bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling the impact of Trichodesmium and nitrogen fixation in the Atlantic Ocean
Authors: Coles Victoria J. , Hood Raleigh R. , Pascual Mercedes , Capone Douglas G.
Published: June 2004

In this paper we use a biological‐physical model with an explicit representation of Trichodesmium to examine the influence of N2 fixation in the Atlantic. Three solutions are examined, one where the N2 fixation rate has been set to observed levels, one where the rate has been increased to levels comparable to geochemical estimates, and one with no N2 fixation. All solutions are tuned to reproduce satellite surface chlorophyll concentrations, so that differences in the runs are manifested in productivity and export. Model runs with N2 fixation have different phytoplankton production and export distributions than runs without. Over the Atlantic basin the ecosystem “fixes” nitrogen at the rate of 1.47 × 1012 mol N yr−1, when tuned to observed phytoplankton and Trichodesmium biomass. This rate is comparable to the lower range of direct estimates of 1.3–2.2 × 1012mol N yr−1 [Capone et al., 1997; J. N. Galloway et al., manuscript in preparation, 2003; D. Capone et al., New nitrogen input in the tropical North Atlantic Ocean by nitrogen fixation, submitted to Nature, 2004, hereinafter referred to as Capone et al., submitted manuscript, 2004] but less than geochemical indirect estimates over a reduced domain (2.0 × 1012 mol N yr−1 [Gruber and Sarmiento, 1997] versus 0.55 × 1012 mol N yr−1 for the model). The nitrogen from N2 fixation increases new production by 30% and total production by 5%. However, it does not supplement upwelled nitrate sufficiently to bring production and export into line with remote sensing and geochemically derived estimates. Simulations with N2 fixation rates comparable to geochemical estimates show that reasonable phytoplankton concentrations can be maintained if export is increased. Moreover, phytoplankton productivity increases to values approaching remote‐sensing‐based estimates in the oligotrophic ocean. However, Trichodesmium biomass may be higher than observed.
Observations of tidal variability on the New England shelf
Authors: Shearman R. Kipp , Lentz Steven J.
Published: June 2004

Observations from the Coastal Mixing and Optics experiment moored array, deployed from August 1996 through June 1997, are used to describe barotropic and baroclinic tidal variability over the New England shelf. The dominant M2 tidal elevations decrease toward the northeast to a minimum over the Nantucket shoals (about 34 cm), and barotropic tidal current amplitudes increase strongly toward the northeast to a maximum over the shoals (about 35 cm s−1). Estimates of the depth‐averaged M2 momentum balance indicate that tidal dynamics are linear, and along‐shelf pressure gradients are as large as cross‐shelf pressure gradients. In addition, tidal current ellipses are weakly polarized, confirming that the dynamics are more complex than simple plane waves. The vertical structure of the M2 currents decreases in amplitude and phase (phase lead near bottom) over the bottom 20 m. The M2 momentum deficit near the bottom approximately matches direct covariance estimates of stress, confirming the effects of stress on current structure in the tidally driven bottom boundary layer. Baroclinic current variability at tidal frequencies is small (2 cm s−1 amplitude), with a predominantly mode 1 vertical structure. High‐frequency (approaching the buoyancy frequency) internal solitons are observed following the pycnocline. The internal solitons switch from waves of depression to waves of elevation when the depth of maximum stratification is deeper than half the water column depth. Both low‐mode baroclinic tidal and high‐frequency internal wave energy decrease linearly with bottom depth across the shelf.
Enhanced uptake of atmospheric CO2 during freezing of seawater: A field study in Storfjorden, Svalbard
Authors: Anderson Leif G. , Falck Eva , Jones E. Peter , Jutterström Sara , Swift Jim H.
Published: June 2004

The waters of Storfjorden, a fjord in southern Svalbard, were investigated in late April 2002. The temperature was at the freezing point throughout the water column; the salinity in the top 30 m was just above 34.8, then increased nearly linearly to about 35.8 at the bottom. Nutrient and oxygen concentrations showed a minimal trend all through the water column, indicating minimal decay of organic matter. Normalized dissolved inorganic carbon, fCO2, and CFCs increase with depth below the surface mixed layer, while pH decreases. In waters below 50 m, there was an increase in dissolved inorganic carbon, corrected for decay of organic matter using the phosphate profile, corresponding to about 9 g C m−2 relative to the surface water concentration. We suggest this excess is a result of enhanced air‐sea exchange of CO2 caused by sea ice formation. This enhancement is suggested to be a result of an efficient exchange through the surface film during the ice crystal formation and the rapid transport of the high salinity brine out of the surface layer.
Deposition and recirculation of tritium in the North Pacific Ocean
Authors: Stark Sheila , Jenkins William J. , Doney Scott C.
Published: June 2004

Tritium data, primarily from the GEOSECS and WOCE cruises of the 1970s and 1990s, are used to estimate the time‐evolving 3H inventory of the North Pacific basin. In the years between the two surveys, there have been changes both laterally and vertically in the distribution of 3H in the North Pacific that reflect the mean circulation and exchanges of the basin. We develop a simple multibox model of the shallow circulation of the North Pacific to explore the long‐term redistribution and changes in 3H inventories within the basin. To do this, we derived a new estimate of the delivery of bomb 3H to the North Pacific by precipitation for the period 1960–1997 and include other minor sources such as rivers. Vapor deposition dominates over direct precipitation of tritium to the basin, while inputs from continental runoff and the inflow from the south contribute over an order of magnitude less. The model predicted tritium budget of 25.1 ± 3.3 kg compares well with the estimated WOCE inventory of 23.4 ± 2.0 kg. We explore in detail the sensitivity of the budget calculations to model circulation and assumptions, as well as uncertainties in observations. We find that the ratio of tritium in vapor to that in precipitation is the most sensitive variable in the model budget, and the basin tritium inventory is consistent with a vapor‐to‐precipitation ratio of 0.67 (range 0.60–0.74), predictably somewhat less than the isotopic equilibrium value of 0.89. An inverse calculation shows that despite uncertainties in the tritium source function, the data also help constrain aspects of the basin circulation, including the Indonesian Throughflow.
Geometrical constraints on the evolution of ridged sea ice
Authors: Amundrud Trisha L. , Melling Humfrey , Ingram R. Grant
Published: June 2004

A numerical model of the evolving draft distribution of seasonal pack ice is driven by freezing and ice field compression in one dimension. Spatial transects of sea ice draft acquired during winter in the Beaufort Sea are used to evaluate the model. Histograms obtained by ice‐profiling sonar on subsea moorings reveal changes in the draft distribution, while observations of ice velocity by Doppler sonar allow calculation of the strain to which the draft distribution is responding. Numerical diffusion in thermal ice growth is controlled using a remapping algorithm. Mechanical redistribution algorithms in common use generate much more deep ridged ice than is observed. Geometric constraints on ridge‐keel development that reflect the finite extent of level floes available for ridge building and the true average shape of keels produce more realistic results. In the seasonal pack ice of the Beaufort Sea, 75% of all floes are too small to provide a volume of ice sufficient to construct a keel of draft equal to that commonly assumed in ice dynamics modeling. On average, the distribution of draft within keels has a negative exponential form, implying a cusped keel shape with more area on the thinner flanks than at the crest; models commonly assume a uniform redistribution of ice into a keel of triangular shape. Clearly, the spatial organization of ice within seasonal pack or, equivalently, the existence of ridges and floes should be an acknowledged factor in redistribution theory for pack ice thickness.
Radiation transport within oceanic (case 1) water
Authors: Morel André , Gentili Bernard
Published: June 2004

A spectral model of the inherent optical properties (IOP) of oceanic case 1 waters, as previously developed for studying the near‐surface bidirectional reflectance, provides the input parameters for the present computations of radiative transport (RT), now extended throughout the water column (three times the euphotic zone). All spectral apparent optical properties (AOP) are computed at each of the levels (30) for six chlorophyll values (from 0.03 to 10 mg m−3) and for six values of the zenith Sun angle (from 0° to 75°). The Raman emission is accounted for. From the irradiances and radiances values the various attenuation coefficients (K), the average cosines (), and the reflectance (R) are derived for all depths and layers. Their variations resulting from the Sun's position are also studied, which removes the static character of previous empirical models inasmuch as the diurnal changes of the parameters describing the in‐water light field can be predicted. The AOPs observed within the deepest levels are also compared to values independently derived from an asymptotic (iterative) solution of the RT. The rate of approach to the asymptotic regime is numerically analyzed; this rate is actually governed by τb, i.e., this fraction of τ (the optical thickness) that corresponds only to scattering. Practical applications of these systematic computations are examined, such as the change (with solar position) of the euphotic depth, the time‐ and wavelength‐dependent scalar irradiance that controls during the day the energy available for photosynthesis (or the heating rate), and the interpretation of radiometric field experiments involving upward and downward irradiance measurements. Some approximate expressions relating AOPs to IOPs are examined in the light of exact computations.
Current state of modeling the photochemistry of Titan's mutually dependent atmosphere and ionosphere
Authors: Wilson E. H. , Atreya S. K.
Published: June 2004

In the context of recent observations, microphysical models, and laboratory data, a photochemical model of Titan's atmosphere, including updated chemistry focusing on rate coefficients and cross sections measured under appropriate conditions, has been developed to increase understanding of these processes and improve upon previous Titan photochemical models. The model employs a two‐stream discrete ordinates method to characterize the transfer of solar radiation, and the effects of electron‐impact, cosmic‐ray deposition, and aerosol opacities from fractal and Mie particles are analyzed. Sensitivity studies demonstrate that an eddy diffusion profile with a homopause level of 850 km and a methane stratospheric mole fraction of 2.2% provides the best fit of stratospheric and upper atmosphere observations and an improved fit over previous Titan photochemical models. Lack of fits for C3H8, HC3N, and possibly C2H3CN can be resolved with adjustments in aerosol opacity. The model presents a benzene profile consistent with its detection in Titan's stratosphere [Coustenis et al., 2003], which may play an important role in the formation of Titan hazes. An electron peak concentration of 4200 cm−3 is calculated, which exceeds observations by 20%, considerably lower than previous ionosphere models. With adjustments in aerosol opacities and surface fluxes the model illustrates that reasonable fits to existing observations are possible with a single eddy diffusion profile, contrary to the conclusions of previous Titan models. These results will aid in the receipt and interpretation of data from Cassini‐Huygens, which will arrive at Titan in 2004 and deploy a probe into Titan's atmosphere in January 2005.
Laboratory studies of formation of molecules on dust grain analogues under ISM conditions
Authors: Vidali G. , Roser J. E. , Manicó G. , Pirronello V.
Published: June 2004

Certain important molecules of the interstellar medium (ISM), such as H2 and CO2, are believed to have been formed on surfaces of dust grains. We describe experimental methods that we used to study the formation of H2 and CO2 on dust grain analogues in conditions approximating the ones found in key interstellar environments. By using state‐of‐the‐art surface science techniques we obtained information on the efficiency of the molecular formation reactions, the reaction kinetics, and the reaction dynamics. Selected results are presented on the formation of molecular hydrogen on surfaces of silicates, amorphous carbon, and amorphous ice and on the synthesis of carbon dioxide. We then briefly show how these results have been applied to the quantitative determination of processes occurring in the ISM.
Characteristics of the convergence zone at the eastern edge of the Pacific warm pool
Authors: Maes Christophe , Picaut Joël , Kuroda Yoshifumi , Ando Kentaro
Published: June 2004

The characteristics of the convergence zone at the eastern edge of the equatorial Pacific warm pool are studied using a compilation of in‐situ current and salinity measurements during the period 1992–2001. The displacement of the convergence zone is observed, for the first time, as far west as 140°E in the far western Pacific, mainly during La Niña periods, and near 140°W in the central Pacific during the 1997–98 El Niño. The convergence zone may be associated with a salinity front dividing the fresh waters of the warm pool from the salty waters upwelled in the central equatorial Pacific. Despite a zonal displacement ranging over about one fifth of the equatorial circumference of the earth, the characteristics of the main parameters involved in the air‐sea interactions are nearly constant on each side of the convergence zone/salinity front. These results suggest that coupled models used for El Niño research and forecasting should be able to reproduce these important features.
Soil moisture as an indicator of weather extremes
Authors: Lakshmi Venkat , Piechota Thomas , Narayan Ujjwal , Tang Chunling
Published: June 2004

In this paper, we investigate floods and droughts in the Upper Mississippi basin over a 50‐year period (1950–1999) using a hydrological model (Variable Infiltration Capacity Model – 3 Layer). Simulations have been carried out between January 1950 and December 1999 at daily time‐step and 1/8° spatial resolution for the water budget and at hourly time‐step and 1° spatial resolution for the energy balance. This paper will provide valuable insights to the slow response components of the hydrological cycle and its diagnostic/predictive value in the case of floods and droughts. The paper compares the use of the Palmer Drought Severity Index against the anomalies of the third layer soil moisture for characterizing droughts and floods. Wavelet and coherency analysis is performed on the soil moisture, river discharge, precipitation and PDSI time series confirm our hypothesis of a strong relationship between droughts and the third layer soil moisture.
Effect of adrenalectomy and corticosterone replacement on prepulse inhibition and locomotor activity in mice
Authors: Van Den Buuse Maarten , Morris Margaret , Chavez Carolina , Martin Sally , Wang JianHong
Published: June 2004

Stress is a risk factor in psychiatric illnesses such as schizophrenia. The aim of the present study was to investigate the effect of different circulating levels of the adrenal steroid corticosterone (CORT) on locomotor hyperactivity and prepulse inhibition of acoustic startle, two behavioural animal models of aspects of schizophrenia.

Male C57BL/6J mice (n=10 per group) were anaesthetised with isoflurane and sham‐operated or adrenalectomised (ADX). ADX mice were implanted with 50 mg pellets consisting of 100% cholesterol, or 2, 10 or 50 mg of CORT mixed with cholesterol. CORT pellet implantation dose dependently increased plasma CORT levels 3 weeks after surgery. Starting 1 week after surgery, mice were tested for prepulse inhibition after injection of saline or 5 mg kg−1 of haloperidol.

In intact mice and in mice implanted with 10 mg of CORT, haloperidol treatment significantly increased prepulse inhibition (average values from 38 – 42 to 52%). Similar results were observed when testing the mice for amphetamine‐induced locomotor hyperactivity (5 mg kg−1). In contrast, there was no significant effect of haloperidol in mice implanted either with cholesterol or 2 or 50 mg of CORT.

These results in behavioural animal models of schizophrenia suggest an important role of the stress hormone CORT in modulating dopaminergic activity in this illness.

British Journal of Pharmacology (2004) 142, 543–550. doi:10.1038/sj.bjp.0705511
Protective effect of edaravone against hypoxia–reoxygenation injury in rabbit cardiomyocytes
Authors: Yamawaki Masahiro , Sasaki Norihito , Shimoyama Masaki , Miake Junichiro , Ogino Kazuhide , Igawa Osamu , Tajima Fumito , Shigemasa Chiaki , Hisatome Ichiro
Published: June 2004

We examined whether edaravone (Eda), a clinically available radical scavenger, directly protects cardiomyocytes from ischemia/reperfusion (I/R) injury, and whether the timing of its application is critical for protection.

Cardioprotective effects of edaravone were tested in the modified cell‐pelleting model of ischemia and under exogenous oxidative stress (hydrogen peroxide: H2O2) in isolated adult rabbit ventricular cells. Cell death and reactive oxygen species (ROS) generation were detected using propidium iodide (PI) and DCFH‐DA, respectively. These parameters were evaluated objectively using flow cytometory.

Hypoxia and reoxygenation aggravated the proportion of dead cells from 32.2±1.8% (Baseline) to 51.3±2.7% (Control). When 15 μM edaravone was applied either throughout the entire experiment (Through) or only at reoxygenation (Reox), cell death was significantly reduced to 39.9±1.8% (P<0.01 vs Control) and 43.3±2.5% (P<0.05 vs Control), respectively. In contrast, when edaravone was applied 10 min after reoxygenation, its protective effect disappeared. Cardioprotection by edaravone was more remarkable than that afforded by other free radical scavengers, such as ascorbate and superoxide dismutase (SOD). There is a positive correlation between the cardioprotective effect of edaravone and the extent of ROS reduction.

Edaravone blunted the H2O2‐induced changes in electrical properties, and significantly prolonged the time to contracture induced by H2O2 in single ventricular myocytes.

Taken together, edaravone directly protects cardiomyocytes from I/R injury by attenuating ROS production, even when applied at the time of reoxygenation, suggesting that edaravone could be a potent cardioprotective therapeutic agent against hypoxia–reoxygenation injury.

British Journal of Pharmacology (2004) 142, 618–626. doi:10.1038/sj.bjp.0705775
LNP 906, the first high‐affinity photoaffinity ligand selective for I1 imidazoline receptors
Authors: Dragan Urosevic , Stephan Schann , Jean‐Daniel Ehrhardt , Pascal Bousquet , Hugues Greney
Published: June 2004

The hypotensive effect of imidazoline‐like drugs, such as clonidine, was attributed both to α2‐adrenergic receptors and nonadrenergic imidazoline receptors, which are divided into I1, I2 and I3 subtypes.

We have recently synthesized a derivative of (2‐(2‐chloro‐4‐iodo‐phenylamino)‐5‐methyl‐pyrroline (LNP 911), the first high‐affinity and selective ligand for I1 receptors (I1R), with a photoactivable function (LNP 906).

This work aims to test whether this derivative retained the binding properties of LNP 911 and bound irreversibly to I1R.

Binding studies showed that LNP 906 exhibited nanomolar affinity for I1R and was selective for I1R over I2 receptors and α2‐adrenergic receptors (α2Ars).

Upon exposure to u.v. light, LNP 906 irreversibly blocked the binding of [125I]‐paraiodoclonidine (PIC) to I1R, time‐ and dose‐dependently, on PC12 cell membranes and interacted with I1R in a reversible and competitive manner in the absence of light. Pharmacological studies showed that this blockade was prevented by the concomitant presence of rilmenidine (a well‐known I1 agonist), but not by rauwolscine (an α2 antagonist).

Finally, LNP 906 clearly antagonized the decrease in forskolin‐stimulated cAMP level induced by rilmenidine, but not by melatonin.

These results indicate that LNP 906 is the first high‐affinity and selective photoaffinity ligand for I1R and that it behaves as an I1R antagonist.

British Journal of Pharmacology (2004) 142, 609–617. doi:10.1038/sj.bjp.0705784
Functional M3 muscarinic acetylcholine receptors in mammalian hearts
Authors: Wang Zhiguo , Shi Hong , Wang Huizhen
Published: June 2004

In contrast to most peripheral tissues where multiple subtypes of muscarinic acetylcholine receptor (mAChR) coexist, with each of them playing its part in the orchestra of parasympathetic innervation, the myocardium has been traditionally considered to possess a single mAChR subtype. Although there is much evidence to support the notion that one receptor subtype (M2) orchestrates myocardial muscarinic transduction, there is emerging evidence that M1 and M3 receptors are also expressed and are of potential physiological, pathophysiological and pharmacological relevance. Clarifying this issue has a profound impact on our thinking about the cholinergic control of the heart function and disease and approaches to new drug development for the treatment of heart disease associated with parasympathetic dysfunction. This review article presents evidence for the presence of the M3 receptor subtype in the heart, and analyzes the controversial data from published pharmacological, functional and molecular studies. The potential roles of the M3 receptors, in parasympathetic control of heart function under normal physiological conditions and in heart failure, myocardial ischemia and arrhythmias, are discussed. On the basis of these considerations, we have made some proposals concerning the future of myocardial M3 receptor research.

British Journal of Pharmacology (2004) 142, 395–408. doi:10.1038/sj.bjp.0705787
Influence of sodium substitutes on 5‐HT‐mediated effects at mouse 5‐HT3 receptors
Authors: Barann M , Schmidt K , Göthert M , Urban B W , Bönisch H
Published: June 2004

The influence of sodium ion substitutes on the 5‐hydroxytryptamine (5‐HT)‐induced flux of the organic cation [14C]guanidinium through the ion channel of the mouse 5‐HT3 receptor and on the competition of 5‐HT with the selective 5‐HT3 receptor antagonist [3H]GR 65630 was studied, unless stated otherwise, in mouse neuroblastoma N1E‐115 cells.

Under physiological conditions (135 mM sodium), 5‐HT induced a concentration‐dependent [14C]guanidinium influx with an EC50 (1.3 μM) similar to that in electrophysiological studies.

The stepwise replacement of sodium by increasing concentrations of the organic cation hydroxyethyl trimethylammonium (choline) concentration dependently caused both a rightward shift of the 5‐HT concentration–response curve and an increase in the maximum effect of 5‐HT. Complete replacement of sodium resulted in a 34‐fold lower potency of 5‐HT and an almost two times higher maximal response. A low potency of 5‐HT in choline buffer was also observed in other 5‐HT3 receptor‐expressing rodent cell lines (NG 108‐15 or NCB 20).

Replacement of Na+ by Li+ left the potency and maximal effects of 5‐HT almost unchanged. Replacement by tris (hydroxymethyl) methylamine (Tris), tetramethylammonium (TMA) or N‐methyl‐D‐glucamine (NMDG) caused an increase in maximal response to 5‐HT similar to that caused by choline. The potency of 5‐HT was only slightly reduced by Tris, to a high degree decreased by TMA (comparable to the decrease by choline), but not influenced by NMDG.

The potency of 5‐HT in inhibiting [3H]GR65630 binding to intact cells was 35‐fold lower when sodium was completely replaced by choline, but remained unchanged after replacement by NMDG.

The results are compatible with the suggestion that choline competes with 5‐HT for the 5‐HT3 receptor; the increase in maximal response may be partly due to a choline‐mediated delay of the 5‐HT‐induced desensitization. For studies of 5‐HT‐evoked [14C]guanidinium flux through 5‐HT3 receptor channels, NMDG appears to be an ‘ideal’ sodium substituent since it increases the signal‐to‐noise ratio without interfering with 5‐HT binding.

British Journal of Pharmacology (2004) 142, 501–508. doi:10.1038/sj.bjp.0705788
Noladin ether, a putative endocannabinoid, attenuates sensory neurotransmission in the rat isolated mesenteric arterial bed via a non‐CB1/CB2 Gi/o linked receptor
Authors: Duncan Marnie , Millns Paul , Smart Darren , Wright James E , Kendall David A , Ralevic Vera
Published: June 2004

Noladin ether has recently been reported to be an endocannabinoid, with selectivity for the cannabinoid (CB) CB1 receptor. In the present study, we investigated the effects of noladin ether in the rat isolated mesenteric arterial bed, cultured dorsal root ganglia (DRG) cells and human vanilloid (TRPV1)‐receptor‐expressing HEK293 cells (TRPV1‐HEK293 cells).

Electrical field stimulation of the mesenteric bed evoked frequency‐dependent vasorelaxation due to the action of calcitonin gene‐related peptide (CGRP) released from sensory nerves. Noladin ether (0.1–3 μM) attenuated sensory neurogenic relaxation in a concentration‐dependent manner. Noladin ether (1 μM) reduced vasorelaxation at a submaximal frequency (8 Hz), from 57.3±6.8 to 23.3±3.8% (P<0.05, n=4).

The inhibitory effects of noladin ether were unaffected by the CB1 antagonists SR141716A and LY320135, and the CB2 antagonist SR144528 (1 μM).

Noladin ether had no effect on vasorelaxation elicited by exogenous CGRP or capsaicin. These data suggest that noladin ether is acting at a prejunctional site and no interaction with TRPV1 is involved.

In mesenteric beds from pertussis toxin (PTX)‐pretreated rats, the inhibitory actions of noladin ether on sensory neurotransmission were abolished, indicating the involvement of Gi/o protein‐coupled receptors.

Noladin ether evoked a concentration‐dependent increase in intracellular Ca2+ concentration in TRPV1‐HEK293 cells at 10 μM (36.5±3.2% of maximal capsaicin‐induced response), but it was a less potent agonist than both capsaicin and anandamide and at 1 μM it was essentially inactive. Noladin ether (1 μM) had no effect on capsaicin‐evoked Ca2+ responses in DRG cells, and produced no response alone, indicating it neither modulates nor acts directly on TRPV1 receptors.

These data demonstrate that noladin ether attenuates sensory neurotransmission in rat mesenteric arteries via a non‐CB1 non‐CB2 PTX‐sensitive prejunctional site, independently of TRPV1 receptors.

British Journal of Pharmacology (2004) 142, 509–518. doi:10.1038/sj.bjp.0705789
Investigation of the effects of P2 purinoceptor ligands on the micturition reflex in female urethane‐anaesthetized rats
Authors: King Brian F , Knowles Ian D , Burnstock Geoffrey , Ramage Andrew G
Published: June 2004

The effects of purinoceptor ligands for P2X1 and/or P2X3 receptors (α,β‐meATP, IP5I, TNP‐ATP, MRS 2179, PPADS, Phenol red and RO116‐6446/008; i.v., n=4–5) and for P2Y1 receptors (PPADS, MRS 2179 and MRS 2269; i.v., n=3–5) were investigated on the distension‐evoked ‘micturition reflex’ in the urethane‐anaesthetized female rat.

α,β‐meATP (180 nmol kg−1 min−1), IP5I (10, 30 and 100 nmol kg−1), TNP‐ATP (1 μmol kg−1), MRS 2179 (1 μmol kg−1) and PPADS (17 μmol kg−1) each caused maintained bladder contractions to occur during the infusion of saline into the bladder. PPADS (17 μmol kg−1 min−1) had a similar effect when infused intravesicularly. Regular bladder contractions were not observed until the infusion of saline was halted. For IP5I, TNP‐ATP, MRS 2179 and PPADS, the magnitude of postinfusion isovolumetric contractions was significantly reduced and, for IP5I, this action was also associated with a significant reduction in urethral relaxation. Additionally, TNP‐ATP caused a significant increase in the pressure and volume thresholds required to initiate a reflex.

Phenol red (a P2X1/P2X3 antagonist; 0.1 and 1 μmol kg−1) caused a significant increase in the pressure and volume thresholds required to initiate a reflex and, at the higher dose, also caused a reduction in postinfusion isovolumetric contractions.

RO116‐6446/008 (a P2X1‐selective antagonist; 1 and 10 μmol kg−1) only caused a reduction in postinfusion isovolumetric contractions.

It is concluded that P2X1 and P2X3 receptors play a fundamental role in the micturition reflex in urethane‐anesthetized female rats. P2X3 receptor blockade raised the pressure and volume thresholds for the reflex, whereas P2X1 receptor blockade diminished motor activity associated with voiding. P2Y1 receptors may be involved in inhibition of rat detrusor tone.

British Journal of Pharmacology (2004) 142, 519–530. doi:10.1038/sj.bjp.0705790
NO and KATP channels underlie endotoxin‐induced smooth muscle hyperpolarization in rat mesenteric resistance arteries
Authors: Wu C C , Chen S J , Garland C J
Published: June 2004

Smooth muscle membrane potential and tension measurements were made in isolated mesenteric resistance arteries from rats exposed to bacterial endotoxin (lipopolysaccharide, LPS; 10 mg kg−1, i.p.) for 3 h to mimic septic shock syndrome.

Over this period, rats developed an endotoxaemic response, assessed in vivo as a 41±4 mmHg drop in mean blood pressure, vascular hyporeactivity to noradrenaline (1 μg kg−1, i.v.) and a significant increase in core body temperature.

In mesenteric small resistance arteries from these rats (o.d. 180 – 240 μm), phenylephrine (0.01–3 μM)‐evoked contraction was not altered when compared with arteries from sham‐operated animals, but the concentration–relaxation curve to acetylcholine (ACh; 0.01 – 3 μM) displayed a small, but significant, shift to the right.

The smooth muscle resting membrane potential (−70.3±1.6 mV) in arteries from LPS‐treated rats was significantly greater than in control arteries (−55.4±1.2 mV), but in both cases the smooth muscle was depolarized to a similar potential by the application of Nω‐nitro‐L‐arginine methyl ester (L‐NAME; 0.3 mM; −54.1±2.3 vs −52.4±2.5 mV) or glibenclamide (10 μM; −55.0±2.1 vs −50.4±2.0 mV).

ACh (1 μM) elicited a maximal hyperpolarization, which ranged from −14.7±3.2 mV (in arteries from LPS‐treated rats) to –20.6±2.4 mV (in arteries from sham‐operated rats), and was not altered by the presence of L‐NAME. Levcromakalim (1 μM) increased the smooth muscle membrane potential by around −24 mV in arteries from both sets of experimental animals.

These results indicate that at the level of the resistance vasculature, endotoxaemia is associated with pronounced smooth muscle hyperpolarization reflecting the action of NO on KATP channels. These changes were not associated with vascular hyporeactivity or depressed endothelial cell function in vitro, suggesting that mesenteric resistance arteries may not contribute to equivalent changes in vivo.

British Journal of Pharmacology (2004) 142, 479–484. doi:10.1038/sj.bjp.0705794
Inhibition of cardiac HERG currents by the DNA topoisomerase II inhibitor amsacrine: mode of action
Authors: Thomas Dierk , Hammerling Bettina C , Wu Kezhong , Wimmer Anna‐Britt , Ficker Eckhard K , Kirsch Glenn E , Kochan Mary C , Wible Barbara A , Scholz Eberhard P , Zitron Edgar , Kathöfer Sven , Kreye Volker A W , Katus Hugo A , Schoels Wolfgang , Karle Christoph A , Kiehn Johann
Published: June 2004

The topoisomerase II inhibitor amsacrine is used in the treatment of acute myelogenous leukemia. Although most anticancer drugs are believed not to cause acquired long QT syndrome (LQTS), concerns have been raised by reports of QT interval prolongation, ventricular fibrillation and death associated with amsacrine treatment. Since blockade of cardiac human ether‐a‐go‐go‐related gene (HERG) potassium currents is an important cause of acquired LQTS, we investigated the acute effects of amsacrine on cloned HERG channels to determine the electrophysiological basis for its proarrhythmic potential.

HERG channels were heterologously expressed in human HEK 293 cells and Xenopus laevis oocytes, and the respective potassium currents were recorded using patch‐clamp and two‐microelectrode voltage‐clamp electrophysiology.

Amsacrine blocked HERG currents in HEK 293 cells and Xenopus oocytes in a concentration‐dependent manner, with IC50 values of 209.4 nM and 2.0 μM, respectively.

HERG channels were primarily blocked in the open and inactivated states, and no additional voltage dependence was observed. Amsacrine caused a negative shift in the voltage dependence of both activation (−7.6 mV) and inactivation (−7.6 mV). HERG current block by amsacrine was not frequency dependent.

The S6 domain mutations Y652A and F656A attenuated (Y652A) or abolished (F656A, Y652A/F656A) HERG current blockade, indicating that amsacrine binding requires a common drug receptor within the pore‐S6 region.

In conclusion, these data demonstrate that the anticancer drug amsacrine is an antagonist of cloned HERG potassium channels, providing a molecular mechanism for the previously reported QTc interval prolongation during clinical administration of amsacrine.

British Journal of Pharmacology (2004) 142, 485–494. doi:10.1038/sj.bjp.0705795
Differential modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by the local anesthetic lidocaine
Authors: Chevrier P , Vijayaragavan K , Chahine M
Published: June 2004

Voltage‐gated Na+ channels are transmembrane proteins that are essential for the propagation of action potentials in excitable cells. Nav1.7 and Nav1.8 dorsal root ganglion Na+ channels exhibit different kinetics and sensitivities to tetrodotoxin (TTX). We investigated the properties of both channels in the presence of lidocaine, a local anesthetic (LA) and class I anti‐arrhythmic drug.

Nav1.7 and Nav1.8 Na+ channels were coexpressed with the β1‐subunit in Xenopus oocytes. Na+ currents were recorded using the two‐microelectrode voltage‐clamp technique.

Dose–response curves for both channels had different EC50 (dose producing 50% maximum current inhibition) (450 μM for Nav1.7 and 104 μM for Nav1.8). Lidocaine enhanced current decrease in a frequency‐dependent manner. Steady‐state inactivation of both channels was also affected by lidocaine, Nav1.7 being the most sensitive. Only the steady‐state activation of Nav1.8 was affected while the entry of both channels into slow inactivation was affected by lidocaine, Nav1.8 being affected to a larger degree.

Although the channels share homology at DIV S6, the LA binding site, they differ in their sensitivity to lidocaine. Recent studies suggest that other residues on DI and DII known to influence lidocaine binding may explain the differences in affinities between Nav1.7 and Nav1.8 Na+ channels.

Understanding the properties of these channels and their pharmacology is of critical importance to developing drugs and finding effective therapies to treat chronic pain.

British Journal of Pharmacology (2004) 142, 576–584. doi:10.1038/sj.bjp.0705796
Ginseng saponins induce store‐operated calcium entry inXenopusoocytes
Authors: Jeong Sang Min , Lee Jun‐Ho , Kim Sunoh , Rhim Hyewhon , Lee Byung‐Hwan , Kim Jong‐Hoon , Oh Jae‐Wook , Lee Sang‐Mok , Nah Seung‐Yeol
Published: June 2004

We investigated the effect of the active ingredients ofPanaxginseng, ginsenosides, on store‐operated Ca2+entry (SOCE) using a two‐electrode voltage clamp technique inXenopusoocytes in which SOCE is monitored through Ca2+‐activated Cl−currents.

Under hyperpolarizing voltage clamp conditions, treatment with ginsenosides produced a biphasic Ca2+‐activated Cl−current consisting of a rapid transient inward current and a slowly developing secondary sustained inward current. The transient inward current was inactivated rapidly, whereas the sustained inward current persisted for nearly 10 min. The effect of ginsenosides on the biphasic current was dose‐dependent and reversible. The EC50was 42.8±11.6 and 46.6±7.1μg ml−1for the transient and sustained inward current, respectively.

In the absence of extracellular Ca2+ginsenosides induced only a transient inward current but in the presence of extracellular Ca2+ginsenosides induced the biphasic current. Magnitudes of the sustained currents were dependent on extracellular Ca2+concentration. Sustained inward current induced by ginsenosides, but not transient inward current, and ginsenoside‐induced store‐operated Ca2+(SOC) currents (ISOC) were blocked by La3+, a Ca2+channel blocker, suggesting that the sustained inward current andISOCwas derived from an influx of extracellular Ca2+.

Treatment with 2‐APB and heparin, which are IP3receptor antagonists, inhibited the ginsenoside‐induced biphasic current. Treatment with the PLC inhibitor, U73122, also inhibited the ginsenoside‐induced biphasic current. Intraoocyte injection of ATP‐γS, but not adenylyl AMP‐PCP, induced a persistent activation of ginsenoside‐induced sustained current but did not affect the transient current.

In rat hippocampal neurons, ginsenosides inhibited both carbachol‐stimulated intracellular Ca2+release and intracellular Ca2+depletion‐activated SOCE.

These results indicate that ginsenoside might act as a differential regulator of intracellular Ca2+levels in neurons andXenopusoocytes.

British Journal of Pharmacology(2004)142, 585–593. doi:10.1038/sj.bjp.0705797
Effects of chronic treatment with escitalopram or citalopram on extracellular 5‐HT in the prefrontal cortex of rats: role of 5‐HT1A receptors
Authors: Ceglia I , Acconcia S , Fracasso C , Colovic M , Caccia S , Invernizzi R W
Published: June 2004

Microdialysis was used to study the acute and chronic effects of escitalopram (S‐citalopram; ESCIT) and chronic citalopram (CIT), together with the 5‐HT1A receptor antagonist WAY100,635 (N‐[2‐[methoxyphenyl)‐1‐piperazinyl]ethyl]‐N‐(2‐pyridinyl) cyclohexane carboxamide trihydrochloride) and the 5‐HT1A receptor agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), on extracellular 5‐hydroxytryptamine (5‐HT) levels in the rat prefrontal cortex.

Extracellular 5‐HT rose to 234 and 298% of basal values after subcutaneous (s.c.) acute doses of 0.15 and 0.63 mg kg−1 ESCIT. No further increase was observed at 2.5 mg kg−1 ESCIT (290%).

The effect of 13‐day s.c. infusion of 10 mg kg−1day−1 ESCIT on extracellular 5‐HT (422% of baseline) was greater than after 2 days (257% of baseline), whereas exposure to ESCIT was similar. In contrast, the increase in extracellular 5‐HT induced by the infusion of CIT for 2 (306%) and 13 days (302%) was similar. However, brain and plasma levels of S‐citalopram in rats infused with CIT for 13 days were lower than after 2 days.

Acute treatment with 2.5 mg kg−1 ESCIT or 5 mg kg−1 CIT raised extracellular 5‐HT by 243 and 276%, respectively, in rats given chronic vehicle but had no effect in rats given ESCIT (10 mg kg−1 day−1) or CIT (20 mg kg−1 day−1) for 2 or 13 days, suggesting that the infused doses had maximally increased extracellular 5‐HT. WAY100,635 (0.1 mg kg−1 s.c.) increased extracellular 5‐HT levels by 168, 174 and 169% of prechallenge values in rats infused with vehicle or ESCIT for 2 or 13 days, respectively. WAY100,635 enhanced extracellular 5‐HT levels to 226, 153 and 164% of prechallenge values in rats infused with vehicle or CIT for 2 and 13 days, respectively.

8‐OH‐DPAT (0.025 mg kg−1) reduced extracellular 5‐HT by 54% in control rats, but had no effect in those given ESCIT and CIT for 13 days.

This series of experiments led to the conclusion that chronic treatment with ESCIT desensitizes the 5‐HT1A receptors, regulating the release of 5‐HT in the prefrontal cortex and enhances the effect of the drug on extracellular 5‐HT. They also indicate that chronic treatment with ESCIT and CIT did not prevent WAY100,635 from raising extracellular 5‐HT.

British Journal of Pharmacology (2004) 142, 469–478. doi:10.1038/sj.bjp.0705800
Heterogeneity in the mechanisms of vasorelaxation to anandamide in resistance and conduit rat mesenteric arteries
Authors: O'Sullivan Saoirse E , Kendall David A , Randall Michael D
Published: June 2004

In order to address mechanistic differences between arterial vessel types, we have compared the vasorelaxant actions of anandamide in resistance (G3) and conduit (G0) mesenteric arteries.

Anandamide produced concentration‐dependent relaxations of pre‐constricted G3 arteries with a maximal response that was significantly greater than seen in G0.

The CB1 receptor selective antagonists SR141716A (100 nM) and AM251 (100 nM) caused reductions in the vasorelaxant responses to anandamide in both arteries. Maximal vasorelaxant responses to anandamide were reduced in both arteries after treatment with capsaicin to deplete sensory neurotransmitters (10 μM for 1 h).

Vasorelaxation to anandamide was not affected by the nitric oxide synthase inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME, 300 μM) in either artery. Only responses in G3 arteries were sensitive to removal of the endothelium. In G3 vessels only, vasorelaxation to anandamide was reduced by inhibition of EDHF activity with a combination of charybdotoxin (100 nM) and apamin (500 nM) in the presence of L‐NAME (300 μM) and indomethacin (10 μM).

Antagonism of the novel endothelial cannabinoid receptor (O‐1918, 1 μM) caused a reduction in the sensitivity to anandamide in G3 but not G0.

G3, but not G0, vessels showed a small reduction in vasorelaxant responses to anandamide after inhibition of gap junctional communication with 18α‐GA (100 μM).

These results demonstrate that there are differences in the mechanisms of vasorelaxation to anandamide between conduit and resistance mesenteric arteries. In small resistance vessels, vasorelaxation occurs through stimulation of vanilloid receptors, CB1 receptors, and an endothelial receptor coupled to EDHF release. By contrast, in the larger mesenteric artery, vasorelaxation is almost entirely due to stimulation of vanilloid receptors and CB1 receptors, and is endothelium‐independent.

British Journal of Pharmacology (2004) 142, 435–442. doi:10.1038/sj.bjp.0705810
A novel inhibitor of vacuolar ATPase, FR167356, which can discriminate between osteoclast vacuolar ATPase and lysosomal vacuolar ATPase
Authors: Niikura Kazuaki , Takano Mikiko , Sawada Masae
Published: June 2004

Vacuolar ATPase (V‐ATPase) has been proposed as a drug target in lytic bone diseases. Studies of bafilomycin derivatives suggest that the key issue regarding the therapeutic usefulness of V‐ATPase inhibitors is selective inhibition of osteoclast V‐ATPase. Previous efforts to develop therapeutic inhibitors of osteoclast V‐ATPase have been frustrated by a lack of synthetically tractable and biologically selective leads. Therefore, we tried to find novel potent and specific V‐ATPase inhibitors, which have new structural features and inhibition selectivity, from random screening using osteoclast microsomes. Finally, a novel V‐ATPase inhibitor, FR167356, was obtained through chemical modification of a parental hit compound.

FR167356 inhibited not only H+ transport activity of osteoclast V‐ATPase but also H+ extrusion from cytoplasm of osteoclasts, which depends on the V‐ATPase activity. As expected, FR167356 remarkably inhibited bone resorption in vitro.

FR167356 also showed inhibitory effects on other V‐ATPases, renal brush border V‐ATPase, macrophage microsome V‐ATPase and lysosomal V‐ATPase. However, FR167356 was approximately seven‐fold less potent in inhibiting lysosomal V‐ATPase compared to osteoclast V‐ATPase. Moreover, LDL metabolism in cells, which depends on acidification of lysosome, was blocked merely at higher concentration than bone resorption, suggesting that FR167356 inhibits V‐ATPase of osteoclast ruffled border membrane still more selectively than lysosome at the cellular level.

These results from the experiments seem to indicate that osteoclast V‐ATPase may be different from lysosomal V‐ATPase in respect of their structure.

FR167356 had a novel chemical structural feature as well as inhibitory characteristics distinctly different from any previously known V‐ATPase inhibitor family. Therefore, FR167356 is thought to be a useful tool for estimating the essential characteristics of V‐ATPase inhibitors for drug development.

British Journal of Pharmacology (2004) 142, 558–566. doi:10.1038/sj.bjp.0705812
Chronic NGF treatment of rat nociceptive DRG neurons in culture facilitates desensitization and deactivation of GABAA receptor‐mediated currents
Authors: Fabbro Alessandra , Nistri Andrea
Published: June 2004

The present study tested the hypothesis that nerve growth factor (NGF) could affect presynaptic inhibition mediated by GABAA (GABA‐sensitive ionotropic receptors) receptors on the afferents of nociceptive dorsal root ganglia (DRG) neurons, thus reducing the filtering of central nociceptive signals.

To investigate this issue, small‐diameter, nociceptive DRG neurons were cultured for 48–72 h either in the normal medium or in the presence of NGF (50 ng ml−1). After 15 min washout, cells were patch clamped with Cs+ containing electrodes to block GABAB (GABA‐sensitive metabotropic receptors) receptor‐activated currents.

Chronically treated DRG neurons showed no difference in the peak amplitude of GABA‐induced currents. However, NGF‐treated cells exhibited increased fading of the response to continuous GABA application, with faster desensitization onset, decreased residual current at the end of agonist application and slower recovery from desensitization. Moreover, the deactivation phase after brief agonist pulses was also accelerated.

Unlike responses to GABA, chronic NGF treatment had no effect on the desensitization process to the excitatory transmitter ATP, as no difference in peak amplitude, fast and slow time constants of current decay was found.

Experimental tests indicated that the observed effects on GABA currents were not a reactive process triggered by washing out NGF after its long application. Acutely applied NGF did not change GABAA receptor‐mediated responses.

NGF‐treated neurons showed decreased sensitivity to the antagonist picrotoxin. The action of pentobarbitone, midazolam, bicuculline or gabazine was, however, unchanged.

These observations suggest that the modulation of GABAA receptor function of DRG nociceptors by NGF may contribute to the algogenic action of this neurotrophin.

British Journal of Pharmacology (2004) 142, 425–434. doi:10.1038/sj.bjp.0705813