bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of diadenosine tetraphosphate (Ap4A) binding sites in cultured chromaffin cells: evidence for a P2y site
Authors: Pintor Jesús , Torres Magdalena , Castro Enrique , Miras‐Portugal M. Teresa 
Published: July 2012

Diadenosine tetraphosphate (Ap4A) a dinucleotide, which is stored in secretory granules, presents two types of high affinity binding sites in chromaffin cells. A Kd value of 8 ± 0.65 × 10−11 m and Bmax value of 5420 ± 450 sites per cell were obtained for the high affinity binding site. A Kd value of 5.6 ± 0.53 × 10−9 m and a Bmax value close to 70,000 sites per cell were obtained for the second binding site with high affinity.
The diadenosine polyphosphates, Ap3A, Ap4A, Ap5A and Ap6A, displaced [3H]‐Ap4A from the two binding sites, the Ki values being 1.0 nm, 0.013 nm, 0.013 nm and 0.013 nm for the very high affinity binding site and 0.5 μm, 0.13 μm, 0.062 μm and 0.75 μm for the second binding site.
The ATP analogues displaced [3H]‐Ap4A with the potency order of the P2y receptors, adenosine 5′‐O‐(2 thiodiphosphate) (ADP‐β‐S) > 5′‐adenylyl imidodiphosphate (AMP‐PNP) > α,β‐methylene ATP (α,β‐MeATP), in both binding sites. The Ki, values were respectively 0.075 nm, 0.2 nm and 0.75 nm for the very high affinity binding site and 0.125 μm, 0.5 μm and 0.9 μm for the second binding site.
The effects of phosphoramidon on the regional haemodynamic responses to human proendothelin [1–38] in conscious rats
Authors: Gardiner Sheila M. , Compton Alix M. , Kemp Philip A. , Bennett Terence 
Published: July 2012

Cardiovascular responses to human proendothelin [1–38], in the absence and presence of phosphoramidon, were studied in conscious Long Evans rats, chronically instrumented for the continuous recording of heart rate, systemic arterial blood pressure and renal, mesenteric and hindquarters blood flows.
A dose of 0.1 nmol kg−1 human proendothelin [1–38] caused a slight pressor effect (maximum 5 ± 2mmHg), but a clear bradycardia (maximum −29 ± 7 beats min−1). Renal haemodynamics were unchanged but there was mesenteric vasoconstriction and a vasodilatation followed by a vasoconstriction in the hindquarters.
A dose of 1.0 nmol kg−1 human proendothelin [1–38] caused a gradual hypertension (maximum 42 ± 4 mmHg at 10 min) and a profound bradycardia (–149 ± 10 beats min−1 at 30 min). There were gradual but marked, renal and hindquarters vasoconstrictions, whereas there was a substantial mesenteric vasoconstriction that was relatively rapid in onset.
In 2 animals, administration of human proendothelin [1–38] at a dose of 10 nmol kg−1 caused an initial hypotension followed by a rapidly‐developing pressor effect; there were renal and mesenteric vasoconstrictions and vasodilatation followed by vasoconstriction in the hindquarters. These changes were very similar to those seen following injection of endothelin‐1 (0.1 nmol kg−1).
Phosphoramidon (2 μmol kg−1) had no cardiovascular effects itself and it did not affect significantly the pressor or mesenteric vasoconstrictor effects of human proendothelin [1–38], but it reduced the bradycardia and renal and hindquarters vasoconstrictor responses. A higher dose of phosphoramidon (10 μmol kg−1) caused significant attenuation of all the responses to human proendothelin [1–38], but a substantial mesenteric vasoconstrictor response still occurred under these conditions.
The results are consistent with the involvement of phosphoramidon‐sensitive enzyme systems in the conversion of human proendothelin [1–38] to endothelin‐1 in vivo. In addition, considering the different patterns of responses to human proendothelin [1–38] in the effector tissues studied (heart, and renal, mesenteric and hindquarters vascular beds), and the differential degrees of inhibition of them by phosphoramidon, it is likely that the effects of human proendothelin [1–38] were due to its local (rather than systemic) conversion to endothelin‐1 by processes with differing degrees of susceptibility to phosphoramidon.
Potencies of antagonists indicate that 5‐HT1C receptors mediate 1–3(chlorophenyl)piperazine‐induced hypophagia
Authors: Kennett G.A. , Curzon G. 
Published: July 2012

1–3(Chlorophenyl)piperazine (mCPP) (5 mg kg−1, i.p.) inhibited 2 h food intake in rats previously deprived of food for one day. Ten 5‐hydroxytryptamine (5‐HT) antagonists given s.c. opposed this hypophagic response. Calculated ID50 values correlated significantly with reported affinities (r = 0.81, n = 10, P < 0.01) for 5‐HT1C but not for 5‐HT2, 5‐HT1A, 5‐HT1B or 5‐HT1D receptors.
ID50 values of the ten antagonists against 5‐hydroxytryptophan (5‐HTP) + carbidopa‐induced head shakes (a 5‐HT2‐mediated response) correlated significantly (r = 0.81, n = 10, P < 0.01) with their affinities for 5‐HT2, but not for 5‐HT1A, 5‐HT1B, 5‐HT1C or 5‐HT1D receptors.
ID50 values for inhibition of hypophagia and head shakes did not correlate significantly with each other.
Ratios of ID50 values against hypophagia and 5‐HT2‐mediated head shakes gave indices of relative in vivo potencies independent of differences in drug metabolism and disposition. These ratios correlated highly significantly (r = 0.91, n = 10, P < 0.001) with the ratios of the affinities of the drugs for 5‐HT1C (but not for 5‐HT1A, 5‐HT1B or 5‐HT1B or 5‐HT1D receptors) and with their affinities for 5‐HT2 receptors. These results strongly support the hypothesis that mediation of mCPP‐induced hypophagia is by stimulation of 5‐HT1C receptors and the mediation of 5‐HTP‐induced head twitches by 5‐HT2 receptors.
The neuroprotective action of dizocilpine (MK‐801) in the rat middle cerebral artery occlusion model of focal ischaemia
Authors: Gill R. , Brazell C. , Woodruff G.N. , Kemp J.A. 
Published: July 2012

An acute model of focal ischaemia, which involves permanent occlusion of the middle cerebral artery of the rat with 4 h survival, was used to find the minimum effective plasma concentration of dizocilpine (MK‐801) and to determine its dose‐effect relationship.
MK‐801 was administered at the time of occlusion and was given as an i.v. bolus followed by an infusion for 4 h to maintain a steady state plasma concentration of the drug throughout the study. MK‐801 was given at 3 dose levels; 0.04 mg kg−1 i.v. bolus + 0.6 μg kg−1 min−1 infusion; 0.12 mg kg−1 i.v. bolus + 1.8 μg kg−1 min−1 infusion; 0.4 mg kg−1 i.v. bolus + 6 μg kg−1 min−1 infusion, which gave mean plasma levels over the 4h of 8.0 ng ml−1, 18.9 ng ml−1 and 113.2 ng ml−1 respectively.
MK‐801 at 8.0 ng ml−1 gave 10% reduction in the volume of ischaemic brain damage in the cerebral cortex which just reached significance. The middle dose of MK‐801 (18.9 ng ml−1) gave a highly significant reduction in the volume of ischaemic brain damage in the cerebral cortex and hemisphere, volumes of ischaemic tissue being reduced by 60% and 50% compared to saline‐treated animals, respectively. The highest plasma concentration of MK‐801 (113.2 ng ml−1) resulted in a 35% reduction in the volume of hemispheric damage and a 40% reduction in the volume of cortical damage, which were significant.
The reduction in the amount of protection afforded by the highest dose of MK‐801 may be due to the hypotensive effect of this dose. There was no protection against the volume of damage in the caudate nucleus for any of the doses of MK‐801 tested.
Therefore the minimum effective plasma concentration of MK‐801 was 8.0 ng ml−1, although the greatest protection was seen with a plasma level of 18.9 ng ml−1. This correlates well with the concentration of MK‐801 required to block N‐methyl‐d‐aspartate (NMDA) receptors and prevent NMDA receptor mediated neurotoxicity in vitro.
Prostacyclin activates tachykinin release from capsaicin‐sensitive afferents in guinea‐pig bronchi through a ruthenium red‐sensitive pathway
Authors: Mapp Cristina Elisabetta , Fabbri Leonardo Michele , Boniotti Anna , Maggi Carlo Alberto 
Published: July 2012

We have investigated the ability of prostacyclin (PGI2) to contract guinea‐pig isolated bronchi and the possible involvement of capsaicin‐sensitive primary afferents in the response to PGI2.
PGI2 (0.1–100 μm) produced concentration‐dependent contractions of the guinea‐pig isolated bronchi. In vitro capsaicin desensitization (10 μm for 30 min followed by washing) significantly reduced the PGI2‐induced contraction at all concentrations tested. A capsaicin‐resistant component of contraction (40–60% of the overall response) was also evident.
Ruthenium red (3 μm), an inorganic dye which acts as a selective functional antagonist of capsaicin, significantly decreased PGI2‐induced contractions, without affecting the response to substance P, neurokinin A or acetylcholine.
MEN 10, 207, (Tyr5, d‐Trp6,8,9, Arg10)‐neurokinin A (4–10) (3 μm), a selective antagonist of NK2‐tachykinin receptors, significantly decreased PGI2‐induced contractions and neurokinin A‐induced contractions, without affecting the response to acetylcholine.
The effect of ruthenium red and MEN 10,207 on the one hand, and that of ruthenium red and capsaicin on the other was non additive.
These results indicate that PGI2‐induced contraction of the guinea‐pig isolated bronchi involves two distinct mechanisms, one of which involves transmitter (tachykinins) release from peripheral endings of capsaicin‐sensitive primary afferents. In as much as PGI2‐activation of primary afferents is sensitive to ruthenium red, we suggest that PGI2 shares a common mechanism of tachykinin release with that activated by capsaicin.
Fenoverine inhibition of calcium channel currents in single smooth muscle cells from rat portal vein and myometrium
Authors: Mironneau J. , Arnaudeau S. , Mironneau C. 
Published: July 2012

The effects of fenoverine, an antispasmodic drug, have been studied on the Ca2+channel currents of isolated cells from rat portal vein and pregnant myometrium by the patch‐clamp technique (whole‐cell configuration).
Fenoverine inhibited both fast and slow Ca2+channel currents in a concentration‐dependent manner. Half‐inhibition of fast Ca2+channel current (holding potential of −70 mV) and slow Ca2+channel current (holding potential of −40 mV) in portal vein smooth muscle were obtained at concentrations of 7.5 and 1.9 μm, respectively. In myometrium, the fenoverine concentration which blocked 50% of the slow Ca2+channel current (holding potential of −70 mV) was 2.3 μm.
Administration of fenoverine at rest reduced both Ca2+channel currents. Currents activated repetitively, at a rate between 0.05 and 0.1 Hz, were inhibited equally which indicates an absence of use‐dependent inhibition.
When cells held at depolarized membrane potentials at which fast or slow Ca2+channel currents were strongly inactivated, the inhibitory effects of fenoverine were enhanced on both Ca2+channel currents which indicates that the fenoverine‐induced inhibition was voltage‐dependent. The fenoverine concentrations which blocked the inactivated Ca2+channels were 5–7 times lower than those which blocked the resting Ca2+channels.
Our results show that fenoverine depresses inward currents through fast and slow Ca2+channels. This effect may be explained by the preferential binding of fenoverine to resting Ca2+channels. In addition, fenoverine has a higher afinity for inactivated Ca2+channels than for resting channels.
Antagonism of relaxin by glibenclamide in the uterus of the rat in vivo
Authors: Downing Sandra J. , Hollingsworth M. 
Published: July 2012

The effects of glibenclamide (a blocker of adenosine triphosphate [ATP]‐dependent K+‐channels) on the inhibition of uterine contractions by relaxin, salbutamol and cromakalim were compared in vivo.
Glibenclamide (20 mg kg−1) did not antagonize salbutamol. Glibenclamide produced a parallel rightward shift in the dose‐response curve to cromakalim with a 5.5 fold decrease in uterine sensitivity (post‐vehicle log ID50, −0.87 mg kg−1; post‐glibenclamide log ID50, −0.07 mg kg−1). Glibenclamide produced a non‐parallel rightward shift in the dose‐response curve to relaxin (post‐vehicle log ID50, 0.99 μg kg−1; post‐glibenclamide log ID50, 2.28 μg kg−1).
Glibenclamide reversed established inhibition of uterine contractions by cromakalim or relaxin but not that by salbutamol.
Insulin produced no antagonism of relaxin on isolated uterus of the rat, demonstrating that glibenclamide antagonism of relaxin in vivo is not by released insulin. Apamin did not antagonize relaxin in vivo, suggesting that small calcium‐activated K+‐channels are not involved in the action of relaxin.
Comparison of the lack of antagonism of salbutamol with the non‐competitive‐like antagonism of relaxin by glibenclamide suggests that relaxin does not relax uterine smooth muscle predominantly by increasing intracellular adenosine 3′, 5′‐cyclic monophosphate concentrations. Comparison of the non‐competitive‐like antagonism of relaxin and the competitive‐like antagonism of cromakalim by glibenclamide suggests that the two relaxants may share, in part, a common mechanism of action and that additional mechanism(s) may also be involved in the inhibitory action of relaxin.
Effects of 5‐HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents
Authors: Njung'e K. , Handley S.L. 
Published: July 2012

The effects of 5‐hydroxytryptamine (5‐HT) uptake inhibitors, agonists and antagonists have been evaluated on mouse marble‐burying behaviour, a putative test for anxiolytic agents. The high levels of locomotor activity occurring on first exposure to a circular runway (runway activity) were used as a separate test of non‐specific drug effects.
Fluvoxamine, zimeldine, indalpine and citalopram dose‐dependently inhibited burying without affecting runway activity. 5‐Hydroxytryptophan (5‐HTP, with carbidopa), 5‐methoxy‐N,N‐dimethyltryptamine, 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OHDPAT), buspirone, gepirone and ipsapirone reduced burying only at doses reducing runway activity. RU 24969 increased runway activity at all effective doses. 1‐(2,5‐Dimethoxy‐4‐iodophenyl)‐2 aminopropane (DOI), 1,‐(3‐trifluoromethylphenyl) piperazine (TFMPP) and l‐(3‐chlorophenyl)‐piperazine (mCPP) potently and differentially reduced burying at doses below those affecting runway activity.
5‐HT antagonists only reduced burying at high doses which also reduced runway activity. Burying inhibition by DOI was antagonized by ritanserin, ICI 169 369 and cyproheptadine but not by pindolol or a low (0.25 mg kg−1) dose of metergoline. Burying inhibition by mCPP was not altered by any of these agents except that it was potentiated by pindolol 5 mg kg−1.
Zimeldine burying inhibition was potentiated by ritanserin, ICI 169 369, ICS 205–930, cyproheptadine and pindolol. Runway activity was not affected by these drug combinations.
Zimeldine was administered in drinking water at a dose of 10 mg kg−1 daily for 21 days. Burying inhibition had disappeared by day 14 and did not recur 24 or 48 h after withdrawal at which times responses to DOI were at control levels.
Selective inhibition of marble burying was not found to be a property of 5‐HT‐related putative and actual anxiolytics such as buspirone, gepirone, ipsapirone, ritanserin and ondansetron. Nevertheless it was a general property of both 5‐HT uptake inhibitors and 5‐HT releasing agents; this generality suggests that elevated synaptic 5‐HT could be responsible for the effects of these latter agents. The action of DOI may be attributable to effects at the 5‐HT2 receptor but those of the 5‐HT agonist and releasing agent mCPP, and the uptake inhibitor zimeldine, could not be attributed to effects at any one 5‐HT receptor subtype. This, together with the potentiating effect of several 5‐HT antagonists on the response to zimeldine, raises the possibility of multiple interactions between 5‐HT receptor subtypes.
Effects of Ca2+antagonists on glutamate release and Ca2+influx in the hippocampus with in vivo intracerebral microdialysis
Authors: Lu Y. Ming , Zhang J. Tian , Zhao F. Qing , Qin Y. Fi 
Published: July 2012

The extracellular glutamate content and Ca2+level in vivo in rat hippocampus were measured by brain microdialysis following administration of two depolarizing agents (veratridine, KCl) and quinolinic acid (Quin).
The two depolarizing agents increased the extracellular glutamate level (to between 280 and 320% basal) and decreased the extracellular Ca2+content (to 48% of basal). However, Quin did not change the glutamate level but decreased the Ca2+content.
The effects of Ca2+antagonists on the changes of glutamate and Ca2+level were evaluated in this experimental model. At a dose of 0.5 mg kg−1, i.v., nimodipine (L‐type channel blocker) did not produce significant changes in the stimulated‐glutamate release. A statistically significant inhibition of Ca2+influx was observed at a dose of 0.05 mg kg−1. In contrast, in those animals receiving the N‐type Ca2+antagonist, daurisoline (0.1, 1 or 5 mg kg−1, i.v.), a potent attenuation of both glutamate release and Ca2+influx was found.
We propose that the pharmacological properties of Ca2+influx and of neurotransmitter release differ and that nimodipine‐sensitive L‐type channels may not be very common in nerve terminals but are localized in cell soma. Daurisoline‐sensitive N‐type channels in nerve terminals have a much greater influence on excitatory amino acid release.
Muscarinic antagonists attenuate the increase in accumbens and striatum dopamine metabolism produced by clozapine but not by haloperidol
Authors: Rivest Robert , Marsden Charles A. 
Published: July 2012

The effect of the muscarinic antagonists, scopolamine and atropine, were examined on the increase in extracellular 3,4‐dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens and the striatum induced by haloperidol and clozapine by use of in vivo differential pulse voltammetry with carbon fibre electrodes in anaesthetized rats.
Animals received saline (1 ml kg−1, s.c.), scopolamine (1 mg kg−1, o.p.) or atropine (20 μg, i.c.v.) followed 15 min later by saline (10 μ1, i.c.v.), haloperidol (1 mg kg−1, s.c.) or clozapine (30 mg kg−1, i.p.) and extracellular DOPAC was simultaneously recorded in the nucleus accumbens and the striatum every 5 min for 60 min after drug administration.
Scopolamine or atropine alone had no effect on the DOPAC peak height but attenuated the increase in extracellular DOPAC induced by clozapine in both brain regions. Neither scopolamine nor atropine altered the haloperidol‐induced increase in accumbens or striatal extracellular DOPAC.
The present results demonstrate that muscarinic antagonists attenuate the increase in accumbens and striatal dopamine metabolism in vivo produced by the atypical neuroleptic clozapine but not the haloperidol‐induced increase in dopamine metabolism. The results indicate that central muscarinic receptors are involved in the actions on dopaminergic function of clozapine but not haloperidol.
Sedation and histamine H1‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene
Authors: Nicholson A.N. , Pascoe Peta A. , Turner Claire , Ganellin C.R. , Greengrass P.M. , Casy A.F. , Mercer Amanda D. 
Published: July 2012

The effects of 10 mg (+)‐ and (−)‐chlorpheniramine and 5 mg (+)‐ and (−)‐dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well‐being were studied in 6 healthy young adult humans. Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos.
Daytime sleep latencies were reduced with triprolidine, (+)‐chlorpheniramine and (−)‐dimethindene, and subjects also reported that they felt more sleepy after (+)‐chlorpheniramine and (−)‐dimethindene. Performance on digit symbol substitution was impaired with (+)‐chlorpheniramine.
Changes in measures with (−)‐chlorpheniramine and (+)‐dimethindene were not different from changes with placebo.
In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine H1‐receptor. These findings strongly suggest that sedation can arise from H1‐receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.
Differences in inositol phosphate production in blood vessels of normotensive and spontaneously hypertensive rats
Authors: Vila E. , Macrae I.M. , Reid J.L. 
Published: July 2012

Total inositol phosphate formation was measured in labelled femoral and iliac arteries and veins of 14 week‐old spontaneously hypertensive rats (SHR) and age‐matched Wistar Kyoto (WKY) controls, either unstimulated or in the presence of noradrenaline.
Basal levels of [3H]‐inositol phosphates and [3H]‐phosphatidylinositol were significantly enhanced in SHR femoral artery, but not in the other 3 vessels, compared with WKY.
Noradrenaline stimulated phosphoinositide hydrolysis in all four vessels of SHR and WKY. Pretreatment with prazosin (10−7–10−6m) but not with yohimbine (10−7m), inhibited the noradrenaline‐induced inositol phosphate formation indicating an α1‐adrenoceptor‐mediated response.
In the femoral artery of SHR compared to WKY, [3H]‐inositol phosphate accumulation induced by noradrenaline (10−7–10−5m) was significantly reduced when expressed relative to basal values although the response to higher concentrations (10−4–10−3m) was not altered. In contrast, a significant reduction of inositol phosphates was seen only with 10−7m noradrenaline when absolute values were compared. In the other three vessels, no difference in noradrenaline‐induced [3H]‐inositol phosphate formation was observed between strains.
These data suggest that phosphoinositide hydrolysis‐mediated by α1‐adrenoceptors may be reduced in some but not all blood vessels of adult SHR.
Characterization of the biological effects of 2‐methylthio‐ATP on rat hepatocytes: clear‐cut differences with ATP
Authors: Keppens Stefaan , De Wulf Henri 
Published: July 2012

In several tissues, 2‐methylthio adenosine triphosphate (2MeSATP) is a very potent P2Y‐purine agonist. In rat hepatocytes, 2MeSATP half‐maximally activated glycogen phosphorylase at 20 nm and was therefore about 25 times more effective than ATP (Ka 0.5–0.8 μm). This strong glycogenolytic potency of 2MeSATP suggests on its own the presence of P2Y‐purinoceptors in liver.
Displacement of the radioligand ATPα[35S] from its receptor however occurred at much higher concentrations of 2MeSATP than was anticipated on the basis of its glycogenolytic potency.
The interaction of 2MeSATP with the receptor, characterized with ATPα[35S] as radioligand, cannot be considered as a pure competitive interaction.
2MeSATP did not share the ability of ATP to counteract the effect of glucagon on the adenosine 3′:5′‐cyclic monophosphate levels.
2MeSATP barely increased the levels of inositol trisphosphate (IP3).
The glycogenolytic effect of 2MeSATP was completely abolished by pretreatment of the hepatocytes with phorbol myristic acetate.
It is tentatively concluded that 2MeSATP and ATP are interacting with different P2 purinoceptors.