bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition by rapamycin of leukocyte migration and bronchial hyperreactivity induced by injection of Sephadex beads to guinea‐pigs
Authors: de Francischi Janetti Nogueira , Conroy Dolores M. , Maghni Karim , Sirois Pierre 
Published: July 2012

The effect of rapamycin (0.001 to 5 mg kg−1) on the increased leukocyte counts in bronchoalveolar lavage (BAL) fluid and hyperreactivity of isolated bronchial strips to histamine and acetylcholine (ACh) was studied following the intravenous injection of Sephadex beads to guinea‐pigs.
The intramuscular (i.m.) injection of rapamycin (0.012 to 5 mg kg−1) dose‐dependently inhibited the increase in leukocyte counts in BAL fluid. Rapamycin (5 mg kg−l) reduced the numbers of eosinophils neutrophils, macrophages and lymphocytes in BAL fluid by 64, 55, 19 and 50% respectively. In addition, rapamycin (0.012 to 5 mg kg−1) significantly inhibited the Sephadex‐induced hyperreactivity of bronchial tissue to both histamine and ACh.
At a dose of 0.001 mg kg−1, rapamycin did not significantly reduce leukocyte infiltration or bronchial hyperreactivity.
Cyclosporin (5 mg kg−1) significantly reduced both lymphocyte and eosinophil numbers in BAL fluid of Sephadex‐injected guinea‐pigs whereas dexamethasone (1 mg kg−1) significantly reduced lymphocyte numbers. Neither drug affected the bronchial hyperreactivity to histamine and ACh.
It is concluded that the new immunosuppressive drug, rapamycin, is a potent inhibitor of leukocyte migration and bronchial hyperreactivity observed following the intravenous injection of Sephadex beads to guinea‐pigs. Rapamycin also appears to be more effective than cyclosporin or dexamethasone in reducing leukocyte counts and bronchial hyperreactivity in this model.
Our results suggest that inflammatory mechanisms which are inhibited by rapamycin may be important in the induction of Sephadex‐induced hyperreactivity.
Different muscarinic receptor subtypes mediating the phasic activity and basal tone of pig isolated intravesical ureter
Authors: Hernández M. , Simonsen U. , Prieto D. , Rivera L. , García P. , Ordaz E. , García‐Sacristán A. 
Published: July 2012

We have studied the effects of muscarinic cholinoceptor agonists and specific antagonists on both phasic activity and basal tone of the isolated intravesical ureter of the pig by means of isometric techniques in vitro.
Acetylcholine in the presence and absence of physostigmine increased both phasic activity and basal tone of ureteral strips in a concentration‐dependent manner. Moreover carbachol, methacholine and oxotremorine‐M increased both contractile parameters while bethanechol and McN‐A‐343 evoked only increases in tone without affecting the frequency of the phasic contractions.
The nicotinic receptor blocker, hexamethonium (10−6–10−4 m), failed to modify the contractions evoked by a single dose of carbachol (10−5 m), whilst the muscarinic antagonist, atropine inhibited both phasic and tonic responses.
The muscarinic M1 (pirenzepine), M2 (AF‐DX 116 and methoctramine), M3 (4‐DAMP, HHSiD and p‐F‐HHSiD), and putative M4 receptor (tropicamide) antagonists significantly reversed increases in both frequency of phasic activity and baseline tone induced by a submaximal dose of carbachol (10−5 m). The pIC50 values for inhibition of the induced phasic activity were: atropine (10.16) > 4‐DAMP (9.12) > HHSiD (8.22) = methoctramine (7.98) = p‐F‐HHSiD (7.88 > tropicamide (7.62) = pirenzepine (7.53) = AF‐DX 116 (7.45) and for inhibition of basal tone were: atropine (10.73) > 4‐DAMP (9.32) > HHSiD (8.65) = pirenzepine (8.43) = p‐F‐HHSiD (8.38) > methoctramine (7.79) > tropicamide (7.53) > AF‐DX 116 (7.04).
The antagonist profile indicates that an M1 receptor mediates the tonic response while the phasic activity could involve either both M2 and M3 or an M4 muscarinic receptor. These results suggest that different muscarinic receptor subtypes mediate the phasic and tonic contractile activity induced by a submaximal concentration of carbachol in the porcine intravesical ureter.
Dual contractile effects of ATP released by field stimulation revealed by effects of α,β‐methylene ATP and suramin in rat tail artery
Authors: Bao Jian‐Xin , Stjärne Lennart 
Published: July 2012

The field stimulation‐induced release of endogenous ATP and noradrenaline (NA) and contractile response in rat isolated tail artery were examined. The release of ATP was studied by extracellular electrophysiological recording and that of NA by a novel voltammetrical technique. The effects of the P2‐purinceptor antagonist, suramin, on these parameters were compared with those of α,β‐methylene ATP, a P2X‐purinoceptor desensitizing agent.
Neither α,β‐methylene ATP (10 μm) nor suramin (100−500 μm) had significant effects on the extracellularly recorded nerve terminal action potential but both abolished the ATP‐induced excitatory junction current caused by stimulation at 0.1 Hz. Neither agent affected significantly the voltammetrically measured release of NA induced by 10 or 100 pulses at 20 Hz.
Combined blockade of both postjunctional α1‐ and α2‐adrenoceptors by prazosin and yohimbine (both 0.1 μm) profoundly depressed the contractile response to 10 pulses at 20 Hz. The small and fast residual contraction in the presence of these agents was abolished by α,β‐methylene ATP (10 μm) and inhibited by suramin in a concentration‐dependent manner (10–500 μm; IC50 75 μm) and was hence probably caused by ATP or a related nucleotide.
When added first, α,β‐methylene ATP (10 μm) or suramin (100–500 μm) delayed the onset and enhanced the amplitude of the neurogenic contraction. This enhanced response was abolished by further addition of prazosin and yohimbine (both 0.1 μm).
The K+ channel blocker, tetraethylammonium (10 mm), dramatically enhanced the contractile response to 100 pulses at 1 Hz and caused it to become diphasic. Addition of α,β‐methylene ATP (10 μm) or suramin (100–500 μm) abolished the large initial twitch component of this contraction and depressed the tonic phase.
Like α,β‐methylene ATP, suramin (500 μm) had no effect on the contraction caused by exogenous NA (10 nm − 100 μm) or KCl (60 mm); both agents almost abolished the contraction caused by ATP (100 μm).
In conclusion, (i) the contractile response of rat tail artery to electrical field stimulation is mediated by both ATP and NA, and is thus an expression of ATP‐NA co‐transmission, (ii) the released ATP exerts two opposite effects via ‘P2X‐like’ purinoceptors, triggering the initial rapid phase of the neurogenic contraction and restricting the NA‐mediated component of the contraction; and (iii) the source and possible physiological role of the ATP which causes the inhibitory effect are unknown at present.
Mechanism of rat uterine smooth muscle contraction induced by endothelin‐1
Authors: Tsunoda Hajime , Miyauchi Takashi , Fujita Kayo , Kubo Takeshi , Goto Katsutoshi 
Published: July 2012

Endothelin (ET)‐1 has been demonstrated to cause contraction of uterine smooth muscle. We investigated the role of ET receptor subtypes (ETA and ETB receptors) in ET‐1‐induced contraction of rat uterine smooth muscle by using the ETA receptor antagonist BQ‐123 and the ETB receptor agonist BQ‐3020.
ET‐1 caused a contraction with superimposed oscillations of the rat isolated uterus suspended in Krebs‐Ringer solution; both the amplitude of contraction as well as the oscillation frequency increased in a dose‐dependent manner (10−11–10−7 m).
BQ‐123 (10−6 m) markedly shifted the dose‐response curve of ET‐1 for both contractile effects and oscillation frequency to the right.
BQ‐3020 (10−11–3 × 10−7 m) did not cause uterine contraction; neither did it affect the dose‐response curve of ET‐1 for either the contractile effect or the increase in oscillation frequency. Thus, stimulation of ETB receptors is not involved in these responses.
The present findings suggest that ET‐1‐induced contractile responses and the increase in oscillation frequency in rat uterine smooth muscle is mediated through ETA receptors, and that ETB receptors, play no role in these responses.
Evidence for functional dissociation of dependence and tolerance in guinea‐pig isolated ileal segments following 20 hour exposure to morphine in vitro
Authors: David C. , Davis N. , Mason R. , Wilson V.G. 
Published: July 2012

In the present study we have examined the relationship between tolerance and dependence in isolated ileal segments from the guinea‐pig under three different conditions: fresh preparations not previously exposed to morphine (fresh/morphine naive); preparations stored overnight at 4°C in modified Krebs‐Henseleit saline (overnight‐stored/morphine‐naive); preparations stored overnight at 4°C in Krebs‐Henseleit saline containing 10 μm morphine and extensively washed with modified Krebs‐Henseleit saline to remove residual morphine (overnight‐stored/morphine‐exposed).
Morphine produced a concentration‐dependent inhibition of the response of ileal segment to 0.1 Hz, 1 ms and 10 V transmural field stimulation in fresh/morphine‐naive, overnight‐stored/morphine‐naive and overnight‐stored/morphine‐exposed preparations. The maximum effect observed was similar in all three preparations—approximately 80% inhibition. Although, morphine was significantly more potent in the fresh/morphine‐naive preparations (pD2 6.72 ± 0.05, n = 8) than either the overnight‐stored/morphine‐naive (pD2 6.42 ± 0.11, n = 8) or the overnight‐stored/morphine‐exposed (pD2 6.44 ± 0.14, n = 8), there was no significant difference between the overnight models in their sensitivity to morphine. The latter observation indicates that overnight exposure to ileal segments to 10 μm morphine at 4°C failed to induce tolerance to morphine.
The μ opiate receptor antagonist, naloxone (10 μm), produced contractions in both fresh/morphine‐naive and overnight‐stored/morphine‐naive ileal segments following acute exposure to 10 μm morphine. Naloxone (10 μm) also produced contractions in 2/9 fresh/morphine‐naive, 1/9 overnight‐stored/morphine‐naive and 7/9 overnight‐stored/morphine‐exposed preparations in the absence of morphine. The greater incidence of naloxone‐induced contractions in overnight‐stored/morphine‐exposed preparations, suggests that dependence in this model is the product of adaptive changes that outlive the presence of morphine.
The selective α2‐adrenoceptor agonists, clonidine (0.3 μm) and 5‐bromo‐6‐[2‐imidazolin‐2‐ylamino]‐quinoxaline bitartrate (UK‐14304, 1 μm), inhibited naloxone‐induced contractions in overnight‐stored/morphine‐exposed preparations of ileal segments (n = 4 preparations for each agonist), suggesting that the response is due to transmitter release from the myenteric plexus.
The findings in the present study indicate that tolerance and dependence to morphine in ileal segments of the guinea‐pig can be functionally dissociated by overnight exposure to morphine at 4°C. The development of tolerance to morphine, unlike dependence, appears to be a temperature‐dependent process. This also raises the possibility that naloxone possesses intrinsic negative agonism at morphine‐sensitive receptors, which is manifested as a functional response only after adaptive changes in the myenteric plexus following exposure to morphine.
Ionotropic glutamate receptor types leading to adenosine‐mediated inhibition of electrically evoked [3H]‐noradrenaline release in rabbit brain cortex slices
Authors: von Kügelgen Ivar , Späth Leni , Starke Klaus 
Published: July 2012

Glutamate inhibits the electrically evoked release of noradrenaline in rabbit brain cortex slices; the inhibition is mediated by adenyl compounds, presumably adenosine. The aim of the present study was to identify the receptors involved in this indirect inhibitory effect of glutamate. Slices of the occipitoparietal cortex were preincubated with [3H]‐noradrenaline and then superfused and stimulated by trains of 6 pulses, 100 Hz.
The ionotropic glutamate receptor agonists α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA; 10–100 μm), kainate (10–100 μm) and N‐methyl‐d‐aspartate (NMDA; 30–300 μm) but not the metabotropic glutamate receptor agonist, 1‐amino‐1,3‐cyclopentanedicarboxylate (ACPD; 10–100 μm) reduced the electrically evoked overflow of tritium.
The effects of AMPA, kainate and NMDA were attenuated or abolished by the adenosine A1‐receptor antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) as well as by adenosine deaminase but not by the α2‐adrenoceptor antagonist yohimbine, the γ‐aminobutyric acid (GABA) receptor antagonists, bicuculline and 2‐hydroxysaclofen and the NO synthase inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME).
The NMDA receptor antagonist, 2‐amino‐5‐phosphonopentanoate (AP5) blocked the inhibitory effect of NMDA but not that of AMPA and kainate. The non‐NMDA‐receptor antagonist, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) blocked the effect of AMPA but not of kainate and NMDA.
In addition to decreasing the electrically evoked overflow of tritium, AMPA, kainate and NMDA but not ACPD caused a steep but transient rise of basal tritium efflux. This immediate releasing effect was not significantly changed by DPCPX, adenosine deaminase, yohimbine, bicuculline, 2‐hydroxy‐saclofen and l‐NAME (except that l‐NAME enhanced the effect of kainate). AP5 and CNQX antagonized the immediate releasing effects in the same way that they antagonized the inhibition by AMPA, kainate and NMDA of the electrically evoked overflow of tritium.
It is concluded that AMPA, kainate and NMDA, like glutamate, reduce the electrically evoked release of noradrenaline by releasing adenosine or an adenine nucleotide which is then degraded to adenosine. Activation of each of the three ionotropic glutamate receptors, AMPA, kainate and NMDA receptors, but not activation of metabotropic glutamate receptors can initiate this indirect inhibitory effect on the release of noradrenaline (as well as the known noradrenaline releasing effect).
The effect of defibrotide on thromboembolism in the pulmonary vasculature of mice and rabbits and in the cerebral vasculature of rabbits
Authors: Paul W. , Gresele P. , Momi S. , Bianchi G. , Page C.P. 
Published: July 2012

Administration of bovine thrombin (100 u kg−1) into the carotid artery of rabbits induces a sustained accumulation of 111Indium‐labelled platelets within the cranial vasculature over the subsequent 3 h.
Intracarotid (i.c.) administration of defibrotide (64 mg kg−1 bolus plus 64 mg kg−1 h−1 for 1 h) prior to i.c. thrombin (100 u kg−1) significantly reduces the ability of thrombin to induce cranial thromboembolism in rabbits.
Intravenous (i.v.) administration of thrombin (20 u kg−1) in rabbits induces a reversible accumulation of radiolabelled platelets into the thoracic circulation which is significantly reduced by i.v. administration of defibrotide (64 mg kg−1 bolus plus 64 mg kg−1 h−1 for 1 h) prior to i.v. thrombin. In contrast, platelet accumulation in response to adenosine diphosphate (ADP; 20 μg kg−1, i.v.) or platelet activating factor (PAF; 50 ng kg−1, i.v.) is not significantly affected by this treatment.
Intravenous administration of the nitric oxide (NO)‐synthase inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME; 10 mg kg−1) potentiates platelet accumulation induced by low dose thrombin (10 u kg−1, i.v.) within the pulmonary vasculature of rabbits. The potentiated response is significantly abrogated following pretreatment with defibrotide (64 mg kg−1 bolus plus 64 mg kg−1 h−1 for 1 h, i.v.).
Intravenous injection of human thrombin (1250 u kg−1) to mice induces death within the majority of animals which is significantly reduced by pretreatment with defibrotide (150–175 mg kg−1, i.v.). In contrast, death induced by i.v. collagen (1.25 mg kg−1) plus adrenaline (75 μg kg−1) is not significantly affected by defibrotide pretreatment.
The inhibitory effect of defibrotide in mice is abolished following concomitant treatment with the inhibitor of fribrinolysis, tranexamic acid (100 mg kg−1, i.v.), but is unaffected following treatment with the cyclo‐oxygenase inhibitor, aspirin (300 mg kg−1, i.p.).
The protective effect of defibrotide against thrombin‐induced thromboembolism in the mouse is potentiated by recombinant tissue‐plasminogen activator (rt‐PA; 1 mg kg−1, i.v.) or unfractionated heparin (10 u kg−1, i.v.) administration.
The results suggest that defibrotide may possess antithrombotic activity on thrombin‐induced thromboembolism which, at least in the mouse, may be partially mediated via induction of the fibrinolytic pathway.
Toxic inhibition of smooth muscle contractility by plant‐derived sesquiterpenes caused by their chemically reactive α‐methylenebutyrolactone functions
Authors: Hay Alastair J.B. , Hamburger Matthias , Hostettmann K. , Hoult J.R.S. 
Published: July 2012

Previous studies have shown that extracts of feverfew (Tanacetum parthenium) and parthenolide, a sesquiterpene α‐methylenebutyrolactone obtained from it, inhibit smooth muscle contractility in a time‐dependent, non‐specific and irreversible manner.
The hypothesis that this toxic effect is due specifically to the presence in the sesquiterpene lactone of the potentially reactive α‐methylene function was tested on rabbit isolated aortic ring preparations. This was done (a) by comparing the effects of two plant‐derived sesquiterpene lactones purified from yellow star thistle (Centaurea solstitialis): cynaropicrin (an α‐methylenebutyrolactone) and solstitialin 13‐acetate (lacking the α‐methylene function), and (b) by chemically inactivating the α‐methylene functions in cynaropicrin and parthenolide by reaction with cysteine.
The results show that the characteristic smooth muscle inhibitory profile is demonstrated by the two α‐methylenebutyrolactones (parthenolide and cynaropicrin), but not by the compound lacking this functional group (solstitialin 13‐acetate), or by those previously active compounds in which it has been inactivated with cysteine.
Thus the α‐methylene function is critical for this aspect of the toxic pharmacological profile of the sesquiterpene butyrolactones, which are natural products widely distributed in the Compositae family of flowering plants.
Comparison of two new inhibitors of catechol O‐methylation on striatal dopamine metabolism: a microdialysis study in rats
Authors: Törnwall M. , Kaakkola S. , Tuomainen P. , Kask A. , Männistö P.T. 
Published: July 2012

Effects of two new inhibitors of catechol O‐methylation (CGP 28014 and entacapone; 30 mg kg−1, i.p.) were compared by means of brain microdialysis in rats treated with l‐3,4‐dihydroxyphenylalanine (l‐dopa)/carbidopa (50/50 mg kg−1, i.p., respectively) or saline.
In saline‐treated rats, CGP 28014 maximally (max) increased striatal dopamine and 3,4‐dihydroxyphenylacetic acid (DOPAC) effluxes by 41% and 49%, respectively, whereas homovanillic acid (HVA) levels were decreased by 71%.
In the presence of l‐dopa/carbidopa, a peripherally active inhibitor of catechol O‐methyltransferase (COMT) entacapone had a short‐lasting increasing effect on l‐dopa efflux. Compared to the effects of l‐dopa/carbidopa alone 3‐O‐methyldopa (3‐OMD) levels were effectively reduced (max 79%) by entacapone, but not by CGP 28014.
Entacapone, in contrast to CGP 28014, increased striatal dopamine efflux (max 492% of that after l‐dopa/carbidopa alone). Also DOPAC levels were increased by entacapone (255% at 180 min), but not significantly by CGP 28014 (159% at 180 min).
Both compounds initially decreased HVA efflux. The effect of CGP 18014 was longer‐lasting. By the end of the measurement, entacapone even increased HVA levels (max 259%).
Our results demonstrate that entacapone is a peripheral COMT inhibitor and support the view that CGP 18014 is mainly a centrally acting inhibitor of O‐methylation.
Regulation of aromatic l‐amino acid decarboxylase in rat striatal synaptosomes: effects of dopamine receptor agonists and antagonists
Authors: Zhu Meng‐Yang , Juorio Augusto V. , Paterson I. Alick , Boulton Alan A. 
Published: July 2012

In this study we investigated the effects of dopamine receptor agonists and antagonists on rat striatal synaptosomal aromatic l‐amino acid decarboxylase (AADC) activity.
The results show that 10−5–10−7 m cis‐flupenthixol increased the striatal synaptosomal AADC activity (by 25% to 57%) in a time‐dependent manner. SCH 23390 and remoxipride alone had little or no effect on striatal synaptosomal AADC activity, but in combination they increased AADC activity by 20%, suggesting that the increases in striatal synaptosomal AADC activity occurred only after blockade of both dopamine D1 and D2 receptors.
Treatment with (+)‐amphetamine and (±)‐2‐(N‐phenylethyl‐N‐propyl)amino‐5‐hydroxytetralin hydrochloride ((±)‐PPHT) produced a reduction of striatal synaptosomal AADC activity in a concentration‐ and time‐dependent manner. SKF 38393 and (−)‐quinpirole, however, exhibited no effect on striatal synaptosomal AADC activity, suggesting that only the mixed dopamine receptor agonists can reduce the AADC activity. Incubation with apomorphine at a concentration of 10−4 m inhibited the AADC activity by 74% and this inhibition cannot be antagonized by SCH 23390, remoxipride or cis‐flupenthixol, suggesting that apomorphine‐induced inhibition of striatal synaptosomal AADC activity was not mediated by dopamine receptors.
cis‐Flupenthixol can reverse the reduction of AADC activity induced by (+)‐amphetamine and (±)‐PPHT. The inhibition of AADC activity elicited by (±)‐PPHT also can be reversed by SCH 23390 and remoxipride.
The inhibition of striatal synaptosomal AADC activity induced by (±)‐PPHT is calcium‐dependent and protein kinase C may play a role in the regulation of striatal AADC activity.
These studies show that striatal synaptosomal AADC activity is regulated by dopamine receptors and indicate that in vitro dopamine D1 and D2 receptors have a synergistic effect in this regulation.
Regulation of baseline vascular resistance in the canine diaphragm by nitric oxide
Authors: Ward Michael E. , Hussain Sabah N.A. 
Published: July 2012

The role played by nitric oxide (NO) in the regulation of blood flow to the canine isolated hemidiaphragm was evaluated by determining (a) the effects of the l‐arginine analogues NG‐nitro‐l‐arginine methyl ester (l‐NAME), NG‐nitro‐l‐arginine (l‐NOARG), and argininosuccinic acid (ArgSA) on baseline vascular resistance and of the latter two agents on endothelium‐dependent (acetylcholine, ACh) and endothelium independent (sodium nitroprusside, SNP) vasodilatation; (b) the effects of l‐ and d‐arginine on baseline vascular resistance; and (c) the effects of l‐glutamine, an inhibitor of intracellular recycling of l‐citrulline to l‐arginine, on baseline resistance and on the response to ACh and SNP.
l‐NAME, l‐NOARG and ArgSA (6 × 10−4 m final concentration) increased baseline diaphragmatic vascular resistance to a similar extent (28.6 ± 4.2%, 26.7 ± 4.3% and 32.8 ± 4.6% respectively). l‐NOARG and ArgSA reversed the vasodilator effect of ACh but not of SNP.
l‐ and d‐arginine had no effect on vascular resistance.
l‐Glutamine (10−3 m) increased baseline vascular resistance by 10 ± 1.9% (P < 0.05) but did not alter responses to either ACh or SNP.
Basal NO release plays a role in the regulation of baseline diaphragmatic vascular resistance. l‐Arginine analogues tested potently and specifically inhibited this process. Moreover, extracellular l‐arginine appears to have no effect on baseline diaphragmatic vascular resistance.