min) and PGI2 (>20 min) was observed.
In contrast to bradykinin stimulation, thimerosal‐induced autacoid release was associated with only a slight increase of [Ca2+]i to 201 ± 13 nM after 40min.
After removal of extracellular Ca2+ from thimerosal‐stimulated endothelial cells, [Ca2+]i was little affected during the observation time of 90 s. EDRF release was completely abolished within 90 s whereas PGI2 release was unchanged.
We conclude that EDRF production is directly controlled by extracellular Ca2+ during both receptor‐dependent and independent stimulation. This effect of extracellular Ca2+ is not mediated by changes in [Ca2+]i. In contrast, PGI2 release is closely correlated to [Ca2+]i in bradykinin‐stimulated endothelial cells. However, the results obtained during thimerosal stimulation indicate that there is not necessarily a tight coupling between the absolute level of [Ca2+]i and the amount of PGI2 released.
Evaluation of opioid‐induced antinociceptive effects in anaesthetized and conscious animals
Authors: Clark S.J. , Folienfant R.L. , Smith T.W. 
Published: July 2012

The activity profiles of opioid agonists and non‐steroidal analgesic agents have been compared against different nociceptive stimuli in the mouse and rat.
Opioid agonists, but not non‐steroidal analgesic agents, inhibited reflex depressor responses evoked by visceral distension in anaesthetized rats. The ranked order of potency of opioids in the visceral distension reflex was identical to that observed in the mouse writhing assay.
Opioid‐induced inhibition of reflex depressor responses and writhing was observed with ligands acting on μ‐ and κ‐, but not λ‐receptors. Antinociceptive activity of opioids in the rat cold water tail‐flick assay was restricted to μ‐receptor agonists.
Morphine‐ and ethylketocyclazocine (EKC)‐induced inhibition of the visceral distension reflex was blocked by naloxone, but not by the quaternary opioid antagonist N‐methylnalorphine.
Direct cardiovascular effects were observed with ligands for the μ‐ and κ‐receptor. Blood pressure changes induced by morphine and Tyr. D‐Ala. Gly. MePhe. Gly‐ol (DAGOL), but not EKC, were blocked by N‐methylnalorphine. Pretreatment with 16‐methylcyprenorphine (M8008) antagonized morphine‐, DAGOL‐ and EKC‐induced cardiovascular effects, but not those of dynorphin‐(1–13) or U50488.
It is concluded that reflex circulatory responses evoked by visceral distension in anaesthetized rats are a valid index for the evaluation of opioid‐induced antinociception. A simultaneous assessment of cardiovascular effects of opioids was achieved.
Selective inhibition of adrenaline‐induced human platelet aggregation by the structurally related Paf antagonist Ro 19–3704
Authors: Schattner Mirta , Parini Angelo , Fouque Françoise , Vargaftig B. Boris , Touqui Lhousseine 
Published: July 2012

Two non‐lipid antagonists of platelet‐activating factor acether (Paf), BN 52021 and WEB 2086, at concentrations which completely blocked Paf‐induced platelet aggregation, failed to interfere with aggregation by adrenaline. In contrast, Ro 19–3704, a structurally related antagonist of Paf, inhibited concentration‐dependently aggregation induced by adrenaline or by the simultaneous addition of submaximal concentrations of adrenaline and Paf. Reversal of aggregation was obtained when Ro 19–3704 was added to the platelet suspension after adrenaline.
Ro 19–3704 was selective for Paf and adrenaline since it failed to interfere with platelet aggregation induced by arachidonic acid or ADP. CV‐3988, an antagonist of Paf structurally similar to Ro 19–3704, also inhibited adrenaline‐induced aggregation. However, a morpholine analogue (MA) of Paf, which has no anti‐Paf activity, failed to interfere with the aggregation induced by adrenaline. This suggests that the effect of Ro 19–3704 and CV‐3988 on adrenaline is not simply due to their lipid structure.
Experiments on plasma membrane preparations showed that Ro 19–3704 inhibited [3H]‐yohimbine binding with an inhibition constant (Ki) of 7 ± 3 μm. In contrast, BN 52021 and MA did not interfere with [3H]‐yohimbine binding. Equilibrium binding experiments showed that Ro 19–3704 increased the apparent KD of [3H]‐yohimbine binding from 2.02 ± 0.15 to 7.3 ± 0.4 nm. The Paf antagonist Ro 19–3704 interacts specifically with the α2‐adrenoceptor and may thus prevent the early steps involved in the mechanism of adrenaline‐induced platelet activation.
Concurrent determination of effects of p‐chloroamphetamine on central extracellular 5‐hydroxytryptamine concentration and behaviour
Authors: Hutson P.H. , Curzon G. 
Published: July 2012

The effects of p‐chloroamphetamine (PCA) (5 mg kg−1, i.p.) on extracellular concentrations of 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) were monitored in the frontal cortex of conscious, freely moving rats by means of intracerebral dialysis. Concomitant behaviour comprising the 5‐HT behavioural syndrome (reciprocal forepaw treading, headweaving, wet dog shakes) and locomotion and grooming was also recorded.
PCA markedly and transiently increased extracellular 5‐HT but extracellular 5‐HIAA values decreased to a moderate extent.
The time‐course of 5‐HT changes correlated positively (P < 0.001) with those of the three components of the 5‐HT syndrome but did not correlate significantly with locomotion and correlated negatively (P < 0.01) with grooming.
As previous work using conventional methodology did not reveal clear relationships between the effects of PCA on 5‐HT metabolism and behaviour, the present results emphasise the value of in vivo dialysis in the study of the neurochemical mediation of the behavioural effects of drugs.
Caesium ions: a glycine‐activated channel agonist in rat spinal cord neurones grown in cell culture
Authors: Smith Stephen M. , McBurney Robert N. 
Published: July 2012

The chloride (Cl−) currents activated by caesium ions (Cs+), glycine and γ‐aminobutyric acid (GABA) were compared following their application to rat neurones that had been grown in cell culture. Recordings were made using the whole‐cell patch clamp technique under voltage clamp conditions.
In spinal cord neurones, bicuculline methiodide antagonized GABA‐activated currents more effectively than Cs+‐ or glycine‐activated currents. However, strychnine was more effective at blocking the currents activated by Cs+ or glycine than those activated by GABA.
Of the 3 agonists, only GABA activated currents in cells from the intermediate lobe of the rat pituitary.
In spinal neurones the size of the currents activated by 70 mm Cs+ was correlated to the size of the currents activated by 15 μm glycine (P < 0.005; n = 10, Spearman's rank correlation), but there was no significant correlation between the size of the currents activated by these agents and 10 μm GABA.
The joint application of glycine and Cs+ activated currents that were approximately twice as big as the sums of the currents activated by separate applications of the same doses. This synergism was consistent with Cs+ acting at the same receptor as glycine (7 μm glycine being equivalent to 31 ± 7 mm Cs+).
It was concluded that Cs+ activates the same Cl− channel as the inhibitory neurotransmitter glycine.
Antagonism of calcium by zinc in guinea‐pig isolated taenia caeci and trachealis muscle
Authors: Sarriá B. , Cortijo J. , Martí‐Cabrera M. , Morcillo E. , Esplugues J. 
Published: July 2012

In guinea‐pig isolated taenia caeci and trachealis bathed in a K+‐rich, Ca2+‐free medium, CaCl2 (0.01–10 mm) produced a concentration‐dependent contraction. Zn2+ (0.01–1 mm), Cd2+ (0.01–1 mm), verapamil (0.01–100 μm) and trifluoperazine (1–100 μm) were effective antagonists of CaCl2‐induced responses.
Zn2+ and Cd2+ in concentrations from 0.01 to 1 mm were without effect on the tone of taenia and trachea in normal Tris solution. Conversely, Zn2+ and Cd2+, in concentrations of 1 mm, caused contraction of these tissues in a K+‐rich, Ca2+‐free medium. Zn2+ (1 mm)‐induced contractions of taenia and trachea were completely inhibited by verapamil (10 μm).
In taenia and trachea skinned of their plasma membranes, tension development induced by Ca2+ (10 μm or 1 μm, respectively) was unaffected by verapamil (100 μm), whereas trifluoperazine (100 μm) depressed the maximal tension produced by Ca2+. Segments of skinned preparations contracted in response to low concentrations of Zn2+ (10 μm) or Cd2+ (10 μm).
It is concluded that Zn2+ may suppress Ca2+‐induced spasm by a direct action on the binding sites of the Ca2+ channel.
The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres
Authors: Gruber R. , Carmeliet E. 
Published: July 2012

The effect of disopyramide on the maximum upstroke velocity () and the sodium current of rabbit cardiac Purkinje fibres was studied with the two‐microelectrode voltage‐clamp technique.
In the absence of stimulation the drug did not cause block at membrane potentials ranging from −100 to −65 mV. Use‐dependent block of was most pronounced at −75 mV. At hyperpolarized membrane potentials development of use‐dependent block was faster than at depolarized membrane potentials. The time course of development of use‐dependent block was not significantly influenced by the duration of the depolarizing pulse. These results strongly suggest that disopyramide predominantly blocks activated sodium channels.
The relative decrease of the sodium current at the beginning of a 2 s depolarizing clamp to −45 mV was almost the same as at the end, implying a rapid blockade of activated sodium channels. The Hill plots were linear with slopes ranging from 0.98 to 1.08 indicating a first order reaction; the dissociation constant for activated channels was 70 μm.
Recovery of from use‐dependent block during rest was strongly voltage‐dependent, the time constant of recovery increasing upon hyperpolarization. When the fraction of charged molecules was reduced by changing the pH of the external solution, the voltage‐dependence of recovery was decreased. In contrast, recovery of for a change in holding potential from −80 to −95 mV was very fast during repetitive stimulation.
It is concluded that disopyramide blocks the sodium channel during activation and is trapped in the channel when the activation gate closes.
Prejunctional modulation of acetylcholine release from the skeletal neuromuscular junction: link between positive (nicotinic)− and negative (muscarinic)‐feedback modulation
Authors: Vizi E.S. , Somogyi G.T. 
Published: July 2012

Presynaptic receptor‐mediated modulation of stimulation‐evoked [3H]‐acetylcholine([3H]‐ACh) release from the neuromuscular junction was studied in the region of the mouse hemidiaphragm which contains the motor endplates, and which can easily be loaded with [3H]‐choline. This method made it possible to detect exclusively the [Ca2+]o‐dependent, quantal release of [3H]‐ACh in response to axonal stimulation.
Atropine enhanced, and non‐depolarizing muscle relaxants ((+)‐tubocurarine, pancuronium and pipecuronium) reduced, the release of [3H]‐ACh evoked by high frequency trains of stimulation (50 Hz, 40 shocks) of the phrenic nerve. The effect of (+)‐tubocurarine was frequency‐dependent as at 5 Hz (40 shocks) it was less effective than at 50 Hz. The resting release of [3H]‐ACh was not affected by these compounds. These findings indicate that ACh released into the synaptic gap by axonal firing reaches a concentration sufficient to influence its own release by a prejunctional effect.
The anticholinesterase, physostigmine sulphate, enhanced the release of [3H]‐ACh in a concentration‐dependent manner. This effect was mediated via prejunctional nicotinic receptor stimulation: (+)‐tubocurarine, pancuronium and pipecuronium completely prevented the effect of physostigmine.
When the prejunctional nicotinic and muscarinic receptors were stimulated by a high concentration of extracellular ACh which had accumulated in the junctional gap in the presence of physostigmine, atropine did not influence the evoked release of [3H]‐ACh. However, when the effect of endogenous ACh on nicotinic receptors was prevented by (+)‐tubocurarine, atropine enhanced the release.
It is concluded that quantally‐released ACh from motor endplates is subject to prejunctional automodulation: (a) ACh facilitates its own release via an effect on prejunctional nicotinic receptors (positive feedback), (b) ACh release is reduced by an action on muscarinic receptors. When the nicotinic receptor‐mediated facilitation is fully operative, the muscarinic receptor‐mediated negative feedback is much less effective. It is supposed that there is a link between the two feedback mechanisms possibly at the level of the second messenger system(s).
Sympathetic denervation caused by long‐term noradrenaline infusions; prevention by desipramine and superoxide dismutase
Authors: Teixeira A. Albino , Azevedo Isabel , Branco Domingas , Rodrigues‐Pereira E. , Osswald Walter 
Published: July 2012

The effects of continuous intravenous infusion of noradrenaline (0.01 and 0.1 μg kg−1 h−1) were studied in both the infused lateral saphenous vein and the contralateral saphenous vein of normal dogs. Noradrenaline, saline, noradrenaline + desipramine or noradrenaline + superoxide dismutase were infused using Alzet osmotic minipumps.
After a 5 day infusion period, the noradrenaline content in plasma and in both saphenous veins was determined, and the venous tissues submitted to light microscope morphometry and ultrastructural study and used for the determination of their O‐methylation capacity (with [3H]‐isoprenaline as a substrate).
Noradrenaline caused dose‐dependent damage to the sympathetic nerve endings of the lateral saphenous veins. Concomitant changes in extraneuronal structure and function were observed (hypertrophy of smooth muscle cells, nuclear dismorphy, thickening of the vessel wall, impairment in O‐methylation capacity).
Desipramine and superoxide dismutase prevented or reduced the effects of noradrenaline on both the morphological and the biochemical parameters; the protection afforded by superoxide dismutase was more marked than that by desipramine.
It is concluded that moderately high doses of noradrenaline exert a 6‐hydroxydopamine‐like effect and that this chemical sympathectomy is partially or totally prevented by desipramine or superoxide dismutase. The data suggest that a substance derived from noradrenaline, in the formation of which free oxygen radicals are involved and which is subject to neuronal uptake, is the chemical entity responsible for the neurotoxic effect observed.
Reactive blue 2 selectively inhibits P2y‐purinoceptor‐stimulated surfactant phospholipid secretion from rat isolated alveolar Type II cells
Authors: Rice Ward R. , Singleton Fannie M. 
Published: July 2012

The effect of reactive blue 2 on adenosine 5′‐triphosphate (ATP), 12‐O‐tetradecanoylphorbol 13‐acetate (TPA) and terbutaline‐induced surfactant phospholipid secretion from rat isolated alveolar Type II cells was studied.
Reactive blue 2 significantly inhibited ATP‐induced surfactant phospholipid secretion, but was without effect on C‐kinase agonist (TPA) or β‐adrenoceptor agonist (terbutaline)‐stimulated surfactant phospholipid secretion. The IC50 for inhibition of ATP‐induced surfactant secretion was 1.5 × 10−4 m.
These data are consistent with a P2y‐purinoceptor regulating surfactant phospholipid secretion from isolated Type II cells and support previous work suggesting reactive blue 2 is a specific inhibitor at P2y‐purinoceptors.
Calcium mobilization and response recovery following P2‐purinoceptor stimulation of rat isolated alveolar type II cells
Authors: Dorn Curtis C. , Rice Ward R. , Singleton Fannie M. 
Published: July 2012

The effect of adenosine 5′‐triphosphate (ATP) on surfactant phospholipid secretion, calcium mobilization, and the time course for recovery of the response system was studied in isolated alveolar Type II cells of the rat.
ATP (10 μm) stimulated a biphasic intracellular Ca2+ transient monitored by changes in Fura‐2 fluorescence, from a basal level of 126 ± 9 nm, to a rapid peak of 391 ± 1 nm, followed by a prolonged plateau 26 ± 4 nm above baseline (mean ± s.e.mean, n = 26).
ATP‐stimulated surfactant phospholipid secretion and peak Ca2+ levels had similar EC50 s** (1 × 10−6 m), and were unaffected by chelation of extracellular Ca2+. However, the prolonged plateau phase was abolished by chelation of extracellular Ca2+.
There was a 15 min refractory period before full recovery of the Ca2+‐response to ATP. Recovery was dependent on extracellular Ca2+, was accelerated by removing extracellular agonist and was prolonged following stimulation with the poorly hydrolyzed ATP analogue, ATP‐γ‐S.
While the Type II cell was capable of multiple ATP‐induced Ca2+ transients following recovery, no additional surfactant phospholipid was released with sequential stimulation.
These findings suggest initial exposure of Type II cells to ATP mobilizes intracellular Ca2+, stimulates phospholipid secretion and rapidly desensitizes the cell to further stimulation by ATP. Recovery of the ATP‐induced Ca2+‐response depends on presence of extracellular Ca2+ and removal of agonist.
Antagonism of Paf‐induced oedema formation in rabbit skin: a comparison of different antagonists
Authors: Hellewell Paul G. , Williams Timothy J. 
Published: July 2012

Eight platelet activating factor (Paf) antagonists were evaluated as inhibitors of oedema formation in rabbit skin induced by intradermal injection of Paf plus prostaglandin E2 (PGE2). Antagonists were tested by both intradermal (i.d.) and intravenous (i.v.) routes.
Intradermal injection of two antagonists structurally‐related to Paf (SRI 63–675 and CV‐3988) resulted in a partial inhibition of Paf‐induced oedema formation but at high doses of antagonist, marked agonist activities were detected. CV‐3988 administered i.v. inhibited Paf‐induced plasma leakage by 73–80%; however, oedema responses to a range of other inflammatory mediators were also reduced, albeit to a lesser extent (40–60%). SRI 63–675 administered i.v. did not significantly inhibit Paf‐induced oedema.
The antagonist 48740 RP administered either i.d. or i.v. showed partial, but selective, inhibition of Paf‐induced oedema formation, although the doses required were high when compared with other antagonists.
BN 52021 was a weak Paf antagonist when injected i.d., but following i.v. administration the responses to Paf were inhibited by 63–71%. Responses to all other mediators tested were unaffected.
Kadsurenone and its synthetic derivatives, L‐652,731 and L‐659,989 all blocked responses to Paf in the skin. L‐659,989 was the most potent, achieving almost total inhibition when injected i.d. and i.v.; moreover, it was selective for Paf. L‐652,731 was more potent than kadsurenone.
WEB 2086 given i.d. and i.v. showed similar activity to L‐659,989 and it was also selective for Paf‐induced oedema formation.
These results illustrate that in rabbit skin not all Paf antagonists are selective for Paf, some showing agonist‐like activity which can mask antagonist properties. It is suggested that before ascribing a role for endogenous Paf in an inflammatory reaction based on results with antagonists, the activity of the antagonists in the model under investigation should be rigorously established.
Potentiation by TRH of the effect of antidepressants in the forced‐swimming test, involvement of dopaminergic and opioid systems
Authors: Reny‐Palasse Véronique , Constans Martine , Rips Richard 
Published: July 2012

It has been shown that thyrotropin releasing hormone (TRH) can potentiate the effects of the antidepressant, imipramine, as measured by the mouse forced‐swimming test. This potentiation is not associated with an increase of effective levels of noradrenaline in the synaptic clefts, but depends upon the integrity of opioid systems. The present study was designed to investigate: (a) the potentiation by TRH of the effects of other antidepressants, using the same test; (b) the possible involvement of other neuronal systems, such as the 5‐hydroxytryptaminergic and dopaminergic systems; (c) the contribution of the opioid and dopaminergic systems to the potentiation of the actions of other antidepressants by TRH.
The effects of nortriptyline, amineptine, maprotiline, nomifensine and mianserin, but not that of clomipramine, were potentiated by TRH (2 mg kg−1, i.p.). The inhibitor of 5‐hydroxytryptamine synthesis, p‐chlorophenylalanine (PCPA), did not prevent the effect induced by imipramine plus TRH. Blockade of dopaminergic systems by γ‐butyrolactone (GBL) (37.5 mg kg−1, i.p.), α‐methyl‐p‐tyrosine (AMPT) (125 mg kg−1, i.p.) and apomorphine (0.025 mg kg−1, i.p.) antagonized the effects induced by various antidepressants alone (at high, effective doses) or at lower ineffective doses in association with TRH. The effect induced by imipramine plus TRH was also blocked by sulpiride (16 mg kg−1, i.p.). Pretreatment with the opioid antagonist, naloxone, inhibited the effects induced by nomifensine plus TRH or mianserin plus TRH but not those induced by nortriptyline plus TRH, maprotiline plus TRH or amineptine plus TRH. When high active doses of the antidepressants were used alone, only the clomipramine effect was blocked by naloxone.
These data indicate that TRH is able to potentiate the effect not only of imipramine but of other antidepressants in the mouse forced‐swimming test, although these other antidepressants act in various ways on cerebral amines. The antagonism of the effects induced by the antidepressants alone or in association with TRH after blockade of dopaminergic systems may indicate a reversal of the effect of the antidepressants by blockade of dopaminergic systems. Hence, the same mechanisms would be involved in the effects induced by antidepressants alone or in association with TRH, with respect to dopaminergic systems. However, different mechanisms of action seem to be responsible for the potentiation of TRH of the effect of the various antidepressants, since the involvement of the opioid systems varies according to the antidepressant tested.