bluuebunny/crossref_metadata_2025 huggingface dataset:
TOWARD AN ECONOMIC THEORY OF REALITY: AN INTERVIEW WITH GUILLERMO A. CALVO
Authors: MENDOZA ENRIQUE G.
Published: January 2005

Guillermo Calvo is one of the most influential economists in the field of international macroeconomics of the past 30 years. He has produced seminal articles in every area of macroeconomics and international economics that he has worked on, including his early classic articles on capacity utilization and time inconsistency, his 1980's works on efficiency wages, price stickiness, and policy credibility, and his recent studies on sudden stops and emerging market crises. Yet, the defining feature of Guillermo Calvo's contribution to our profession is not the depth and wide scope of the economic theories he has developed, but the central emphasis he puts in all his work on the role of economics as a tool for understanding reality and improving the quality of human life.

Guillermo Calvo's passion for the policy implications of economic theory is obvious to anyone who has met him since his days as Senior Advisor of the Research Department of the IMF in the mid-1980's. This feature of his professional interests was much less obvious to those who interacted with him during his early years as an important figure of the rational expectations revolution. It was probably hard to see that behind the highly technical treatment presented in his articles at that time was an author who had his feet soundly set on the ground and focused on understanding how society could benefit from the renaissance of macroeconomic theory that was taking place. Interestingly, Michael Rothschild did figure out the true nature of Guillermo Calvo in those early years. When the University of California at San Diego tried to hire Calvo in the mid-1980's, Rothschild explained to Calvo that he was an excellent fit for San Diego because he was a particular type of theoretician: “Most theoreticians make theory out of theory,” Rothschild noted, but Calvo was different because he made “theory out of reality, taking what is really out there and presenting it in a much wider and complex form than a well-developed but narrow theory.”

The following pages are excerpts from three interview sessions that Guillermo Calvo and I had at his office in the Inter-American Development Bank in the spring of 2003. These interviews provide a clear summary picture of Calvo as the theoretician of reality that Michael Rothschild described. The recollection of the conversation with Rothschild is one of many fascinating memories of Calvo's personal life and professional career that emerged during our meetings. We taped and transcribed the three meetings in Spanish and then Calvo and I together edited that material to produce this much shorter interview in English for Macroeconomic Dynamics.
Quantifying tropospheric volcanic emissions with AIRS: The 2002 eruption of Mt. Etna (Italy)
Authors: Carn S. A. , Strow L. L. , de Souza‐Machado S. , Edmonds Y. , Hannon S.
Published: January 2005

The Atmospheric Infrared Sounder (AIRS) is a hyperspectral IR spectrometer orbiting on the EOS/Aqua spacecraft since May 2002. In late October 2002, AIRS detected lower tropospheric sulfur dioxide and ash emitted by an eruption of Mt. Etna (Italy), in plumes which could be tracked over 1000 km from the volcano into north Africa. We report retrievals of SO2 and ash column amounts and ash particle size in the Etna plumes. AIRS total SO2 compares favorably with contemporaneous ground‐based correlation spectrometry (COSPEC) measurements. Retrieval of ash cloud parameters in the eruption plumes permits quantitative studies of distal ash fallout. The Etna data demonstrate the potential of AIRS to improve measurements of volcanic SO2 and ash loading in the troposphere, and to refine our understanding of volcanic cloud composition, structure and evolution.
Solar control on Jupiter's equatorial X‐ray emissions: 26–29 November 2003 XMM‐Newton observation
Authors: Bhardwaj Anil , Branduardi‐Raymont G. , Elsner R. F. , Gladstone G. R. , Ramsay G. , Rodriguez P. , Soria R. , Waite J. H. , Cravens T. E.
Published: January 2005

During Nov. 26–29, 2003 XMM‐Newton observed soft (0.2–2 keV) X‐ray emission from Jupiter for 69 hours. The low‐latitude X‐ray disk emission of Jupiter is observed to be almost uniform in intensity with brightness that is consistent with a solar‐photon driven process. The simultaneous light curves of Jovian equatorial X rays and solar X rays (measured by the TIMED/SEE and GOES satellites) show similar day‐to‐day variability. A large solar X‐ray flare occurring on the Jupiter‐facing side of the Sun is found to have a corresponding feature in the Jovian X rays. These results support the hypothesis that X‐ray emission from Jovian low‐latitudes are solar X rays scattered from the planet's upper atmosphere, and suggest that the Sun directly controls the non‐auroral X rays from Jupiter's disk. Our study also suggests that Jovian equatorial X rays can be used to monitor the solar X‐ray flare activity on the hemisphere of the Sun that is invisible to space weather satellites.
Cruise observations of a cold core ring and β – spiral on the East China Sea continental shelf
Authors: Qiao Fangli , Zheng Quanan , Ge Renfeng , Yu Fei , Fang Guohong
Published: January 2005

Cruise observations with CTDs (Conductivity‐Temperature‐Depth profiler) and a moored ADCP (Acoustic Doppler Current Profiler) were carried out on the continental shelf of southern East China Sea (ECS) in summer 2003. Analyses of the cruise data reveal a low temperature belt sandwiched by warm waters on the shallow water side and on the continental slope side. Within the belt there are three cold centers with horizontal scales of 30 to 100 km distributed as a chain from the southwest to the northeast. The upward protruding isotherms and β – spiral‐like daily averaged horizontal velocity structure indicate that the northeast cold center has all features of a mesoscale cold core ring. Estimated vertical velocity is of the order of 5 × 10−5 m s−1.
Radiation efficiency and apparent stress of small earthquakes in a South African gold mine
Authors: Yamada Takuji , Mori James J. , Ide Satoshi , Kawakata Hironori , Iio Yoshihisa , Ogasawara Hiroshi
Published: January 2005

Nine triaxial borehole accelerometers were installed within 200 m along a 2650‐m‐deep haulage tunnel in the Mponeng gold mine in South Africa. We analyzed the high sample rate recordings (15 kHz) to determine source parameters of small earthquakes in the mine. To study the source processes, we carried out multiple time window waveform inversions for five larger events (0.8 < M < 1.4) that occurred within 150 m of the stations. From the inversion results we could determine the fault planes for all five events and estimate the range of rupture speed. We can conclude that rupture speeds were faster than 2.5 km/s (65% of the shear wave velocity). The radiation efficiency is written as a function of the rupture speed and becomes greater with increasing rupture speed. This study indicates that radiation efficiencies of small earthquakes in the South African gold mine are almost equal to those of larger natural earthquakes. We also calculated radiated seismic energies and static stress drops of the five events to investigate their apparent stresses. Apparent stresses of the five events were from 1 to 10 MPa and static stress drops were 1 to 20 MPa. We found that the source parameters (rupture speed, apparent stress, radiation efficiency, and static stress drop) did not largely differ from values for larger natural earthquakes. This suggests that the dynamic rupture processes of these small events were similar to those of the larger natural earthquakes.
Strength of fracture zones from their bathymetric and gravitational evolution
Authors: Hall Chad E. , Gurnis Michael
Published: January 2005

Fracture zone evolution is investigated using dynamic models that allow the fault zones to freely slip. This is an improvement over past formulations where bathymetric offsets were imposed kinematically. The models use a viscoelastoplastic rheology that incorporates the influence of fault friction on fracture zone slip history. Using viscoelastic plates, we assess the role of small‐scale convection on removal of the lowermost thermal lithosphere beneath fracture zones. Through a comparison of synthetic gravity to free‐air gravity across fracture zones we find that the amplitude of the gravity jump across fracture zones is best fit by models with weak faults that have depth‐averaged yield strengths <10 MPa. Fracture zones with such low strengths can convert to subduction zones with ∼100 km of convergence. Many fracture zones do not fit plate subsidence models with locked or slipping faults but are better fit by systems that are tectonically deformed by modest amounts of extension.
Near‐inertial waves on the “nontraditional” β plane
Authors: Gerkema T. , Shrira V. I.
Published: January 2005

Propagation of linear near‐inertial waves on the β plane is considered, taking into account the horizontal component of the Earth's rotation, . (Terms, effects etc., due to this component will be referred to as “nontraditional,” for brevity.) It is shown that the combined effect of β and changes the dynamics in a fundamental way. For a vertically unbounded domain, an exact solution shows that near‐inertial waves can pass through the inertial latitude, unlike under the traditional approximation. For parameter values typical of the ocean, the subinertial domain extends several hundreds of kilometers poleward of the inertial latitude. The solution undergoes a profound change if a vertically bounded, instead of unbounded, domain is considered. Part of the wave energy then accumulates at the poleward end of the subinertial domain, which involves an evolution toward infinitesimal horizontal and vertical scales. For vertically nonuniform stratification, examined here using the Garrett‐Munk exponential profile, one finds a wedge‐like waveguide, which becomes increasingly narrow in the poleward direction, and drives subinertial waves into the region of the weakest stratification, i.e., the abyss. For typical parameters, the relative amount of poleward traveling energy that gets trapped is estimated to lie between 10 and 30%; its dependence on latitude and stratification is also outlined. The observational evidence and possible implications for abyssal mixing are discussed.
Farside deep moonquakes and deep interior of the Moon
Authors: Nakamura Yosio
Published: January 2005

An effort to find farside deep moonquakes among the recently discovered nests of deep moonquakes has identified about 30 nests that are likely to be on the farside. Although only a few of them are locatable with currently available data and those few provide little new information about the deep interior of the Moon, the inferred distribution of the rest of these nests indicates that either the region of the Moon's deep interior within about 40 degrees from the antipode of the Moon is nearly aseismic or, alternatively, the very deep interior of the Moon severely attenuates or deflects seismic waves. Since this has important bearing on the origin and evolution of the Moon, future missions to the Moon need to be oriented toward resolving this uncertainty. Some limited data favor the attenuation/deflection hypotheses.
On the probability of droughts: The compound renewal model
Authors: Loáiciga Hugo A.
Published: January 2005

Droughts influence the planning and design of water supply infrastructure. Hydrologists ascertain drought duration, severity, and pattern of recurrence from instrumental and reconstructed records (e.g., using tree rings) of streamflow and precipitation. This work introduces a compound renewal model for the probabilistic analysis of multiyear drought recurrence. The compound renewal process generalizes the Poisson process. In the former the interarrival time between two consecutive events is the duration of nondrought conditions, and the events (i.e., droughts) have a probabilistic duration of at least θ years. The sum of the interarrival time and its subsequent drought duration is called the renewal time, which regenerates over time according to probabilistic laws derived in this work. Drought severity is incorporated in the analysis by means of a threshold quantile (e.g., the median or the average), so that low‐streamflow conditions become a drought whenever they last over θ years. A case study dealing with a river basin that has multiyear storage capacity, and in which droughts recurred frequently in the twentieth century, demonstrates the analytical power of the compound renewal model.
A time series approach to inferring groundwater recharge using the water table fluctuation method
Authors: Crosbie Russell S. , Binning Philip , Kalma Jetse D.
Published: January 2005

The water table fluctuation method for determining recharge from precipitation and water table measurements was originally developed on an event basis. Here a new multievent time series approach is presented for inferring groundwater recharge from long‐term water table and precipitation records. Additional new features are the incorporation of a variable specific yield based upon the soil moisture retention curve, proper accounting for the Lisse effect on the water table, and the incorporation of aquifer drainage so that recharge can be detected even if the water table does not rise. A methodology for filtering noise and non‐rainfall‐related water table fluctuations is also presented. The model has been applied to 2 years of field data collected in the Tomago sand beds near Newcastle, Australia. It is shown that gross recharge estimates are very sensitive to time step size and specific yield. Properly accounting for the Lisse effect is also important to determining recharge.
Imidapril treatment improves the attenuated inotropic and intracellular calcium responses to ATP in heart failure due to myocardial infarction
Authors: Saini Harjot K , Shao Qiming , Musat Sorin , Takeda Nobuakira , Tappia Paramjit S , Dhalla Naranjan S
Published: January 2005

M Adenosine 5′‐triphosphate (ATP) is known to augment cardiac contractile activity and cause an increase in intracellular Ca2+ concentration ([Ca2+]i) in isolated cardiomyocytes. However, no information regarding the ATP‐mediated signal transduction in the myocardium in congestive heart failure (CHF) is available.

CHF due to myocardial infarction (MI) in rats was induced by the occlusion of the left coronary artery for 8 weeks. The positive inotropy due to ATP was depressed in failing hearts. Treatment of 3 weeks infarcted animals with imidapril (1 mg kg−1 day−1) for a period of 5 weeks improved the left ventricle function and decreased the attenuation of inotropic response to ATP.

ATP‐induced increase in [Ca2+]i was significantly depressed in cardiomyocytes isolated from the failing heart and this change was partially attenuated by imidapril treatment. However, the binding characteristics of 35S‐labeled adenosine 5′‐(γ‐thio) triphosphate in sarcolemma isolated from the failing heart remained unaltered.

ATP‐induced increase in [Ca2+]i was depressed by verapamil and cibacron blue in both control and failing heart cardiomyocytes; however, the ATP response in the failing hearts, unlike the control preparations, was not decreased by ryanodine. This insensitivity to ryanodine was attenuated by imidapril treatment.

Treatment of infarcted rats with enalapril and losartan produced effects similar to imidapril.

These findings indicate that the positive inotropic response to ATP and ATP‐induced increase in [Ca2+]i in cardiomyocytes are impaired in heart failure. Furthermore, blockade of renin angiotensin system prevented the impairment of the ATP‐mediated inotropic and [Ca2+]i responses in the failing heart.

British Journal of Pharmacology (2005) 144, 202–211. doi:10.1038/sj.bjp.0705867
Extracellular protons differentially potentiate the responses of native AMPA receptor subtypes regulating neurotransmitter release
Authors: Pittaluga Anna , Segantini Daniela , Feligioni Marco , Raiteri Maurizio
Published: January 2005

The effects of pH changes on the basal and evoked release of [3H]noradrenaline ([3H]NA) and [3H]5‐hydrohytryptamine ([3H]5‐HT) from hippocampal synaptosomes and of [3H]dopamine ([3H]DA) and [3H]acetylcholine ([3H]ACh) from striatal and cortical synaptosomes were investigated in rat brain.

Changing pH between 6.4 and 8.0 did not affect the spontaneous release of the four [3H]neurotransmitters; alkalinization to pH 8.8 significantly enhanced release. Acidification to pH 6.4 augmented the AMPA‐evoked overflows of [3H]NA, [3H]5‐HT and [3H]DA, but not that of [3H]ACh. In contrast, lowering pH to 6.4 decreased the K+‐evoked overflows of [3H]NA, [3H]5‐HT, [3H]DA and [3H]ACh.

AMPA released transmitters in a Ca2+‐dependent, exocytotic manner since its effects, at pH 7.4 or 6.4, were abolished by omitting external Ca2+ or by depleting vesicular transmitter stores with bafilomycin A1. AMPA did not evoke carrier‐mediated release because the uptake blockers nisoxetine, 6‐nitroquipazine, GBR12909 and hemicholinium‐3 could not inhibit the AMPA‐induced release of [3H]NA, [3H]5‐HT, [3H]DA and [3H]ACh.

Extraterminal acidification to pH 6.4 prevented the potentiating effect of cyclothiazide on the AMPA‐evoked release of [3H]NA, [3H]DA and [3H]5‐HT, whereas the proton‐insensitive AMPA‐evoked release of [3H]ACh, previously found to be cyclothiazide‐insensitive at pH 7.4 was cyclothiazide‐resistant also at pH 6.4.

To conclude, the cyclothiazide‐sensitive AMPA receptors mediating release of NA, 5‐HT and DA, but not the cyclothiazide‐insensitive AMPA receptors mediating the release of ACh, become more responsive when external pH is lowered to pathophysiologically relevant values. The results with cyclothiazide suggest that H+ ions may prevent desensitization of some AMPA receptor subtypes.

British Journal of Pharmacology (2005) 144, 293–299. doi:10.1038/sj.bjp.0705960
Functional implications of modifying RyR‐activating peptides for membrane permeability
Authors: Dulhunty Angela F , Cengia Louise , Young Jacqui , Pace Suzy M , Harvey Peta J , Lamb Graham D , Chan Yiu‐Ngok , Wimmer Norbert , Toth Istvan , Casarotto Marco G
Published: January 2005

Our aim was to determine whether lipoamino acid conjugation of peptides that are high‐affinity activators of ryanodine receptor (RyR) channels would (a) render the peptides membrane permeable, (b) alter their structure or (a) reduce their activity. The peptides correspond to theAregion of the II–III loop of the skeletal dihydropyridine receptor.

The lipoamino acid conjugation increased the apparent permeability of the peptide across the Caco‐2 cell monolayer by up to ∼20‐fold.

Nuclear magnetic resonance showed that theα‐helical structure of critical basic residues, required for optimal activation of RyRs, was retained after conjugation.

The conjugated peptides were more effective in enhancing resting Ca2+release, Ca2+‐induced Ca2+release and caffeine‐induced Ca2+release from isolated sarcoplasmic reticulum (SR) than their unconjugated counterparts, and significantly enhanced caffeine‐induced Ca2+release from mechanically skinned extensor digitorum longus (EDL) fibres.

The effect of both conjugated and unconjugated peptides on Ca2+release from skeletal SR was 30‐fold greater than their effect on either cardiac Ca2+release or on the Ca2+Mg2+ATPase.

A small and very low affinity effect of the peptide in slowing Ca2+uptake by the Ca2+, Mg2+ATPase was exacerbated by lipoamino acid conjugation in both isolated SR and in skinned EDL fibres.

The results show that lipoamino acid conjugation ofAregion peptides increases their membrane permeability without impairing their structure or efficacy in activating skeletal and cardiac RyRs.

British Journal of Pharmacology(2005)144, 743–754. doi:10.1038/sj.bjp.0705981
Transition from placental to air breathing stimulates haem‐oxygenase‐1 expression without functional consequence for pulmonary vascular adaptation in pigs and mice
Authors: Stanford Salome J , Hislop Alison A , Oltmanns Ute , Nabel Elizabeth G , Sang Hong , Haworth Shelia G , Mitchell Jane A
Published: January 2005

In systemic vessels, haem‐oxygenase (HO) is induced during oxidative stress and known to modulate vasodilatation and vascular remodelling. At birth, with the transition from placental to air breathing, the pulmonary vessels are exposed to oxidative stress and undergo well‐documented remodelling processes. Thus, we investigated the role of HO in the lung during adaptation to extra‐uterine life using a pig and mouse model. In addition to the novel data presented with regard to one isoform, HO‐1, this study is among the first to describe the pulmonary vascular remodelling in the mouse after birth.

We show, for the first time, that another isoform, HO‐2, is present constitutively at birth and HO‐1 protein is induced in the porcine and murine lung after birth in vascular and airway structures, peaking at 14 days in the pig and at about 4 days in the mouse. Furthermore, we show that HO‐1 mRNA declines after birth in the mouse lung.

Inhibitors of HO did not modify vasodilator responses in vessels from 14‐day‐old pigs.

Moreover, lungs from HO‐1‐deficient mice developed normally after birth.

HO‐1 is induced at birth but plays no role in the development of vasodilator responses or remodelling that occurs at this time. These data suggest that HO‐1 expression at birth is a redundant response to oxidative stress in the lungs of healthy mammals. However, it remains possible that this pathway protects if complications occur during or after birth.

British Journal of Pharmacology (2005) 144, 467–476. doi:10.1038/sj.bjp.0705988
Captopril improves cerebrovascular structure and function in old hypertensive rats
Authors: Dupuis François , Atkinson Jeffrey , Limiñana Patrick , Chillon Jean‐Marc
Published: January 2005

We examined the effects of an angiotensin‐converting enzyme inhibitor (ACEI), captopril, on cerebral arterioles in young and old spontaneously hypertensive rats (SHR).

Animals were anesthetized with sodium pentobarbitone (60 mg kg−1 day−1). We measured cerebral blood flow (CBF, arbitrary units) and cerebral arteriolar internal diameter (ID, μm) prior to and during stepwise hypotension (SH) in 6‐ (WKY‐6) and 15‐month‐old (WKY‐15) Wistar Kyoto rats and in age‐matched SHR that were untreated (SHR‐6 and SHR‐15) or treated for 3 months with captopril (SHR‐6C, 105±2 mg kg−1 day−1 and SHR‐15C, 94±1 mg kg−1 day−1). ID and cross‐sectional area of the vessel wall (CSA) were measured in deactivated (EDTA) cerebral arterioles during a second SH.

Captopril decreased the lower limit of CBF autoregulation (61±6 in SHR‐6C and 51±2 in SHR‐15C versus 52±6 in WKY‐6 and 62±7 in WKY‐15 and 83±14 mmHg in SHR‐6 and 120±19 mmHg in SHR‐15; P<0.05) and CSA (510±21 in SHR‐6C and 585±25 in SHR‐15C versus 529±12 in WKY‐6 and 549±20 in WKY‐15 and 644±38 mmHg in SHR‐6 and 704±38 mmHg in SHR‐15; P<0.05).

Captopril increased cerebral arteriolar external diameter of SHR (105±5 in SHR‐6C and 94±4 in SHR‐15C vs 125±8 in WKY‐6 and 108±3 in WKY‐15 and 83±2 mmHg in SHR‐6 and 80±2 mmHg in SHR‐15 for a pial arteriolar pressure step of 35–39 mmHg; P<0.05). Captopril attenuated increases in cerebral arteriolar distensibility in young SHR.

Thus, ACEIs attenuate eutrophic and hypertrophic inward remodeling of cerebral arterioles in young and old SHR, thus decreasing the lower limit of CBF autoregulation.

British Journal of Pharmacology (2005) 144, 349–356. doi:10.1038/sj.bjp.0706001
Role of SKCa and IKCa in endothelium‐dependent hyperpolarizations of the guinea‐pig isolated carotid artery
Authors: Gluais Pascale , Edwards Gillian , Weston Arthur H , Falck John R , Vanhoutte Paul M , Félétou Michel
Published: January 2005

This study was designed to determine whether the endothelium‐dependent hyperpolarizations evoked by acetylcholine in guinea‐pig carotid artery involve a cytochrome P450 metabolite and whether they are linked to the activation of two distinct populations of endothelial KCa channels, SKCa and IKCa.

The membrane potential was recorded in the vascular smooth muscle cells of the guinea‐pig isolated carotid artery. All the experiments were performed in the presence of Nω‐L‐nitro arginine (100 μM) and indomethacin (5 μM).

Under control conditions (Ca2+: 2.5 mM), acetylcholine (10 nM to 10 μM) induced a concentration‐ and endothelium‐dependent hyperpolarization of the vascular smooth muscle cells. Two structurally different specific blockers of SKCa, apamin (0.5 μM) or UCL 1684 (10 μM), produced a partial but significant inhibition of the hyperpolarization evoked by acetylcholine whereas charybdotoxin (0.1 μM) and TRAM‐34 (10 μM), a nonpeptidic and specific blocker of IKCa, were ineffective. In contrast, the combinations of apamin plus charybdotoxin, apamin plus TRAM‐34 (10 μM) or UCL 1684 (10 μM) plus TRAM‐34 (10 μM) virtually abolished the acetylcholine‐induced hyperpolarization.

In the presence of a combination of apamin and a subeffective dose of TRAM‐34 (5 μM), the residual hyperpolarization produced by acetylcholine was not inhibited further by the addition of either an epoxyeicosatrienoic acid antagonist, 14,15‐EEZE (10 μM) or the specific blocker of BKCa, iberiotoxin (0.1 μM).

In presence of 0.5 mM Ca2+, the hyperpolarization in response to acetylcholine (1 μM) was significantly lower than in 2.5 mM Ca2+. The EDHF‐mediated responses became predominantly sensitive to charybdotoxin or TRAM‐34 but resistant to apamin.

This investigation shows that the production of a cytochrome P450 metabolite, and the subsequent activation of BKCa, is unlikely to contribute to the EDHF‐mediated responses in the guinea‐pig carotid artery. Furthermore, the EDHF‐mediated response involves the activation of both endothelial IKCa and SKCa channels, the activation of either one being able to produce a true hyperpolarization.

British Journal of Pharmacology (2005) 144, 477–485. doi:10.1038/sj.bjp.0706003
Protein kinase Cγ mediates ethanol withdrawal hyper‐responsiveness of NMDA receptor currents in spinal cord motor neurons
Authors: Li Hui‐Fang , Mochly‐Rosen Daria , Kendig Joan J
Published: January 2005

The present studies were designed to test the hypothesis that neuronal‐specific protein kinase Cγ (PKCγ) plays a critical role in acute ethanol withdrawal hyper‐responsiveness in spinal cord.

Patch‐clamp studies were carried out in motor neurons in neonatal rat spinal cord slices. Postsynaptic currents were evoked by brief pulses of 2 mM N‐methyl‐D‐aspartic acid (NMDA) in the presence of bicuculline methiodide 10 μM; strychnine 5 μM and tetrodotoxin 0.5 μM.

Both ethanol depression and withdrawal hyper‐responsiveness of NMDA‐evoked currents are dependent on increases in intracellular Ca2+. Blocking intracellular increase in Ca2+ by 30 mM 1,2‐bis(2‐aminophenoxy)‐ethane‐N,N,N′,N′‐tetraacetic acid (BAPTA) not only decreased the ethanol‐induced depression of NMDA‐evoked currents (33±5% in control vs 20±3% in BAPTA, P<0.05) but also eliminated acute ethanol withdrawal hyper‐responsiveness.

Immunohistochemistry studies revealed that neonatal spinal cord motor neurons contain an abundance of nuclear PKCγ.

Exposure to ethanol (100 mM) induced PKCγ translocation from the nucleus to cytoplasm in motor neurons. Pretreatment with the γ‐isozyme‐specific peptide PKC inhibitor, γV5‐3, blocked ethanol‐induced translocation and also blocked withdrawal hyper‐responsiveness.

The results show that PKCγ mediates ethanol withdrawal hyper‐responsiveness in spinal motor neurons; the results may be relevant to some symptoms of ethanol withdrawal in vivo.

British Journal of Pharmacology (2005) 144, 301–307. doi:10.1038/sj.bjp.0706033
Effects of synaptotagmin reveal two distinct mechanisms of agonist‐stimulated internalization of the M4 muscarinic acetylcholine receptor
Authors: Madziva Michael T , Bai Jihong , Bhalla Akhil , Chapman Edwin R , Edwardson J Michael
Published: January 2005

Synaptotagmin has been reported to function in clathrin‐mediated endocytosis. Here, we investigated its involvement in agonist‐stimulated internalization of M4 muscarinic acetylcholine receptors exogenously expressed in human embryonic kidney (HEK‐293 tsA201) cells.

Synaptotagmin I was present at low levels in these cells, and when overexpressed resided at the plasma membrane.

Synaptotagmin overexpression alone did not affect receptor internalization, but ‘rescued’ internalization that had been inhibited by either dominant‐negative dynamin‐1 or dominant‐negative arrestin‐2. Both normal and ‘rescued’ internalization were sensitive to inhibitors of clathrin‐mediated endocytosis, but not to inhibitors of the function of caveolae.

There was no increase in AP‐2 recruitment to the plasma membrane in cells overexpressing synaptotagmin. However, a mutant form of the receptor lacking a potential AP‐2 recruitment motif, while being internalized normally in response to agonist stimulation, was not rescued by synaptotagmin in cells expressing dominant‐negative dynamin or arrestin.

A mutant form of synaptotagmin (K326,327A), which binds phosphatidylinositol‐4,5‐bisphosphate (PIP2) much more weakly than the wild‐type protein, did not rescue internalization. Furthermore, internalization was inhibited by the PH domain of phospholipase C‐δ1, which sequesters PIP2, and synaptotagmin was now unable to rescue.

We propose that AP‐2 binding to the C‐terminal tail of the receptor is not normally required for its endocytosis, but that the synaptotagmin‐mediated rescue involves the formation of a ternary complex with the receptor and AP‐2. PIP2 might play a role as an intermediary in the formation of this complex.

British Journal of Pharmacology (2005) 144, 761–771. doi:10.1038/sj.bjp.0706035
Endothelium‐dependent contractions in hypertension
Authors: Vanhoutte Paul M , Feletou Michel , Taddei Stefano
Published: January 2005

Endothelial cells, under given circumstances, can initiate contraction (constriction) of the vascular smooth muscle cells that surround them. Such endothelium‐dependent, acute increases in contractile tone can be due to the withdrawal of the production of nitric oxide, to the production of vasoconstrictor peptides (angiotensin II, endothelin‐1), to the formation of oxygen‐derived free radicals (superoxide anions) and/or the release of vasoconstrictor metabolites of arachidonic acid. The latter have been termed endothelium‐derived contracting factor (EDCF) as they can contribute to moment‐to‐moment changes in contractile activity of the underlying vascular smooth muscle cells.

To judge from animal experiments, EDCF‐mediated responses are exacerbated by aging, spontaneous hypertension and diabetes.

To judge from human studies, they contribute to the blunting of endothelium‐dependent vasodilatations in aged subjects and essential hypertensive patients.

Since EDCF causes vasoconstriction by activation of the TP‐receptors on the vascular smooth muscle cells, selective antagonists at these receptors prevent endothelium‐dependent contractions, and curtail the endothelial dysfunction in hypertension and diabetes.

British Journal of Pharmacology (2005) 144, 449–458. doi:10.1038/sj.bjp.0706042
Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α2‐adrenoceptor agonists in acute pain models in mice
Authors: Tham Shao M , Angus James A , Tudor Elizabeth M , Wright Christine E
Published: January 2005

Cannabinoid receptor agonists elicit analgesic effects in acute and chronic pain states via spinal and supraspinal pathways. We investigated whether the combination of a cannabinoid agonist with other classes of antinociceptive drugs exerted supra‐additive (synergistic) or additive effects in acute pain models in mice.

The interactions between the cannabinoid agonist CP55,940, α2‐adrenoceptor agonist dexmedetomidine and μ‐opioid receptor agonist morphine were evaluated by isobolographic analysis of antinociception in hot plate (55°C) and tail flick assays in conscious male Swiss mice. Drug interactions were examined by administering fixed‐ratio combinations of agonists (s.c.) in 1 : 1, 3 : 1 and 1 : 3 ratios of their respective ED50 fractions.

CP55,940, dexmedetomidine and morphine all caused dose‐dependent antinociception. In the hot plate and tail flick assays, ED50 values (mg kg−1) were CP55,940 1.13 and 0.51, dexmedetomidine 0.066 and 0.023, and morphine 29.4 and 11.3, respectively. Synergistic interactions existed between CP55,940 and dexmedetomidine in the hot plate assay, and CP55,940 and morphine in both assays. Additive interactions were found for CP55,940 and dexmedetomidine in the tail flick assay, and dexmedetomidine and morphine in both assays.

Thus, an α2‐adrenoceptor agonist or μ opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception in the hot plate test. However, for the tail flick nociceptive response to heat, only cannabinoid and μ opioid receptor antinociceptive synergy was demonstrated. If these results translate to humans, then prudent selection of dose and receptor‐specific agonists may allow an improved therapeutic separation from unwanted side effects.

British Journal of Pharmacology (2005) 144, 875–884. doi:10.1038/sj.bjp.0706045
The selectivity of β‐adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors
Authors: Baker Jillian G
Published: January 2005

β‐Adrenoceptor antagonists (‘β‐blockers’) are one of the most widely used classes of drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly in heart failure) as well as in the management of anxiety, migraine and glaucoma. Where known, the mode of action in cardiovascular disease is from antagonism of endogenous catecholamine responses in the heart (mainly at β1‐adrenoceptors), while the worrisome side effects of bronchospasm result from airway β2‐adrenoceptor blockade. The aim of this study was to determine the selectivity of β‐antagonists for the human β‐adrenoceptor subtypes.

3H‐CGP 12177 whole cell‐binding studies were undertaken in CHO cell lines stably expressing either the human β1‐, β2‐ or the β3‐adrenoceptor in order to determine the affinity of ligands for each receptor subtype in the same cell background.

In this study, the selectivity of well‐known subtype‐selective ligands was clearly demonstrated: thus, the selective β1 antagonist CGP 20712A was 501‐fold selective over β2 and 4169‐fold selective over β3; the β2‐selective antagonist ICI 118551 was 550‐ and 661‐fold selective over β1 and β3, respectively, and the selective β3 compound CL 316243 was 10‐fold selective over β2 and more than 129‐fold selective over β1.

Those β2‐adrenoceptor agonists used clinically for the treatment of asthma and COPD were β2 selective: 29‐, 61‐ and 2818‐fold for salbutamol, terbutaline and salmeterol over β1, respectively. There was little difference in the affinity of these ligands between β1 and β3 adrenoceptors.

The clinically used β‐antagonists studied ranged from bisoprolol (14‐fold β1‐selective) to timolol (26‐fold β2‐selective). However, the majority showed little selectivity for the β1‐ over the β2‐adrenoceptor, with many actually being more β2‐selective.

This study shows that the β1/β2 selectivity of most clinically used β‐blockers is poor in intact cells, and that some compounds that are traditionally classed as ‘β1‐selective’ actually have higher affinity for the β2‐adrenoceptor. There is therefore considerable potential for developing more selective β‐antagonists for clinical use and thereby reducing the side‐effect profile of β‐blockers.

British Journal of Pharmacology (2005) 144, 317–322. doi:10.1038/sj.bjp.0706048
Endothelin‐1 exerts a preconditioning‐like cardioprotective effect against ischaemia/reperfusion injury via the ETA receptor and the mitochondrial KATP channel in the rat in vivo
Authors: Gourine Audrey V , Molosh Audrey I , Poputnikov Dmitry , Bulhak Aliaksandr , Sjöquist Per‐Ove , Pernow John
Published: January 2005

In vitro studies have demonstrated that endothelin‐1 (ET‐1) given before myocardial ischaemia may evoke a preconditioning (PC)‐like cardioprotective effect. The first aim of this study was to investigate whether administration of ET‐1 before ischaemia exerts cardioprotection against ischaemia/reperfusion injury in vivo and to determine involvement of the ET‐1 receptor subtype. The second aim was to examine the role of mitochondrial ATP‐sensitive K+ channels (mitoKATP) as a mediator of this cardioprotection.

Anaesthetised open‐chest Wistar rats were subjected to 30 min of coronary artery occlusion followed by 2 h reperfusion (I/R). In protocol I, the first group was subjected to I/R only (control, n=10). In the second (n=10) group, PC was elicited by three 5 min cycles of coronary artery occlusion, separated by 5 min reperfusion before I/R. The third (n=6) and fourth (n=7) groups were given ET‐1 intravenous (i.v.) during three 5 min infusion periods separated by 5 min before I/R. The fourth group was in addition given the ETA receptor antagonist LU 135252 5 min before the infusions of ET‐1. In protocol II, the first group was I/R control as in protocol I (n=8). The second (n=6), third (n=7) and fourth (n=7) groups were given ET‐1 as in protocol I. The third group was in addition given the nonselective KATP channel antagonist glibenclamide (Glib) 30 min before the ET‐1 infusions and the fourth group the selective mitoKATP channel antagonist 5‐hydroxydecanoic acid (5‐HD) 5 min before I/R.

There were no significant differences in MAP or heart rate between the groups during I/R. In protocol I, PC reduced IS compared to the control group (10±3 vs 35±5%, P<0.01). Infusion of ET‐1 also reduced IS (to 14±3%, P<0.05 vs control). The ETA receptor antagonist blocked the reduction in IS induced by ET‐1 (IS 47±8% after LU+ET‐1; P< 0.05 vs ET‐1). In protocol II, Glib and 5‐HD abolished the cardioprotective effect induced by ET‐1 (IS 48±7% after Glib+ET‐1 and 42±5% after ET‐1+5‐HD vs 18±4% after ET‐1 alone; P<0.05).

In conclusion, administration of ET‐1 before ischaemia resulted in a PC‐like cardioprotective effect. This effect is mediated via the ETA receptor and activation of mitoKATP channels.

British Journal of Pharmacology (2005) 144, 331–337. doi:10.1038/sj.bjp.0706050
Gastrin promotes human colon cancer cell growth via CCK‐2 receptor‐mediated cyclooxygenase‐2 induction and prostaglandin E2 production
Authors: Colucci Rocchina , Blandizzi Corrado , Tanini Marzia , Vassalle Cristina , Breschi Maria Cristina , Tacca Mario Del
Published: January 2005

The present study investigates the effects of gastrin‐17 on human colon cancer HT‐29 cells to examine whether gastrin receptor (CCK‐2), cyclooxygenase (COX‐1, COX‐2) isoforms and prostaglandin receptor pathways interact to control cell growth.

Reverse transcription (RT)–polymerase chain reaction (PCR) analysis demonstrated that HT‐29 cells are endowed with the naïve expression of CCK‐2 receptor (short splice variant), COX‐1, COX‐2 and prostaglandin EP4 receptor, but not gastrin.

Gastrin‐17 significantly promoted cell growth and DNA synthesis. Both these stimulating effects were abolished by L‐365,260 or GV150013 (CCK‐2 receptor antagonists), but were unaffected by SC‐560 (COX‐1 inhibitor). L‐745,337 (COX‐2 inhibitor) or AH‐23848B (EP4 receptor antagonist) partly reversed gastrin‐17‐induced cell growth, while they fully antagonized the enhancing action on DNA synthesis.

HT‐29 cells responded to gastrin‐17 with a significant increase in prostaglandin E2 release. This enhancing effect was completely counteracted by L‐365,260, GV150013 or L‐745,337, while it was insensitive to cell incubation with SC‐560.

Exposure of HT‐29 cells to gastrin‐17 was followed by an increased phosphorylation of both extracellular regulated kinases (ERK‐1/ERK‐2) and Akt. Moreover, gastrin‐17 enhanced the transcriptional activity of COX‐2 gene promoter and stimulated COX‐2 expression. These latter effects were antagonized by L‐365,260 or GV150013, and could be blocked also by PD98059 (inhibitor of ERK‐1/ERK‐2 phosphorylation) or wortmannin (inhibitor of phosphatidylinositol 3‐kinase). Analogously, gastrin‐17‐induced prostaglandin E2 release was prevented by PD98059 or wortmannin.

The present results suggest that (a) in human colon cancer cells endowed with CCK‐2 receptors, gastrin‐17 is able to enhance the transcriptional activity of COX‐2 gene through the activation of ERK‐1/ERK‐2‐ and phosphatidylinositol 3‐kinase/Akt‐dependent pathways; (b) these stimulant actions lead to downstream increments of COX‐2 expression, followed by prostaglandin E2 production and EP4 receptor activation; (c) the recruitment of COX‐2/prostaglandin pathways contributes to the growth‐promoting actions exerted by gastrin‐17.

British Journal of Pharmacology (2005) 144, 338–348. doi:10.1038/sj.bjp.0706053
Excessive stimulation of poly(ADP‐ribosyl)ation contributes to endothelial dysfunction in pre‐eclampsia
Authors: Crocker Ian P , Kenny Louise C , Thornton Wayne A , Szabo Csaba , Baker Philip N
Published: January 2005

Pre‐eclampsia is a serious pregnancy disorder associated with widespread activation of the maternal vascular endothelium. Recent evidence implicates a role for oxidative stress in the aetiology of this condition.

Reactive oxygen species, particularly superoxide anions, invokes endothelial cell activation through many pathways. Oxidant‐induced cell injury triggers the activation of nuclear enzyme poly(ADP‐ribose) polymerase (PARP) leading to endothelial dysfunction in various pathophysiological conditions (reperfusion, shock, diabetes).

We have studied whether the loss of endothelial function in pre‐eclampsia is dependent on PARP activity. Endothelium‐dependent responses of myometrial arteries were tested following exposure to either plasma from women with pre‐eclampsia or normal pregnant women in the presence and absence of a novel potent inhibitor of PARP, PJ34. Additional effects of plasma and PJ34 inhibition were identified in microvascular endothelial cell cultures.

In myometrial arteries, PARP inhibition blocked the attenuation of endothelium‐dependent responses following exposure to plasma from women with pre‐eclampsia. In endothelial cell cultures, plasma from pre‐eclamptics induced measurable oxidative stress and a concomitant increase in PARP activity and reduction in cellular ATP. Again, these biochemical changes were reversed by PJ34.

These results suggest that PARP activity plays a pathogenic role in the development of endothelial dysfunction in pre‐eclampsia and promotes PARP inhibition as a potential therapy in this condition.

British Journal of Pharmacology (2005) 144, 772–780. doi:10.1038/sj.bjp.0706055
Anxiogenic properties of an inverse agonist selective for α3 subunit‐containing GABAA receptors
Authors: Atack John R , Hutson Peter H , Collinson Neil , Marshall George , Bentley Graham , Moyes Christopher , Cook Susan M , Collins Ian , Wafford Keith , McKernan Ruth M , Dawson Gerard R
Published: January 2005

α3IA (6‐(4‐pyridyl)‐5‐(4‐methoxyphenyl)‐3‐carbomethoxy‐1‐methyl‐1H‐pyridin‐2‐one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABAA receptors containing an α3 rather than an α1, α2 or α5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of α3IA are most probably mediated by the α3 subtype.

α3IA has good CNS penetration in rats and mice as measured using a [3H]Ro 15‐1788 in vivo binding assay.

At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e. α1‐containing receptors), α3IA (30 mg kg−1 i.p.), like the nonselective partial inverse agonist N‐methyl‐β‐carboline‐3‐carboxamide (FG 7142), not only caused behavioural disruption in an operant, chain‐pulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic‐like effect that could be blocked with the benzodiazepine antagonist Ro 15‐1788 (flumazenil).

Neurochemically, α3IA (30 mg kg−1 i.p.) as well as FG 7142 (15 mg kg−1 i.p.) increased the concentration of the dopamine metabolite 3,4‐dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle‐treated animals, a response that mimicked that seen following immobilisation stress.

Taken together, these data demonstrate that an inverse agonist selective for GABAA receptors containing an α3 subunit is anxiogenic, and suggest that since α3‐containing GABAA receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.

British Journal of Pharmacology (2005) 144, 357–366. doi:10.1038/sj.bjp.0706056
Conserved structural, pharmacological and functional properties among the three human and five zebrafish α2‐adrenoceptors
Authors: Ruuskanen Jori O , Laurila Jonne , Xhaard Henri , Rantanen Ville‐Veikko , Vuoriluoto Karoliina , Wurster Siegfried , Marjamäki Anne , Vainio Minna , Johnson Mark S , Scheinin Mika
Published: January 2005

Zebrafish has five distinct α2‐adrenoceptors. Two of these, α2Da and α2Db, represent a duplicated, fourth α2‐adrenoceptor subtype, while the others are orthologue of the human α2A‐, α2B‐ and α2C‐adrenoceptors. Here, we have compared the pharmacological properties of these receptors to infer structural determinants of ligand interactions.

The zebrafish α2‐adrenoceptors were expressed in Chinese hamster ovary cells and tested in competitive ligand binding assays and in a functional assay (agonist‐stimulated [35S]GTPγS binding). The affinity results were used to cluster the receptors and, separately, the ligands using both principal component analysis and binary trees.

The overall ligand binding characteristics, the order of potency and efficacy of the tested agonists and the G‐protein coupling of the zebrafish and human α2‐adrenoceptors, separated by ∼350 million years of evolution, were found to be highly conserved. The binding affinities of the 20 tested ligands towards the zebrafish α2‐adrenoceptors are generally comparable to those of their human counterparts, with a few compounds showing up to 40‐fold affinity differences.

The α2A orthologues and the zebrafish α2D duplicates clustered as close pairs, but the relationships between the orthologues of α2B and α2C were not clearly defined. Applied to the ligands, our clustering methods segregated the ligands based on their chemical structures and functional properties. As the ligand binding pockets formed by the transmembrane helices show only minor differences among the α2‐adrenoceptors, we suggest that the second extracellular loop – where significant sequence variability is located – might contribute significantly to the observed affinity differences.

British Journal of Pharmacology (2005) 144, 165–177. doi:10.1038/sj.bjp.0706057