bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calcium‐pH crosstalks in rat mast cells: cytosolic alkalinization, but not intracellular calcium release, is a sufficient signal for degranulation
Authors: Alfonso A , Cabado A G , Vieytes M R , Botana L M 
Published: January 2005

The aim of this work was to study the relationship between intracellular alkalinization, calcium fluxes and histamine release in rat mast cells. Intracellular alkalinization was induced by nigericin, a monovalent cation ionophore, and by NH4Cl (ammonium chloride). Calcium cytosolic and intracellular pH were measured by fluorescence digital imaging using Fura‐2‐AM and BCECF‐AM.
In rat mast cells, nigericin and NH4Cl induce a dose‐dependent intracellular alkalinization, a dose‐dependent increase in intracellular calcium levels by releasing calcium from intracellular pools, and an activation of capacitative calcium influx.
The increase in both intracellular calcium and pH activates exocytosis (histamine release) in the absence of external calcium. Under the same conditions, thapsigargin does not activate exocytosis, the main difference being that thapsigargin does not alkalinize the cytosol.
After alkalinization, histamine release is intracellular‐calcium dependent. With 2.5 mM EGTA and thapsigargin the cell response decreases by 62%.
The cytosolic alkalinization, in addition to the calcium increase it is enough signal to elicit the exocytotic process in rat mast cells.

British Journal of Pharmacology (2000) 130, 1809–1816; doi:10.1038/sj.bjp.0703490
Selective monoamine oxidase subtype inhibition and striatal extracellular dopamine in the guinea‐pig
Authors: Ilani T , Lamensdorf I , Finberg J P M 
Published: January 2005

Striatal microdialysate levels of dopamine (DA) in conscious guinea‐pigs were measured following acute (1 day) and chronic (21 days) treatment with deprenyl (2 and 0.25 mg kg−1 s.c., respectively) or clorgyline (4 and 1 mg kg−1 s.c., respectively), as well as by combination treatment using the same doses of the two inhibitors. These treatments caused selective inhibition of monoamine oxidase type B (MAO‐B) or monoamine oxidase type A (MAO‐A) respectively.
Neither acute nor chronic treatments with deprenyl or clorgyline increased basal or KCl‐induced DA levels. Acute and chronic clorgyline treatments were accompanied by significant reductions in striatal microdialysate 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). On the other hand, both acute and chronic deprenyl treatments were accompanied by significant increases in microdialysate HVA with no effect on DOPAC levels.
Acute or chronic combined treatment with clorgyline and deprenyl increased tissue but not microdialysate DA levels. The combination treatment given chronically also reduced KCl‐induced DA release but enhanced amphetamine‐induced DA release.
Microdialysate DA levels increased to a smaller extent in guinea‐pig than in rat following local striatal infusion of GBR‐12909 (100 μM).
The difference between guinea‐pigs and rats in the response to GBR‐12909, could be the result of a lower dopaminergic innervation and/or density of DA transporter. This difference may explain why striatal microdialysate DA levels increased following chronic deprenyl treatment in the rat but not in the guinea‐pig.

British Journal of Pharmacology (2000) 130, 1992–1998; doi:10.1038/sj.bjp.0703493
Latency to paroxetine‐induced anxiolysis in the rat is reduced by co‐administration of the 5‐HT1A receptor antagonist WAY100635
Authors: Duxon M S , Starr K R , Upton N 
Published: January 2005

We report here the use of rat high‐light social interaction to model the temporal anxiolytic/antidepressant effects of SSRIs seen in the clinic. Compared to vehicle controls, 21, but not 14, days of paroxetine treatment (3 mg kg−1, p.o., daily) produced a marked increase in rat social interaction (Vehicle=71.3±7.3 s; Paroxetine=116.7±14.7 s; P<0.01) with no concurrent effect on locomotor activity, consistent with anxiolysis.
To assess whether concurrent 5‐HT1A receptor blockade reduces the time to onset of anxiolysis seen with paroxetine alone (21 days), rats were implanted with osmotic minipumps to continuously infuse the 5‐HT1A receptor antagonist WAY100635 (1 mg kg−1 day−1, s.c., 7 days) alone or in combination with paroxetine (3 mg kg−1, p.o., daily, 7 days), prior to anxiety testing. Paroxetine (Veh/Par=61.9±7.9 s) or WAY100635 (WAY/Veh=71.6±4.7 s) alone, had no effect on social interaction time compared to vehicle treated controls (Veh/Veh=76.4±4.9 s), whilst coadministration of WAY100635 with paroxetine, produced a marked elevation in social interaction (WAY/Par=149.3±16.8 s; P<0.01) relative to all other groups with no concurrent change in locomotor activity.
In contrast, acute administration of WAY100635 (0.03 mg kg−1, s.c.) with paroxetine (3 mg kg−1, p.o.) did not alter any behavioural measure, suggesting that the anxiolysis induced by the combination after 7 days is attributable to a CNS adaptive response.
This data demonstrates that coadministration of a 5‐HT1A receptor antagonist with paroxetine markedly reduces the latency to anxiolysis, in the rat.
This study supports the use of the rat social interaction test to further delineate adaptive changes in the CNS responsible for the anxiolytic/antidepressant action of SSRIs seen in humans.

British Journal of Pharmacology (2000) 130, 1713–1719; doi:10.1038/sj.bjp.0703496
Characterization of the effects of cannabinoids on guinea‐pig tracheal smooth muscle tone: role in the modulation of acetylcholine release from parasympathetic nerves
Authors: Spicuzza Lucia , Haddad El‐Bdaoui , Birrell Mark , Ling Andrea , Clarke Deborah , Venkatesan Priya , Barnes Peter J , Belvisi Maria G 
Published: January 2005

We investigated the ability of the cannabinoid agonists CP55,940 (CB1/CB2) and anandamide (endogenous cannabinoid) to modulate electrical field stimulation (EFS)‐induced acetylcholine (ACh) release from parasympathetic nerve terminals innervating guinea‐pig trachea. We assessed whether modulation of transmitter release translated to an impact on functional responses by investigating the effect of these agents on contractile responses evoked by EFS and ACh. Furthermore, we evaluated the ability of these compounds to elicit bronchodilation in pre‐contracted guinea‐pig tracheal strips.
CP55,940 and anandamide significantly inhibited EFS‐evoked ACh release (maximal inhibition of 35.1±2.9% and 33.4±6.4% at 1 μM, P<0.05, respectively). The CB1 receptor antagonist SR 141716A (1 μM), had no effect on ACh release and failed to reverse the inhibitory effect of CP55,940 (1 μM).
Paradoxically, CP55,940 had no significant effect on EFS‐evoked cholinergic contractile responses. Furthermore, CP55,940 did not relax pre‐contracted tracheal strips or affect contractile responses to exogenous ACh. This lack of activity on smooth muscle tone is consistent with the fact that no detectable specific binding of [3H] CP55,940 was found in tracheal homogenates.
These data suggest that cannabinoid agonists inhibit ACh release from cholinergic nerve terminals via activation of CB2 receptors but that this inhibitory action does not impact on functional responses such as cholinergic contraction.

British Journal of Pharmacology (2000) 130, 1720–1726; doi:10.1038/sj.bjp.0703497
Selective modifiers of glutathione biosynthesis and ‘repriming’ of vascular smooth muscle photorelaxation
Authors: Megson I L , Holmes Sally A , Magid K S , Pritchard Rebecca J , Flitney F W 
Published: January 2005

Photorelaxation of vascular smooth muscle (VSM) is caused by the release of nitric oxide (NO) from a finite molecular store that can be depleted by irradiating pre‐contracted arteries with visible light. The ability of an ‘exhausted’ vessel to respond to a further period of illumination is lost temporarily but then recovers slowly as the photosensitive store is reconstituted in the dark. The recovery process, termed repriming, displays an absolute requirement for endothelium‐derived NO and is inhibited by pre‐treating arteries with ethacrynic acid, a thiol‐alkylating agent. Here we demonstrate that agents that up‐ or down‐regulate glutathione (GSH) biosynthesis influence the extent to which the store is regenerated in the dark.
Isolated rat tail arteries (RTAs) were perfused internally with Krebs solution containing phenylephrine (PE; mean [PE]±s.e.mean: 5.78±0.46 μM) and periodically exposed to laser light (λ=514.5 nm, 6.3 mW cm−2 for 6 min). Photorelaxations of control RTAs were compared with those from either (a) vessels taken from animals previously injected i.p. with buthionine sulphoximine (BSO), an inhibitor of γ‐glutamylcysteine synthetase (three injections, 100 mg kg−1 at 8 h intervals); or (b) isolated RTAs that were perfused ex vivo with oxothiazolidine (OXO), a precursor of cysteine (10−4 M OXO for 60 min). RTAs from BSO‐treated animals exhibited attenuated photorelaxations: the mean (±s.e.mean) amplitude of the response recorded after 72 min recovery in the dark was 12.4±1.6% versus 21.4±2.9% for control arteries (n=5; P<0.01). Conversely RTAs treated with OXO and allowed to recover for a similar period showed enhanced photorelaxations, 32.6±6.3% as compared to 21.4±2.9% for control arteries (n=5; P<0.01). A hyperbolic curve fit to repriming curves for BSO‐treated and control arteries returned asymptote values (maximum photorelaxations) of (mean±s.e.mean) 24.2±3.2% and 55.2±8.5%, respectively.
The level of GSH in RTA extracts was measured by high‐pressure liquid chromatography (HPLC). Injecting animals with BSO decreased GSH to 85% of control levels (P<0.05) while treatment of isolated vessels with OXO resulted in a 31% increase above control levels (P<0.05). Thus, drug‐induced changes in RTA GSH levels were positively correlated with altered photorelaxations.
The results lead us to postulate that the photosensitive store in VSM is generated, at least in part, from intracellular GSH which becomes converted to S‐nitrosoglutathione (GSNO) by nitrosating species that are formed ultimately from endothelium‐derived NO. The possible physiological significance of a photolabile store of NO in VSM is discussed briefly.

British Journal of Pharmacology (2000) 130, 1575–1580; doi:10.1038/sj.bjp.0703499
Adrenomedullin inhibits spontaneous and bradykinin‐induced but not oxytocin‐ or prostaglandin F2α‐induced periodic contraction of rat uterus
Authors: Yanagita Toshihiko , Yamamoto Ryuichi , Sugano Takashi , Kobayashi Hideyuki , Uezono Yasuhito , Yokoo Hiroki , Shiraishi Seiji , Minami Shin‐ichi , Wada Akihiko 
Published: January 2005

In isolated rat uterine strips, adrenomedullin (AM) inhibited the spontaneous periodic contraction in a concentration‐dependent manner (IC50=22.3±0.7 nM). The inhibitory effect of AM was prevented by either AM22–52, a putative antagonist for AM receptors, or calcitonin gene‐related peptide (CGRP)8–37, a putative antagonist for CGRP receptors. AM also attenuated bradykinin (BK)‐induced periodic uterine contraction, which was blocked by AM22–52 or CGRP8–37, whereas AM had no effect on the periodic contraction caused by oxytocin or prostaglandin F2α (PGF2α). RT–PCR analysis showed that mRNAs for calcitonin receptor‐like receptor (CRLR), receptor‐activity‐modifying protein (RAMP)1, RAMP2 and RAMP3 were expressed in the rat uterus. These results demonstrate that AM selectively inhibits spontaneous and BK‐induced periodic contraction via activating receptors for AM and CGRP.British Journal of Pharmacology (2000) 130, 1727–1730; doi:10.1038/sj.bjp.0703500
Abrogation of lung inflammation in sensitized Stat6‐deficient mice is dependent on the allergen inhalation procedure
Authors: Trifilieff Alexandre , El‐Hasim Ahmed , Corteling Randolph , Owen Charles E 
Published: January 2005

Conflicting results have been reported about the role of Stat6 in allergen‐induced airway inflammation. We have studied the influence of the allergen inhalation procedure on the inflammatory response using wild‐type and Stat6‐deficient mice generated on a C57BL/6 background.
Animals were immunized i.p. on day 0 and 7 with ovalbumin (OVA) and then received aerosolized OVA or phosphate buffer saline challenge (acute on day 14; chronic on day 14, 15, 16, 17 and 18) before being sacrificed at different time points.
Following an acute challenge, Stat6‐deficiency fully abrogated the increase in serum IgE levels and the development of lung inflammation (inflammatory cell infiltration, IL‐4 and IL‐5 release, and increase in plasma leakage).
Following chronic challenge, despite the absence of IgE, IL‐4 and IL‐5, Stat6‐deficient mice develop a characteristic lung inflammation, although the intensity was smaller when compared with the wild‐type mice.
OVA‐induced early bronchoconstriction was observed in wild‐type mice only after chronic challenge, and this was totally abrogated in the Stat6‐deficient animals.
These results suggest that Stat6 signalling is essential for the development of allergic airway inflammation following an acute allergen exposure. However, in a more chronic situation, the airway inflammatory response seems to be only partially mediated by Stat6.

British Journal of Pharmacology (2000) 130, 1581–1588; doi:10.1038/sj.bjp.0703501
Human urotensin‐II is an endothelium‐dependent vasodilator in rat small arteries
Authors: Bottrill Fiona E , Douglas Stephen A , Hiley C Robin , White Richard 
Published: January 2005

The possible role of the endothelium in modulating responses to human urotensin‐II (U‐II) was investigated using isolated segments of rat thoracic aorta, small mesenteric artery, left anterior descending coronary artery and basilar artery.
Human U‐II was a potent vasoconstrictor of endothelium‐intact isolated rat thoracic aorta (EC50=3.5±1.1 nM, Rmax=103±10% of control contraction induced by 60 mM KCl and 1 μM noradrenaline). However the contractile response was not significantly altered by removal of the endothelium or inhibition of nitric oxide synthesis with L‐NAME (100 μM). Human U‐II did not cause relaxation of noradrenaline‐precontracted, endothelium‐intact rat aortae.
Human U‐II contracted endothelium‐intact rat isolated left anterior descending coronary arteries (EC50=1.3±0.8 nM, Rmax=20.1±4.9% of control contraction induced by 10 μM 5‐HT). The contractile response was significantly enhanced by removal of the endothelium (Rmax=55.4±16.1%). Moreover, human U‐II caused concentration‐dependent relaxation of 5‐HT‐precontracted arteries, which was abolished by L‐NAME or removal of the endothelium.
No contractile effects of human U‐II were found in rat small mesenteric arteries. However the peptide caused potent, concentration‐ and endothelium‐dependent relaxations of methoxamine‐precontracted vessels. The relaxant responses were potentiated by L‐NAME (300 μM) but abolished in the additional presence of 25 mM KCl (which inhibits the actions of endothelium‐derived hyperpolarizing factor).
The present study is the first to show that human U‐II is a potent endothelium‐dependent vasodilator in some rat resistance vessels, and acts through release of EDHF as well as nitric oxide. Our findings have also highlighted clear anatomical differences in the responses of different vascular beds to human U‐II which are likely to be important in determining the overall cardiovascular activity of this peptide.

British Journal of Pharmacology (2000) 130, 1865–1870; doi:10.1038/sj.bjp.0703513
Sphingosine‐1‐phosphate reduces rat renal and mesenteric blood flow in vivo in a pertussis toxin‐sensitive manner
Authors: Bischoff Angela , Czyborra Peter , Meyer zu Heringdorf Dagmar , Jakobs Karl H , Michel Martin C 
Published: January 2005

Sphingolipids such as sphingosine‐1‐phosphate (SPP) and sphingosylphosphorylcholine constrict isolated rat intrarenal and mesenteric microvessels in vitro. The present study investigates their effects on the cardiovascular system in vivo in anaesthetized rats.
The animals were given intravenous or intrarenal arterial bolus injections of sphingolipids (0.1–100 μg kg−1) with subsequent measurements of mean arterial pressure, heart rate and renal and mesenteric blood flows (RBF, MBF) using a pressure transducer and electromagnetic flow probes, respectively.
Intravenous injection of SPP rapidly (within 30 s), transiently and dose‐dependently reduced RBF (maximally −4.0±0.3 ml min−1) and MBF (maximally −1.4±0.2 ml min−1), without affecting mean arterial pressure or heart rate. Other sphingolipids had no significant effect.
Intrarenal arterial SPP administration caused greater blood flow reductions (maximally −6.4±0.3 ml min−1) than systemic administration. Upon intrarenal administration, sphingosylphos‐ phorylcholine also lowered RBF (maximally −2.8±0.6 ml min−1), while the other sphingolipids remained without effect.
Pretreatment with pertussis toxin (PTX, 10 μg kg−1) 3 days before the acute experiment abolished the SPP‐induced reductions of RBF and MBF.
These data demonstrate, that SPP is a potent vasoconstrictor in vivo, particularly in the renal vasculature, while the other structurally related sphingolipids had little if any effects. The PTX‐sensitivity strongly suggests that the effects of SPP on renal and mesenteric blood flow are mediated by receptors coupled to Gi‐type G‐proteins.

British Journal of Pharmacology (2000) 130, 1878–1883; doi:10.1038/sj.bjp.0703516
The novel Na+/Ca2+ exchange inhibitor KB‐R7943 also blocks native and expressed neuronal nicotinic receptors
Authors: Pintado Antonio J , Herrero Carlos J , García Antonio G , Montiel Carmen 
Published: January 2005

We studied the effects of the novel Na+/Ca2+ exchange inhibitor KB‐R7943, 2‐[2‐[4‐(4‐nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulphonate, on the native nicotinic receptors present at the bovine adrenal chromaffin cells, as well as on rat brain α3β4 and α7 nicotinic acetylcholine receptors (AChRs) expressed in Xenopus oocytes.
As expected, KB‐R7943 blocked the Na+‐gradient dependent 45Ca2+ uptake into chromaffin cells (IC50 of 5.5 μM); but in addition, the compound also inhibited the 45Ca2+ entry and the increase of cytosolic Ca2+ concentration, [Ca2+]c, stimulated by 5 s pulses of ACh (IC50 of 6.5 and 1.7 μM, respectively).
In oocytes expressing α3β4 and α7 nicotinic AChRs, voltage‐clamped at −60 mV, inward currents elicited by 1 s pulses of 100 μM ACh (IACh) were blocked by KB‐R7943 with an IC50 of 0.4 μM and a Hill coefficient of 0.9.
Blockade of α3β4 currents by KB‐R7943 was noncompetitive; moreover, the blocker (0.3 μM) became more active as the ACh concentration increased (34 versus 66% blockade at 30 μM and 1 mM ACh, respectively).
Inhibition of α3β4 currents by 0.3 μM KB‐R7943 was more pronounced at hyperpolarized potentials. If given within the ACh pulse (10 μM), the inhibition amounted to 33, 64 and 80% in oocytes voltage‐clamped at −40, −60 and −100 mV, respectively. The onset of blockade was faster and the recovery slower at −100 mV; the reverse was true at −40 mV.
In conclusion, KB‐R7943 is a potent blocker of nicotinic AChRs; moreover, it displays many features of an open‐channel blocker at the rat brain α3β4 AChR. These results should be considered when KB‐R7943 is to be used to study Ca2+ homeostasis in cells expressing nicotinic AChRs and the Na+/Ca2+ exchanger.

British Journal of Pharmacology (2000) 130, 1893–1902; doi:10.1038/sj.bjp.0703519
Characterization of prostanoid receptors mediating actions of the isoprostanes, 8‐iso‐PGE2 and 8‐iso‐PGF2α, in some isolated smooth muscle preparations
Authors: Sametz Wolfgang , Hennerbichler Simone , Glaser Sonja , Wintersteiger Reinhold , Juan Heinz 
Published: January 2005

We investigated the contracting actions of the isoprostanes (isoPs), 8‐iso‐prostaglandin (PG) F2α and 8‐iso‐PGE2, in comparison to the effects of the thromboxane (TX) A2‐mimetic U 46619 and the traditional prostaglandin PGE2 in the isolated rat aorta, isolated rat gastric fundus and the isolated guinea‐pig ileum.
U 46619 and 8‐iso‐PGF2α caused contractions in the rat aorta and rat gastric fundus in a concentration‐dependent manner, whereas these agonists showed no effects in the guinea‐pig ileum. However, 8‐iso‐PGE2 and PGE2 caused contractions in all isolated organs used.
The prostanoid TP‐receptor antagonist SQ 29,548 (10 nM) significantly antagonized vasoconstrictions induced by the agonists used in the rat aorta. SQ 29,548 at a final concentration of 3 μM, but not at lower concentrations, significantly inhibited contractions induced by U 46619, 8‐iso‐PGF2α and 8‐iso‐PGE2 in the rat fundus. Responses to PGE2 were unchanged. The prostanoid EP1‐receptor antagonist SC 51089 (3 μM) significantly inhibited contractions induced by 8‐iso‐PGE2 and PGE2 in the rat fundus and in the guinea‐pig ileum. SC 51089 had no effect on responses to any of the agonists tested.
Our results show that 8‐iso‐PGE2, in contrast to 8‐iso‐PGF2α, can also cause contractions by activation of the EP1‐receptors in the rat gastric fundus and the guinea‐pig ileum. The findings of the present study do not support the existence of a unique isoP‐receptor in the tissues used.

British Journal of Pharmacology (2000) 130, 1903–1910; doi:10.1038/sj.bjp.0703522
Gabapentin inhibits excitatory synaptic transmission in the hyperalgesic spinal cord
Authors: Patel Manoj K , Gonzalez M Isabel , Bramwell Steven , Pinnock Robert D , Lee Kevin 
Published: January 2005

In the present study we tested the effects of the antihyperalgesic compound gabapentin on dorsal horn neurones in adult spinal cord. Slices were taken from control and hyperalgesic animals suffering from streptozocin‐induced diabetic neuropathy. At concentrations up to 100 μM, bath application failed to affect the resting membrane properties of dorsal horn neurones taken from both groups of animal. In contrast, bath application of gabapentin dramatically reduced the magnitude of the excitatory postsynaptic current (EPSC) in neurones taken from hyperalgesic animals without altering the magnitude of the EPSC in control animals. Using a paired pulse stimulation protocol, together with analysis of miniature EPSC's, it was possible to demonstrate that gabapentin mediated these effects via a pre‐synaptic site of action.British Journal of Pharmacology (2000) 130, 1731–1734; doi:10.1038/sj.bjp.0703530
Human urotensin‐II is a potent spasmogen of primate airway smooth muscle
Authors: Hay Douglas W P , Luttmann Mark A , Douglas Stephen A 
Published: January 2005

The contractile profile of human urotensin‐II (hU‐II) was examined in primate airway and pulmonary vascular tissues. hU‐II contracted tissues from different airway regions with similar potencies (pD2s from 8.6 to 9.2). However, there were regional differences in the efficacy of hU‐II, with a progressive increase in the maximum contraction from trachea to smaller airway regions (from 9 to 41% of the contraction to 10 μM carbachol). hU‐II potently contracted pulmonary artery tissues from different regions with similar potencies and efficacies: pD2s=8.7 to 9.3 and maximal contractions=79 to 86% of 60 mM KCl. hU‐II potently contracted pulmonary vein preparations taken proximal to the atria, but had no effect in tissues from distal to the atria. This is the first report describing the contractile activity of hU‐II in airways and suggests that the potential pathophysiological role of this peptide in lung diseases warrants investigation.British Journal of Pharmacology (2000) 131, 10–12; doi:10.1038/sj.bjp.0703533