bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory effects of glutamate‐induced activation of thalamic nucleus submedius are mediated by ventrolateral orbital cortex and periaqueductal gray in rats
Authors: Zhang Sun , Tang Jing‐Shi , Yuan Bin , Jia Hong
Published: February 2004

This study found that in lightly‐anesthetized rats a unilateral micro‐injection of glutamate (200 mm, 0.5 μ1) into the thalamic nucleus submedius (Sm) markedly depressed the radiant heat‐evoked tail flick (TF) reflex. After injection, the mean TFL increased 25.6 ± 6.5% (n = 24) of the baseline at 5 min, up to a peak value (48.4 ± 7.2%) at 20 min, and recovered to the baseline level at 60 min. This inhibitory effect was dose‐related and repeatable over a time interval of 1.0–1.5 h in the same animal. Furthermore, micro‐injections of γ‐aminobutyric acid (GABA) (100 mm) into the ipsilateral ventrolateral orbital cortex (VLO) (0.7μl), or bilaterally into the lateral or ventrolateral parts of the periaqueductal gray (PAG) (0.5 μ1 on each side), eliminated the Sm‐evoked inhibition. After GABA was injected into VLO or PAG, the Sm applications of glutamate failed to produce any significant changes in TFL, with the TFL changes being similar to the saline control (p>0.05). These results confirmed our previous findings that electrical stimulation of Sm depressed the rat TF reflex and that this inhibitory effect was blocked by electrolytic lesion of the VLO or PAG. Therefore, the present study provides further support for the hypothesis that Sm plays an important role in modulation of nociception, and that its effects are mediated by the VLO‐PAG pathway, leading to activation of the brainstem descending inhibitory system and depression of the nociceptive inputs at the spinal cord level.
Ectopic mechanosensitivity in injured sensory axons arises from the site of spontaneous electrogenesis
Authors: Chen Y. , Devor M.
Published: February 2004

Injured sensory axons trapped in a neuroma or freely regenerating in the distal nerve stump, frequently display ectopic mechanosensitivity, spontaneous impulse discharge or both. This abnormal neural activity is thought to contribute to spontaneous and movement‐evoked neuropathic paraesthesias, dysaesthesias and pain, as well as to allodynia and hyperalgesia. The present paper examines the relationship between mechanosensitivity and spontaneous discharge in three distinct sciatic nerve injury models in the rat: nerve transection (neuroma), nerve crush and chronic nerve constriction injury (CCI). Impulse pattern analysis was used to determine that the sites of mechanosensitivity and of spontaneous electrogenesis are either identical or very close to one another. This suggests that mechanosensitivity and spontaneous firing are aspects of a single underlying pathophysiological process.
Upside assay sensitivity in a dental pain model
Authors: Breivik E.K. , Haanaes H.R. , Barkvoll P.
Published: February 2004

The extent of surgical trauma was related to postoperative pain intensity in a previous study. However, more extensive surgical procedures with higher baseline pain intensity did not appear to influence the ability to document the additive analgesic effect of codeine when given with paracetamol, partly due to large interindividual variation in baseline pain intensity. The aim of the present study was to attempt to improve upside assay sensitivity in this dental pain model by: (1) selecting patients with high baseline pain intensity; and (2) closer supervision of outpatients' drug intake and compliance with protocol. Only patients with baseline pain ≥ 50 on a 100 mm visual analogue scale after wisdom tooth surgery were included. Twenty patients were given paracetamol 1000 mg with or without codeine 60 mg in repeated doses in a randomized and double‐blind manner. Intake of the first dose of test medication and its effects were closely supervised, while the two following doses were taken at 3‐h intervals after the patient had left the clinic. Pain intensity was measured with the visual analogue scale for 8 h. More pain relief was revealed when codeine 60 mg was added to paracetamol 1000 mg on the following measures of effect: change of pain intensity with time (p<0.05, MannWhitney), sum of pain intensities (p=0.019), pain intensity difference (p≤0.05), sum of pain intensity differences (p<0.05), pain reduction index (p<0.05) and global‐evaluation score (p=0.006).

The study confirms that this dental pain model, when controlled for sufficient and homogeneous baseline pain and patient compliance, does have sufficient upside assay sensitivity to discriminate between paracetamol with and without codeine.
Slider block friction model for landslides: Application to Vaiont and La Clapière landslides
Authors: Helmstetter A. , Sornette D. , Grasso J.‐R. , Andersen J. V. , Gluzman S. , Pisarenko V.
Published: February 2004

Accelerating displacements preceding some catastrophic landslides have been found to display a finite time singularity of the velocity v ∼1/(tc − t) [Voight, 1988a, 1988b]. Here we provide a physical basis for this phenomenological law based on a slider block model using a state‐ and velocity‐dependent friction law established in the laboratory. This physical model accounts for and generalizes Voight's observation: Depending on the ratio B/A of two parameters of the rate and state friction law and on the initial frictional state of the sliding surfaces characterized by a reduced parameter Xi, four possible regimes are found. Two regimes can account for an acceleration of the displacement. For B/A > 1 (velocity weakening) and Xi < 1 the slider block exhibits an unstable acceleration leading to a finite time singularity of the displacement and of the velocity v ∼ 1/(tc − t), thus rationalizing Voight's empirical law. An acceleration of the displacement can also be reproduced in the velocity‐strengthening regime for B/A < 1 and Xi > 1. In this case, the acceleration of the displacement evolves toward a stable sliding with a constant sliding velocity. The two other cases (B/A < 1 and Xi < 1 and B/A > 1 and Xi > 1) give a deceleration of the displacement. We use the slider block friction model to analyze quantitatively the displacement and velocity data preceding two landslides, Vaiont and La Clapière. The Vaiont landslide was the catastrophic culmination of an accelerated slope velocity. La Clapière landslide was characterized by a peak of slope acceleration that followed decades of ongoing accelerating displacements succeeded by a restabilization. Our inversion of the slider block model in these data sets shows good fits and suggests a classification of the Vaiont landslide as belonging to the unstable velocity‐weakening sliding regime and La Clapière landslide as belonging to the stable velocity‐strengthening regime.
Kinematic and dynamic rupture models of the November 3, 2002 Mw7.9 Denali, Alaska, earthquake
Authors: Dreger Douglas S. , Oglesby David D. , Harris Ruth , Ratchkovski Natalia , Hansen Roger
Published: February 2004

Regional seismic waveforms, continuous and campaign‐mode GPS data, and surface slip measurements were used to obtain a kinematic model of the rupture process of the November 3, 2002 Mw 7.9 Denali, Alaska, earthquake. The event initiated as a Mw 7.0 reverse slip event on the north‐dipping Susitna Glacier fault with subsequent right‐lateral slip distributed over approximately 300 km of the Denali fault system. Near‐shear rupture velocity is inferred from the kinematic modeling. The average and maximum slips were found to be 2.14 m and 10.3 m. Static stress drop varies from 1.3 to 5.0 MPa over the 5‐segment fault model. Dynamic modeling shows the rupture propagated along the Susitna Glacier and Denali faults, then transferred to the Totschunda fault before stopping, largely due to the Totschunda's more favorable orientation with respect to the regional stress field.
Thawing sub‐arctic permafrost: Effects on vegetation and methane emissions
Authors: Christensen Torben R. , Johansson Torbjörn , Åkerman H. Jonas , Mastepanov Mihail , Malmer Nils , Friborg Thomas , Crill Patrick , Svensson Bo H.
Published: February 2004

Ecosystems along the 0°C mean annual isotherm are arguably among the most sensitive to changing climate and mires in these regions emit significant amounts of the important greenhouse gas methane (CH4) to the atmosphere. These CH4 emissions are intimately related to temperature and hydrology, and alterations in permafrost coverage, which affect both of those, could have dramatic impacts on the emissions. Using a variety of data and information sources from the same region in subarctic Sweden we show that mire ecosystems are subject to dramatic recent changes in the distribution of permafrost and vegetation. These changes are most likely caused by a warming, which has been observed during recent decades. A detailed study of one mire show that the permafrost and vegetation changes have been associated with increases in landscape scale CH4 emissions in the range of 22–66% over the period 1970 to 2000.
Permeability prediction from thin sections: 3D reconstruction and Lattice‐Boltzmann flow simulation
Authors: Keehm Youngseuk , Mukerji Tapan , Nur Amos
Published: February 2004

We present results and methodology for predicting permeability from thin sections. The method consists of two key components–reconstruction of 3D porous media from 2D thin sections, and 3D flow simulation using the Lattice‐Boltzmann (LB) technique. We construct 3D porous media using sequential indicator simulation (SIS), a geostatistical method, with conditional data and input statistical parameters from thin sections. Permeability is then estimated through flow simulation on the reconstructed porous media. The LB flow simulation successfully handles very complex reconstructed 3D pore geometries. Computed permeabilities from seven thin section samples show good agreement with laboratory measurements over a wide range of permeability. We compare our method to one that uses only thin sections without 3D reconstruction. The comparison shows that our method gives better prediction of permeability, and is less sensitive to statistical errors from discrepancy between thin sections and core samples.
Global seiching of thermocline waters between the Atlantic and the Indian‐Pacific Ocean Basins
Authors: Cessi Paola , Bryan Kirk , Zhang Rong
Published: February 2004

Proxy climate data from the Greenland icecap and marine deposits in the Pacific indicate that warm conditions in the North Atlantic are linked to cool conditions in the Eastern Equatorial Pacific, and vice versa. Our ocean models show that the surface branch of the overturning circulation connecting the North Atlantic to the Equatorial Pacific adjusts by exchanging thermocline water between ocean basins in response to changes in deep water formation in the northern North Atlantic. Planetary ocean waves give rise to a global oceanic seiche, such that the volume of thermocline water decreases in the Pacific‐Indian Ocean while increasing in the Atlantic Ocean. We conjecture that the remotely forced changes in the thermocline of the Eastern Equatorial Pacific may trigger El Niño events. These global seiches have been previously overlooked due to the difficulty of integrating high‐resolution climate models for very long time‐scales.
Atmospheric noble gases in lake sediment pore water as proxies for environmental change
Authors: Brennwald M. S. , Peeters F. , Imboden D. M. , Giralt S. , Hofer M. , Livingstone D. M. , Klump S. , Strassmann K. , Kipfer R.
Published: February 2004

Lake sediment pore water has been proposed as a noble gas archive for paleoenvironmental reconstruction, but appropriate experimental techniques have not been available until recently. Here we present noble gas concentrations measured in the sediment pore water of Lake Issyk‐Kul (Kyrgyzstan) which demonstrate for the first time the value of the sediment pore water archive for paleoclimate reconstruction. The noble gas profiles in the sediment indicate that the salinity of the lake water during the mid‐Holocene was more than twice its present value of 6.0 g/kg, implying a 200‐m lower lake level.
Intermediate depth earthquakes beneath Nelson, New Zealand, and the southwestern termination of the subducted Pacific plate
Authors: Reyners Martin , Robertson Elizabeth de J.
Published: February 2004

There has been debate on how convergence of mantle lithosphere is accommodated during continental collision in the central South Island of New Zealand–whether by intracontinental subduction or continuous deformation of mantle lithosphere. Intermediate depth earthquakes are sparse beneath the central South Island, and abundant seismicity 130–230 km deep within the Hikurangi subduction zone to the northeast ends abruptly beneath the Nelson region of the northern South Island. This termination of seismicity has previously been interpreted as marking the southwestern edge of the subducted slab. Here we investigate the stress and strain regime at this termination of activity, and find that it is very similar to that within the subducted plate both updip and along strike towards the northeast. Our results are consistent with subduction continuing further southwest, albeit largely aseismically, as suggested by shallow earthquakes in the northeastern South Island.
Seasonal development of the properties and composition of landfast sea ice in the Gulf of Finland, the Baltic Sea
Authors: Granskog Mats A. , Leppäranta Matti , Kawamura Toshiyuki , Ehn Jens , Shirasawa Kunio
Published: February 2004

The seasonal development of the structure, salinity, and stable oxygen isotopic composition (δ18O) of landfast sea ice was studied during the winter seasons 1999–2001 in the Gulf of Finland in the Baltic Sea. The main focuses were on the seasonal and the interannual variability in ice properties and composition and on the contribution of meteoric ice to sea ice mass balance. Results provide a first statistical description of the seasonal evolution of sea ice in mild ice climate conditions. The ice has a characteristic structure with an upper granular ice layer, composed almost exclusively of superimposed ice and snow‐ice, averaging at 20–35% of the total ice thickness. The remaining is composed of columnar or intermediate granular columnar ice, depending on growth conditions. While salinity shows a uniform profile through the ice, δ18O shows lower values in the surface because of meteoric ice formation. The thin ice cover is susceptible to changes in atmospheric conditions, and rapid changes in ice salinity are connected to changes in the ice thermal regime and flooding. The contribution of meteoric ice varied from 0 to 35% (by mass), depending on season and year. Superimposed ice formation is a recurring process and significantly contributed to ice growth (up to 20% by mass), especially late in the season during snowmelt‐freeze cycles. Liquid precipitation also cause formation of intermittent superimposed ice layers at these latitudes. The contribution of meteoric ice to sea ice mass balance is largely dependent on the amount and timing of snow accumulation and timing of snowmelt‐freeze processes, which all showed large year‐to‐year variation. The conditions presented here may start to occur at higher latitudes if global warming continues.
Isotopic fractionation of nitrous oxide in the stratosphere: Comparison between model and observations
Authors: Morgan C. G. , Allen M. , Liang M. C. , Shia R. L. , Blake G. A. , Yung Y. L.
Published: February 2004

We investigate the mass dependent isotopic fractionation mechanisms, based on photolytic destruction and reaction with O(1D), to explain the 15N/14N and 18O/16O fractionation of stratospheric N2O and reconcile laboratory experiments with atmospheric observations. The Caltech/JPL two‐dimensional (2‐D) model is utilized for detailed studies of N2O and its isotopologues and isotopomers in the stratosphere. We compare model results with observations of isotopic enrichment using three different methods of calculating photolytic cross‐sections for each of the major isotopologues and isotopomers of N2O. Although the Yung and Miller [1997] successfully modeled the pattern of enrichments for each isotopologue or isotopomer relative to each other, their approach underestimated the magnitude of the enrichments. The ab initio approach by Johnson et al. [2001] provides a better fit to the magnitudes of the enrichments, with the notable exception of the enrichment for the 15N14N16O. A simpler, semi‐empirical approach by Blake et al. [2003] is able to model the magnitude of all the enrichments, including the one for 15N14N16O. The Blake et al. [2003] cross‐sections are temperature‐dependent, but adjustments are needed to match the measurements of Kaiser et al. [2002a]. Using these modified cross‐sections generally improves the agreement between model and mass spectrometric measurements. Destruction of N2O by reaction with O(1D) results in a small but nonnegligible isotopic fractionation in the lower stratosphere. On a per molecule basis, the rates of destruction of the minor isotopologues or isotopomers are somewhat less than that for 14N14N16O. From our 2‐D model we infer the relative rates for isotopologues and isotopomers 14N14N16O (446), 14N15N16O (456), 15N14N16O (546), 14N14N17O (447) and 14N14N18O (448), to be 1, 0.9843, 0.9942, 0.9949, and 0.9900, respectively. Thus the destruction of N2O in the atmosphere results in isotopic fractionations of (456), (546), (447) and (448) by 19.4, 9.5, 5.5 and 12.0‰. If we do not distinguish between the (456) and (546) isotopomers, the mean isotopic fractionation for 15N is 14.5‰. If we assume that the mean tropospheric values for δ456, δ546, δ15N and δ18O are 16.35, −2.35, 7.0 and 20.7‰, respectively, we infer the following isotopic signature for the integrated sources of N2O: δ456 = − 2.9‰, δ546 = −11.7‰, δ15N = −7.3‰ and δ18O = 8.7‰.
Regional model projections of future effects of sulfur and nitrogen deposition on streams in the southern Appalachian Mountains
Authors: Sullivan T. J. , Cosby B. J. , Herlihy A. T. , Webb J. R. , Bulger A. J. , Snyder K. U. , Brewer P. F. , Gilbert E. H. , Moore D. L.
Published: February 2004

We constructed a model‐based evaluation of current and future effects of atmospheric S and N deposition on aquatic resources in the eight‐state southern Appalachian Mountains region. Modeling was conducted with the MAGIC model for about 40 to 50 sites within each of three physiographic provinces, stratified by stream water acid neutralizing capacity (ANC) class. Simulations were based on assumed constant future atmospheric deposition at 1995 levels and on three regional strategies of emissions controls provided by the Southern Appalachian Mountains Initiative (SAMI), based on the Urban to Regional Multiscale One‐Atmosphere model. The National Stream Survey statistical frame was used to estimate the number and percentage of stream reaches in the region that were projected to change their chemistry in response to the emissions control strategies. There was a small decline in the estimated length of projected acidic (ANC ≤ 0) streams in 2040 from the least to the most restrictive emissions control strategy, but there was little difference in projected stream length in the other ANC classes as a consequence of adopting one or another strategy. However, projections of continued future acidification were substantially larger under a scenario in which S and N deposition were held constant into the future at 1995 levels. Model results suggested that the percent of potentially acid‐sensitive streams having chemistry that is chronically unsuitable for brook trout would increase slightly between 1995 and 2040 under all except the most restrictive emissions control strategy.
Identifying and quantifying sources of variability in temporal and spatial soil moisture observations
Authors: Wilson David J. , Western Andrew W. , Grayson Rodger B.
Published: February 2004

Soil moisture is an important component of the hydrological cycle. It is a control in the partitioning of energy and water related to evapotranspiration and runoff and thereby influences the hydrological response of an area. Characterizing the temporal and spatial distribution of soil moisture has important hydrologic applications, yet soil moisture varies in response to many processes acting over a variety of scales; the relative importance of different temporal and spatial controls on soil moisture is still poorly understood. In this paper we analyze both temporal and spatial soil moisture data empirically for two catchments in Australia and a further three in New Zealand. Hydrological conditions at these field sites covered a wide range over a 2 year period. The ground‐based soil moisture data set is unique in its temporal and, in particular, its spatial coverage. Analyses attempt to isolate and quantify different deterministic sources of variability, measurement error, and a remaining unexplained component of variability. Because of limited data (especially relating to soils) we take a pragmatic approach of removing patterns that we can define in time and space (namely, seasonality and terrain) and then analyzing the unexplained variation. We then look for consistent patterns in this unexplained variability and argue that these are related to meteorological conditions, especially precipitation events, in the temporal case, and a combination of soils and vegetation in the spatial case. We were able to explain most of the observed variance in time and space, and the temporal variance was typically 5 times larger than spatial variance. Seasonality is the dominant source of temporal variability at our sites, although this conclusion obviously depends on climate and does not hold where soil water storage is limited. Most importantly, in controlling the distribution of soil moisture in space, the spatial distribution of soils and vegetation seems to be of similar importance to that of topography, a fact often ignored in hydrological modeling, or else surrogate soils patterns are used, but these are often not well correlated to the actual patterns [Grayson and Blöschl, 2000]. Better methods for defining the spatial properties of soils and vegetation as they affect soil moisture patterns are a key challenge.
Role of oxidative stress and nitric oxide in regulation of spontaneous tone in aorta of DOCA‐salt hypertensive rats
Authors: Ghosh Mahua , Wang Hui Di , McNeill J Robert
Published: February 2004

The roles of nitric oxide (NO), superoxide anion (O2−), and hydrogen peroxide (H2O2) in the modulation of spontaneous tone were investigated in isolated aorta from deoxycorticosterone acetate (DOCA)‐salt hypertensive rats.

Increases in preload from 1 to 5 g were accompanied by increases in spontaneous tone in aortic rings from DOCA‐salt hypertensive rats but not from SHAM‐normotensive rats.

Tone was higher in endothelium‐denuded aortic rings than in endothelium‐intact vessels. Inhibition of nitric oxide synthase (NOS) with 300 μM NG‐nitro‐L‐arginine methyl ester (L‐NAME) increased spontaneous tone.

Basal O2− generation was higher in aortic rings from DOCA‐salt hypertensive rats than in those from SHAM‐normotensive rats. Stretch increased O2− levels even further in the DOCA‐salt group. In rings isolated from DOCA‐salt hypertensive rats, administration of the O2− scavenger, superoxide dismutase (SOD, 150 U ml−1), or the nicotinamide adenine dinucleotide phosphate (NADPH)‐oxidase inhibitor, apocynin (100 μM), completely abolished the development of spontaneous tone in endothelium‐intact aortic rings but not in endothelium‐denuded or in L‐NAME‐treated rings. SOD and apocynin decreased the generation of O2− in endothelium‐intact, endothelium‐denuded, and L‐NAME‐treated aortic rings.

Oral treatment of DOCA‐salt hypertensive rats with the O2− scavengers, tempol or tiron, or with apocynin for 3 weeks prevented the development of hypertension and abolished the increases in O2− generation and spontaneous tone.

Administration of catalase (1000 U ml−1) to aortic rings increased spontaneous tone in vessels from DOCA‐salt hypertensive rats.

Administration of the cyclooxygenase (COX) inhibitor, valeroyl salicylate, or the thromboxane/prostaglandin antagonist, SQ 29548, to aortic rings abolished tone.

The results suggest that NO plays a major role in preventing the generation of spontaneous tone in isolated aortic rings from DOCA‐salt hypertensive rats. NADPH‐oxidase‐derived O2− enhanced spontaneous tone by inactivating NO. Endogenous H2O2 appears to mitigate the increase in tone. In addition, a COX component may also contribute to spontaneous tone.

British Journal of Pharmacology (2004) 141, 562–573. doi:10.1038/sj.bjp.0705557
Reduction by gabapentin of K+‐evoked release of [3H]‐glutamate from the caudal trigeminal nucleus of the streptozotocin‐treated rat
Authors: Maneuf Y P , Blake R , Andrews N A , McKnight A T
Published: February 2004

Recently, we showed that gabapentin can inhibit a facilitatory effect of substance P (SP) on K+‐evoked glutamate release in rat trigeminal slices (Maneuf et al., 2001), and we have now examined the effect of gabapentin on glutamate release in the trigeminal slice from the streptozotocin (STZ)‐treated rat.

At 4 weeks following STZ treatment (50 mg kg−1 i.p.), blood glucose was increased in the majority of cases, compared to the control level. All the treated animals showed a significant degree (P<0.001) of tactile allodynia (assessed using von Frey filaments) that did not appear to correlate with blood glucose levels.

In this study, we demonstrated that, after STZ treatment, 30 μM gabapentin reduced K+‐evoked release of [3H]‐glutamate in either normal (11 mM) or high (30 mM) glucose conditions by 24 and 22%, respectively. In the normal rat, gabapentin (up to 100 μM) is ordinarily unable to affect release of glutamate from the trigeminal slice.

The uptake of glutamate in Sp5C punches from streptozotocin‐treated rats was reduced under normal glucose conditions (41.7% of control), whereas high glucose restored uptake to normal (84.7% of control).

The addition of 1 μM substance P potentiated the evoked release of glutamate in both normal (40% increase) and high glucose (28%), and this was blocked by gabapentin (30 μM) in both conditions. It is interesting to speculate that this ability of gabapentin to reduce the release of glutamate in the trigeminal nucleus after streptozotocin treatment may be of relevance to the antihyperalgesic‐allodynic actions of the drug.

British Journal of Pharmacology (2004) 141, 574–579. doi:10.1038/sj.bjp.0705579
Activation of VPAC1 receptors by VIP and PACAP‐27 in human bronchial epithelial cells induces CFTR‐dependent chloride secretion
Authors: Dérand Renaud , Montoni Alicia , Bulteau‐Pignoux Laurence , Janet Thierry , Moreau Bertrand , Muller Jean‐Marc , Becq Frédéric
Published: February 2004

In the human airway epithelium, VIP/PACAP receptors are distributed in nerve fibers and in epithelial cells but their role in transepithelial ion transport have not been reported. Here, we show that human bronchial epithelial Calu‐3 cells expressed the VPAC1 receptor subtype which shares similar high affinity for VIP and PACAP‐27.

The stoichiometric binding parameters characterizing the 125I‐VIP and 125I‐PACAP‐27 binding to these receptors were determined.

We found that VIP (EC50∼7.6 nM) and PACAP‐27 (EC50∼10 nM) stimulated glibenclamide‐sensitive and DIDS‐insensitive iodide efflux in Calu‐3 cells.

The protein kinase A (PKA) inhibitor, H‐89 and the protein kinase C (PKC) inhibitor, chelerythrine chloride prevented activation by both peptides demonstrating that PKA and PKC are part of the signaling pathway. This profile corresponds to the pharmacological signature of CFTR.

In the cystic fibrosis airway epithelial IB3‐1 cell lacking functional CFTR but expressing VPAC1 receptors, neither VIP, PACAP‐27 nor forskolin stimulated chloride transport.

Ussing chamber experiments demonstrated stimulation of CFTR‐dependent short‐circuit currents by VIP or PACAP‐27 applied to the basolateral but not to the apical side of Calu‐3 cells monolayers.

This study shows the stimulation in human bronchial epithelial cells of CFTR‐dependent chloride secretion following activation by VIP and PACAP‐27 of basolateral VPAC1 receptors.

British Journal of Pharmacology (2004) 141, 698–708. doi:10.1038/sj.bjp.0705597
Lymphocyte function antigen‐1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice
Authors: Li Xiang , Klintman Daniel , Weitz‐Schmidt Gabriele , Schramm René , Thorlacius Henrik
Published: February 2004

Sepsis is associated with leukocyte activation and recruitment in the liver. We investigated the role of lymphocyte function antigen‐1 (LFA‐1) in endotoxin‐induced leukocyte–endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene‐targeted mice, blocking antibodies and a synthetic inhibitor of LFA‐1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS)+D‐galactosamine (Gal), and intravital microscopy of the liver microcirculation was conducted 6 h later.

The number of firmly adherent leukocytes in response to LPS/Gal was reduced by 48% in LFA‐1‐deficient mice. Moreover, endotoxin‐induced increases of apoptosis and enzyme markers of hepatocellular injury were decreased by 64 and 69–90%, respectively, in LFA‐1‐deficient mice. Furthermore, sinusoidal perfusion was improved in endotoxemic mice lacking LFA‐1.

A similar protective pattern was observed in endotoxemic mice pretreated with an antibody against LFA‐1. Thus, immunoneutralization of LFA‐1 reduced endotoxin‐induced leukocyte adhesion by 55%, liver enzymes by 64–66% and apoptosis by 42%, in addition to the preservation of microvascular perfusion.

Administration of a novel statin‐derived inhibitor of LFA‐1, LFA703, significantly decreased leukocyte adhesion (more than 56%) and the subsequent liver injury in endotoxemic mice.

Thus, this study demonstrates a pivotal role of LFA‐1 in supporting leukocyte adhesion in the liver. Moreover, interference with LFA‐1‐mediated leukocyte adhesion protects against endotoxemic liver damage, and may constitute a potential therapeutic strategy in sepsis.

British Journal of Pharmacology (2004) 141, 709–716. doi:10.1038/sj.bjp.0705634
Kinin B2 receptor is not involved in enalapril‐induced apoptosis and regression of hypertrophy in spontaneously hypertensive rat aorta: possible role of B1 receptor
Authors: Duguay David , Sarkissian Shant Der , Kouz Rémi , Ongali Brice , Couture Réjean , DeBlois Denis
Published: February 2004

Treatment with enalapril induces smooth muscle cell apoptosis and regression of aortic hypertrophy in spontaneously hypertensive rats (SHRs), whereas combined blockade of angiotensin II AT1 and AT2 receptors does not. We postulated that vascular apoptosis with enalapril involves enhanced half‐life of bradykinin (BK) and kinin B2 receptor stimulation.

SHR, 11‐weeks old, were treated for 4 weeks with enalapril (30 mg kg−1 day−1), Hoe 140 (500 μg kg−1 day−1; B2 receptor antagonist), alone or in combination. Controls received vehicle.

The half‐life of hypotensive responses to intra‐arterial bolus injections of BK were significantly increased in SHR anesthetized after 4 weeks of enalapril, an effect prevented by Hoe 140. The magnitude of BK‐induced hypotension was significantly attenuated in all rats treated with Hoe 140.

As compared to placebo, enalapril treatment significantly reduced blood pressure (−34±2%), aortic hypertrophy (−20±3%), hyperplasia (−37±5%) and DNA synthesis (−61±8%), while it increased aortic DNA fragmentation by two‐fold. Hoe 140 given alone or in combination with enalapril affected none of these parameters.

As a possible alternative mechanism, aortae isolated during the second week of enalapril treatment showed a transient upregulation of contractile responses to des‐Arg9BK (EC50<1 nM), which were significantly reduced by [Leu8]des‐Arg9BK (10 μM). Moreover, in vitro receptor autoradiography revealed an increase in expression of B1 and B2 receptor binding sites by 8–11 days of enalapril treatment.

Aortic apoptosis induction and hypertrophy regression with enalapril do not involve kinin B2 receptors in SHR. Kinins acting via B1 receptors remains a candidate mechanism.

British Journal of Pharmacology (2004) 141, 728–736. doi:10.1038/sj.bjp.0705642
EP4 prostanoid receptor‐mediated vasodilatation of human middle cerebral arteries
Authors: Davis Richard J , Murdoch Colin E , Ali Mozam , Purbrick Stuart , Ravid Rivka , Baxter Gordon S , Tilford Nick , Sheldrick Robert L G , Clark Kenneth L , Coleman Robert A
Published: February 2004

Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E2 (PGE2) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro.

In the presence of indomethacin (3 μM) and the TP receptor antagonist GR32191 (1 μM), PGE2 was found to relax phenylephrine precontracted cerebral arterial rings in a concentration‐dependent manner (mean pEC50 8.0±0.1, n=5).

Establishment of a rank order of potency using the EP4>EP2 agonist 11‐deoxy PGE1, and the EP2>EP4 agonist PGE1‐OH (mean pEC50 of 7.6±0.1 (n=6) and 6.4±0.1 (n=4), respectively), suggested the presence of functional EP4 receptors. Furthermore, the selective EP2 receptor agonist butaprost at concentrations <1 μM failed to relax the tissues.

Blockade of EP4 receptors with the EP4 receptor antagonists AH23848 and EP4A caused significant rightward displacements in PGE2 concentration–response curves, exhibiting pA2 and pKB values of 5.7±0.1, n=3, and 8.4, n=3, respectively.

The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC50 values 8.3±0.1 (n=4) and 8.1±0.1 (n=9), respectively). In contrast, the DP and FP receptor agonists PGD2 and PGF2α failed to cause appreciable relaxation or contraction at concentrations of up to 30 μM. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration‐dependent contraction of cerebral artery (mean pEC50 7.4±0.3, n=3).

These data demonstrate the presence of prostanoid EP4 receptors mediating PGE2 vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.

British Journal of Pharmacology (2004) 141, 580–585. doi:10.1038/sj.bjp.0705645
Potential mechanisms for the enhancement of HERG K+ channel function by phospholipid metabolites
Authors: Wang Jingxiong , Zhang Yiqiang , Wang Huizhen , Han Hong , Nattel Stanley , Yang Baofeng , Wang Zhiguo
Published: February 2004

Phospholipid metabolites lysophospholipids cause extracellular K+ accumulation and action potential shortening with increased risk of arrhythmias during myocardial ischemia. Here we studied effects of several lysophospholipids with different lengths of hydrocarbon chains and charged headgroups on HERG K+ currents (IHERG) expressed in HEK293 cells and the potential mechanisms using whole‐cell patch‐clamp techniques.

Only the lipids with 16 hydrocarbons such as 1‐palmitoyl‐lysophosphatidylcholine (LPC‐16) and 1‐palmitoyl‐lysophosphatidylglycerol (LPG‐16) were found to produce significant enhancement of IHERG and negative shifts of HERG activation, although the voltage dependence of the effects was different between LPC‐16 and LPG‐16 which have differently charged headgroups. The lipid with 18 hydrocarbons modestly increased IHERG. The lipids with 6 or 24 hydrocarbons had no effect or slightly decreased IHERG.

Inhibition or activation of protein kinase C did not alter the effects of LPC‐16 and LPG‐16. Participation of phosphatidylinositol‐4,5‐bisphosphate in IHERG enhancement by LPC‐16/LPG‐16 was also excluded.

Vitamin E augmented the effects of LPC‐16/LPG‐16 whereas xanthine/xanthine oxidase reduced IHERG: indicating that LPC‐16/LPG‐16 produced dual effects on IHERG: direct enhancement of IHERG and indirect suppression via production of superoxide anion.

We conclude that enhancement of HERG function by lysophospholipids is specific to the lipids with 16‐hydrocarbon chain structure and the pattern of voltage dependence is determined by the polar headgroups. The increase in IHERG is best described by direct interactions between lipid molecules and HERG proteins, which is consistent with lack of effects via membrane destabilization or modulation by intracellular signaling pathways.

British Journal of Pharmacology (2004) 141, 586–599. doi:10.1038/sj.bjp.0705646
Comparison of U46619‐, endothelin‐1‐ or phenylephrine‐induced changes in cellular Ca2+ profiles and Ca2+ sensitisation of constriction of pressurised rat resistance arteries
Authors: Shaw Linda , O'Neill Stephen , Jones Carolyn J P , Austin Clare , Taggart Michael J
Published: February 2004

In pressurised rat mesenteric small arteries (50 mmHg), we examined the effects of stimulation with U46619, endothelin‐1 (ET‐1) or phenylephrine (PE) on changes in vessel diameter, global [Ca2+]i, individual smooth muscle cell [Ca2+]i and Ca2+‐sensitisation of contraction.

U46619 or ET‐1 gave tonic diameter reductions, whereas PE‐stimulated vessels gave tonic contractions or initial vasoconstrictions followed by diameter oscillations. Global [Ca2+]i changes were transient for each agonist, with tonic constrictions being accompanied by maintained submaximal global [Ca2+]i levels.

U46619, ET‐1 or PE tonic constrictions were accompanied by apparently asynchronous [Ca2+]i waves in individual smooth muscle cells of the vessel wall, as examined by confocal fluorescent microscopy. In vessels exhibiting vasomotion to PE, some apparent synchrony of activation of individual cells was evident; however, this was incomplete with many cells responding out of phase with their neighbours.

In α‐toxin‐permeabilised preparations, agonist‐induced Ca2+‐sensitisation of constriction at submaximal Ca2+ (pCa6.7) in the presence of GTP was greater with U46619 or ET than PE.

We conclude that, in pressurised mesenteric arteries, (i) a general feature of receptor‐coupled constriction is the generation of periodic smooth muscle [Ca2+]i waves; (ii) complete synchrony of Ca2+ oscillations between smooth muscle cells is not a prerequisite for receptor‐coupled vasomotion; (iii) varied Ca2+‐sensitising actions of agonists may partly determine tonic or phasic vessel responses to different stimuli.

British Journal of Pharmacology (2004) 141, 678–688. doi:10.1038/sj.bjp.0705647
E‐Ring 8‐isoprostanes inhibit ACh release from parasympathetic nerves innervating guinea‐pig trachea through agonism of prostanoid receptors of the EP3‐subtype
Authors: Clarke Deborah L , Giembycz Mark A , Patel Hema J , Belvisi Maria G
Published: February 2004

In the present study, we examined the effect of E‐ring 8‐isoprostanes on cholinergic neurotransmission in guinea‐pig trachea and identified the receptor(s) involved. As isoprostanes are isomeric with prostaglandins, PGE2 and sulprostone (a selective EP3‐receptor agonist) were examined in parallel.

8‐Iso‐PGE1, 8‐iso‐PGE2 (0.1 nM–1 μM), sulprostone (1 nM–1 μM) and PGE2 (1 μM) suppressed EFS‐evoked [3H]ACh release from guinea‐pig trachea in a concentration‐dependent manner, producing 39.5, 53.9, 61.2 and 59.9% inhibition, respectively, at 1 μM. It should be noted that an established maximum effective concentration was not determined.

Neither SQ 29,548 (1 μM; a TP‐receptor antagonist) nor AH 6809 (10 μM; an EP1‐/EP2‐/DP‐receptor antagonist) reversed the inhibitory effect of these compounds.

L‐798,106, a novel and highly selective EP3‐receptor antagonist, produced a parallel shift to the right of the concentration–response curves that described the inhibitory action of sulprostone on EFS‐evoked contractile responses in guinea‐pig vas deferens (an established EP3‐receptor‐expressing tissue), from which a mean pA2 of 7.48 was derived. On guinea‐pig trachea, L‐798,106 also antagonised sulprostone‐induced inhibition of EFS‐induced twitch responses, with similar potency (mean pA2=7.82).

The inhibitory effects of 8‐iso‐PGE1, 8‐iso‐PGE2, sulprostone and PGE2 on EFS‐induced [3H]ACh release was blocked by L‐798,106 at a concentration (10 μM) that binds only weakly to human recombinant EP1‐, EP2‐ and EP4‐receptor subtypes expressed in HEK 293 cells.

These data suggest that E‐ring 8‐isoprostanes, PGE2 and sulprostone inhibit EFS‐evoked [3H]ACh release from cholinergic nerves innervating guinea‐pig trachea, by interacting with prejunctional prostanoid receptors of the EP3‐subtype.

British Journal of Pharmacology (2004) 141, 600–609. doi:10.1038/sj.bjp.0705648
Particular sensitivity to calcium channel blockers of the fast inward voltage‐dependent sodium current involved in the invasive properties of a metastastic breast cancer cell line
Authors: Roger Sébastien , Guennec Jean‐Yves Le , Besson Pierre
Published: February 2004

A voltage‐dependent sodium current has been described in the highly invasive breast cancer cell line MDA‐MB‐231. Its activity is associated with the invasive properties of the cells. The aim of our study was to test whether this current (INa) is sensitive to three representative calcium channel blockers: verapamil, diltiazem and nifedipine. INa was studied in patch‐clamp conditions.

INa was sensitive to verapamil (IC50=37.6±2.5 μM) and diltiazem (53.2±3.6 μM), while it was weakly sensitive to nifedipine.

The tetrodotoxin (TTX) concentration, which fully blocks INa (30 μM), did not affect cell proliferation. Diltiazem and verapamil, at concentrations that do not fully block INa, strongly reduced cell proliferation, suggesting, regarding proliferation, that these molecules act on targets distinct from sodium channels. These targets are probably not other ionic channels, since the current measured at the end of a 500 ms long pulse in the voltage range between −60 and +40 mV was unaffected by verapamil and diltiazem.

We conclude that the sodium channel expressed in MDA‐MB‐231 cells is sensitive to several calcium channel blockers. The present study also underlines the danger of concluding to the possible involvement of membrane channel proteins in any phenomenon on the sole basis of pharmacology, and without an electrophysiological confirmation.

British Journal of Pharmacology (2004) 141, 610–615. doi:10.1038/sj.bjp.0705649
Circadian rhythm of dihydrouracil/uracil ratios in biological fluids: a potential biomarker for dihydropyrimidine dehydrogenase levels
Authors: Jiang Hao , Lu Jing , Ji Jiang
Published: February 2004

In many cancer patients, 5‐fluorouracil (5‐FUra) treatment is toxic and even causes death. Nevertheless, all patients are subjected to a standard therapy regimen because there is no reliable way to identify beforehand those patients who are predisposed to 5‐FUra‐induced toxicity. In this study, we identified the dihydrouracil/uracil (UH2/Ura) ratio in plasma or urine as a potential biomarker reflecting the activity of dihydropyrimidine dehydrogenase (DPD), the rate‐limiting enzyme in 5‐FUra metabolism.

UH2/Ura ratios were measured by high‐performance liquid chromatography tandem triple quadrupole mass spectrometry (HPLC‐MS/MS) in both healthy subjects (n=55) and in patients (n=20) diagnosed with grade I/II gestational trophoblastic tumours. In addition, rats (n=18) were used as an animal model to verify a correlation between UH2/Ura ratios and DPD levels in the liver.

A significant circadian rhythm was observed in UH2/Ura ratios in healthy subjects, whereas a disrupted rhythm occurred in cancer patients who were continuously infused with a high dose of 5‐FUra. In rats, UH2/Ura ratios, liver DPD levels and PBMC DPD levels showed a definite circadian rhythm. Significant linear correlations with liver DPD levels were demonstrated for plasma UH2/Ura ratios (r=0.883, P<0.01), urine UH2/Ura ratios (r=0.832, P<0.01) and PBMC DPD levels (r=0.859, P<0.01).

The UH2/Ura ratio in biological fluid was significantly correlated with liver DPD levels; hence, this ratio could be a potential biomarker to identify patients with a deficiency in DPD.

British Journal of Pharmacology (2004) 141, 616–623. doi:10.1038/sj.bjp.0705651
Characterization of the mouse cold‐menthol receptor TRPM8 and vanilloid receptor type‐1 VR1 using a fluorometric imaging plate reader (FLIPR) assay
Authors: Behrendt H‐J , Germann T , Gillen C , Hatt H , Jostock R
Published: February 2004

TRPM8 (CMR1) is a Ca2+‐permeable channel, which can be activated by low temperatures, menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type‐1 (VR1, TRPV1). We tested whether substances which are structurally related to menthol, or which produce a cooling sensation, could activate TRPM8, and compared the responses of TRPM8 and VR1 to these ligands.

The effects of 70 odorants and menthol‐related substances on recombinant mouse TRPM8 (mTRPM8), expressed in HEK293 cells, were examined using a FLIPR® assay. In all, 10 substances (linalool, geraniol, hydroxycitronellal, WS‐3, WS‐23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists.

The EC50 values of the agonists defined their relative potencies: icilin (0.2±0.1 μM)>FrescolatML (3.3±1.5 μM) > WS‐3 (3.7±1.7 μM) >(−)menthol (4.1±1.3 μM) >frescolatMAG (4.8±1.1 μM) > cooling agent 10 (6±2.2 μM) >(+)menthol (14.4±1.3 μM) > PMD38 (31±1.1 μM) > WS‐23 (44±7.3 μM) > Coolact P (66±20 μM) > geraniol (5.9±1.6 mM) > linalool (6.7±2.0 mM) > eucalyptol (7.7±2.0 mM) > hydroxycitronellal (19.6±2.2 mM).

Known VR1 antagonists (BCTC, thio‐BCTC and capsazepine) were also able to block the response of TRPM8 to menthol (IC50: 0.8±1.0, 3.5±1.1 and 18±1.1 μM, respectively).

The Ca2+ response of hVR1‐transfected HEK293 cells to the endogenous VR1 agonist N‐arachidonoyl‐dopamine was potentiated by low pH. In contrast, menthol‐ and icilin‐activated TRPM8 currents were suppressed by low pH.

In conclusion, in the present study, we identified 10 new agonists and three antagonists of TRPM8. We found that, in contrast to VR1, TRPM8 is inhibited rather than potentiated by protons.

British Journal of Pharmacology (2004) 141, 737–745. doi:10.1038/sj.bjp.0705652
Nicotine attenuates β‐amyloid peptide‐induced neurotoxicity, free radical and calcium accumulation in hippocampal neuronal cultures
Authors: Liu Qiang , Zhao Baolu
Published: February 2004

Recent studies indicate that neuronal loss in Alzheimer's disease (AD) is accompanied by the deposition of β‐amyloid protein (Aβ) in senile plaques. Nicotine as a major component of cigarette smoke has been suggested to have a protective effect for neurons against Aβ neurotoxicity.

Our present study demonstrates that nicotine protected cultured hippocampal neurons against the Aβ‐induced apoptosis. Nicotine effectively inhibits apoptosis in hippocampal cultures caused by Aβ25–35 or Aβ1–40 treatment and increase of caspase activity induced by Aβ25–35 or Aβ1–40.

Measurements of cellular oxidation and intracellular free Ca2+ showed that nicotine suppressed Aβ‐induced accumulation of free radical and increase of intracellular free Ca2+.

Cholinergic antagonist mecamylamine inhibited nicotine‐induced protection against Aβ‐induced caspase‐3 activation and ROS accumulation.

The data show that the protection of nicotine is partly via nicotinic receptors. Our results suggest that nicotine may be beneficial in retarding the neurodegenerative diseases such as AD.

British Journal of Pharmacology (2004) 141, 746–754. doi:10.1038/sj.bjp.0705653