bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract Art and Left-Wing Politics in the Weimar Republic
Authors: Lidtke Vernon L.
Published: March 2004

In the midst of the upheaval created by military defeat, the collapse of the Hohenzollern and other German monarchies, and the threat of radical social revolution, a movement that had been taking shape for some time became a visible presence in German public life. Intellectuals, writers, visual artists, and numerous others declared that they would no longer remain aloof from the world of politics, social reform, and even revolution. On the contrary, they would seek to merge the arts and politics into a synthesis that would help to mold a new and greatly improved society. They issued manifestos and programs, founded organizations and journals, joined political parties — primarily on the left — and went to the streets, at least to observe if not also to act. The majority of the participants in this movement were, at some point in their careers, part of new artistic trends and, as such, contributors to the formation and advancement of aesthetic modernism in Germany.
The Elections Cartel in Regierungsbezirk Bromberg (Bydgoszcz), 1898–1903: Ethnic Rivalry, Agrarianism, and “Practicing Democracy”
Authors: Spickermann Roland
Published: March 2004

In debates on the nature and degree of democratization in the Kaiserreich, the dynamics of rural politics have received perhaps less attention than they merit. Indeed, though the picture is more nuanced now, for a long period the ability of rural elites to dominate nonelites (a core aspect of these dynamics) was simply assumed, as was the relationship of this dominance to Germany's troubled democratization. In his 1943 workBread and Democracy in Germany, for example, Alexander Gerschenkron blamed Germany's entrenched and elitist aristocracy for this trait of bullying voters into antidemocratic politics spanning from the Kaiserreich to the Third Reich. More subtly, the landmark 1966 study of Barrington Moore, Jr. noted the potential for an alliance between entrenched aristocracies and small peasantries, with each as reservoirs for antidemocratic (and potentially fascist) sentiment in several countries, with obvious application to the German case as well.
Vorticity Balance in Coarse-Resolution Global Ocean Simulations
Authors: Lu Youyu , Stammer Detlef
Published: March 2004

The vorticity budget of the vertically integrated circulation from two global ocean simulations is analyzed using a horizontal spacing of 2° × 2° in longitude/latitude. The two simulations differ in their initial hydrographic conditions and surface wind and buoyancy forcing. The constrained simulation obtains optimal initial condition and surface forcing through assimilating observational data using the model's adjoint, whereas the unconstrained simulation uses Levitus climatological conditions for initialization and is driven by NCEP–NCAR reanalysis forcing, plus restoring to the monthly surface temperature and salinity climatological conditions. The goal is to examine the dynamics that sets the time-mean circulation and to understand the differences between the constrained and unconstrained simulations. It is found that, similar to eddy-permitting simulations, the bottom pressure torque (BPT) in coarse-resolution models plays an important role in the western boundary currents and in the Southern Ocean, and largely balances the difference between wind stress curl and βV for the depth-integrated flow. BPT is a controlling factor of the interior abyssal flow. The geostrophic vorticity relation holds in the interior basins in intermediate and deep layers and breaks down in the upper ocean toward the surface. In the upper layer of the interior basins, the model simulations show statistically significant deviation from the Sverdrup balance. In the subtropical gyre regions, the deviation from Sverdrup balance is confined to zonal bands that are balanced by the curls of lateral friction and nonlinear advection. The differences between the constrained and unconstrained simulations are significant in vorticity terms. The adjustment to Levitus hydrographic climatological data as the model's initial condition causes the most significant changes in BPT, which is the main reason for changes in abyssal flow. The analysis also points to needs for further improvement of models and controlling the influence of data errors in ocean state estimation.
A Laboratory Model of Thermocline Depth and Exchange Fluxes across Circumpolar Fronts*
Authors: Cenedese Claudia , Marshall John , Whitehead J. A.
Published: March 2004

A laboratory experiment has been constructed to investigate the possibility that the equilibrium depth of a circumpolar front is set by a balance between the rate at which potential energy is created by mechanical and buoyancy forcing and the rate at which it is released by eddies. In a rotating cylindrical tank, the combined action of mechanical and buoyancy forcing builds a stratification, creating a large-scale front. At equilibrium, the depth of penetration and strength of the current are then determined by the balance between eddy transport and sources and sinks associated with imposed patterns of Ekman pumping and buoyancy fluxes. It is found that the depth of penetration and transport of the front scale like [(fwe)/g′]L and weL2, respectively, where we is the Ekman pumping, g′ is the reduced gravity across the front, f is the Coriolis parameter, and L is the width scale of the front. Last, the implications of this study for understanding those processes that set the stratification and transport of the Antarctic Circumpolar Current (ACC) are discussed. If the laboratory results scale up to the ACC, they suggest a maximum thermocline depth of approximately h = 2 km, a zonal current velocity of 4.6 cm s−1, and a transport T = 150 Sv (1 Sv ≡ 106 m3 s−1), not dissimilar to what is observed.
Aspects of the Mean Wintertime Circulation along Australia's Southern Shelves: Numerical Studies
Authors: Cirano Mauro , Middleton John F.
Published: March 2004

A high-resolution numerical model is used to study the mean wintertime shelf-slope circulation between the Gulfs of South Australia and the west coast of Tasmania. The mean downwelling-favorable winds for the region result in a continuous eastward coastal current (CC) extending from Cape Leeuwin to the eastern coast of Tasmania. The magnitude of the CC is generally largest over the shelf break, has speeds of more than 40 cm s−1 [transport 2.4 Sv (Sv ≡ 106 m3 s−1)], and is generally in good agreement with observations. The relative importance of the Leeuwin Current, zonal winds, and density gradients to the shelf circulation is established. Within Bass Strait, the eastward circulation is in good agreement with observations and simple models show that about 30% of the transport arises from local winds and the remainder from the CC. The total transport through the strait (0.95 Sv) is shown to be controlled by sea level on the east coast of Tasmania. A current of up to 10 cm s−1 is also found to flow from Tasmania to Esperance in the far west (transport 6.8 Sv) and to be centered within the permanent thermocline (depth 600 m) and near the shelf slope. This Flinders Current arises from the equatorward Sverdrup transport but is also fed by the “Tasman outflow” that enters the region off of the southern tip of Tasmania. A sensitivity study shows that dense water formation occurs off of Spencer Gulf and the cascade to depths of 250 m is in qualitative agreement with observations. Dense water formed near the coast can enhance the CC by up to 5 cm s−1. Suggestions for future modeling and observational studies are made.
Deep-Water Flow in the Mariana and Caroline Basins*
Authors: Siedler Gerold , Holfort Jürgen , Zenk Walter , Müller Thomas J. , Csernok Tiberiu
Published: March 2004

Two major water masses dominate the deep layers in the Mariana and Caroline Basins: the Lower Circumpolar Water (LCPW), arriving from the Southern Ocean along the slopes north of the Marshall Islands, and the North Pacific Deep Water (NPDW) reaching the region from the northeastern Pacific Ocean. Hydrographic and moored observations and multibeam echosounding were performed in the East Mariana and the East Caroline Basins to detail watermass distributions and flow paths in the area. The LCPW enters the East Mariana Basin from the east. At about 13°N, however, in the southern part of the basin, a part of this water mass arrives in a southward western boundary flow along the Izu–Ogasawara–Mariana Ridge. Both hydrographic observations and moored current measurements lead to the conclusion that this water not only continues westward to the West Mariana Basin as suggested before, but also provides bottom water to the East Caroline Basin. The critical throughflow regions were identified by multibeam echosounding at the Yap Mariana Junction between the East and West Mariana Basins and at the Caroline Ridge between the East Mariana and East Caroline Basins. The throughflow is steady between the East and West Mariana Basins, whereas more variability is found at the Caroline Ridge. At both locations, throughflow fluctuations are correlated with watermass property variations suggesting layer-thickness changes. The total transport to the two neighboring basins is only about 1 Sverdrup (1Sv ≡ 106 m3 s−1) but has considerable impact on the watermass structure in these basins. Estimates are given for the diapycnal mixing that is required to balance the inflow into the East Caroline Basin. Farther above in the water column, the high-silica tongue of NPDW extends from the east to the far southwestern corner of the East Mariana Basin, with transports being mostly southward across the basin.
Wave Breaking and Ocean Surface Layer Thermal Response
Authors: Mellor George , Blumberg Alan
Published: March 2004

The effect of breaking waves on ocean surface temperatures and surface boundary layer deepening is investigated. The modification of the Mellor–Yamada turbulence closure model by Craig and Banner and others to include surface wave breaking energetics reduces summertime surface temperatures when the surface layer is relatively shallow. The effect of the Charnock constant in the relevant drag coefficient relation is also studied.
The Relationship between Sea Surface Temperature and Thermocline Depth in the Eastern Equatorial Pacific
Authors: Zelle Hein , Appeldoorn Gerrian , Burgers Gerrit , van Oldenborgh Geert Jan
Published: March 2004

The time dependence of the local relation between sea surface temperature (SST) and thermocline depth in the central and eastern equatorial Pacific Ocean is analyzed for the period 1990–99, using subsurface temperature measurements from the Tropical Atmosphere–Ocean Array/Triangle Trans-Ocean Buoy Network (TAO/TRITON) buoy array. Thermocline depth anomalies lead SST anomalies in time, with a longitude-dependent delay ranging from 2 weeks in the eastern Pacific to 1 year in the central Pacific. The lagged correlation between thermocline depth and SST is strong, ranging from r > 0.9 in the east to r ≈ 0.6 at 170°W. Time-lagged correlations between thermocline depth and subsurface temperature anomalies indicate vertical advection of temperature anomalies from the thermocline to the surface in the eastern Pacific. The measurements are compared with the results of forced OGCM and linear model experiments. Using model results, it is shown that the delay between thermocline depth and SST is caused mainly by upwelling and mixing between 140° and 90°W. Between 170°E and 140°W the delay has a different explanation: thermocline depth anomalies travel to the eastern Pacific, where upwelling creates SST anomalies that in turn cause anomalous wind in the central Pacific. SST is then influenced by these wind anomalies.
Gastrointestinal Uptake of Agmatine: Distribution in Tissues and Organs and Pathophysiologic Relevance
Authors: MOLDERINGS GERHARD J. , HEINEN ANJA , MENZEL SIGRID , LÜBBECKE FRIEDRICH , HOMANN JÜRGEN , GÖTHERT MANFRED
Published: March 2004

Abstract: The authors report on (1) the absorption of agmatine from the gastrointestinal tract as an important source of this polycation in the organism, (2) its organ distribution, and (3) its putative role in liver regeneration. When rats received 0.5 mCi [14C]agmatine contained in 5 grams of standard rat chow after a fasting period of 24 hours, radioactivity was recovered in all organs investigated, in blood, and in urine. In the liver 67%± 7% of administered radioactivity was found. After partial (two‐thirds) hepatectomy, administration of 250 mg and 500 mg agmatine by gavage for 6 days reduced liver regeneration at day 7 by 20% and 22%, respectively, compared with animals that received no agmatine. Agmatine is absorbed from the gastrointestinal tract, probably by means of a specific transporter. It is likely that agmatine in the chyme of the gut represents an essential source of agmatine in the tissues of the organism. An increase in the availability of gastrointestinal agmatine for absorption impairs liver regeneration and may contribute to the development of liver diseases.
Agmatine Crosses the Blood‐Brain Barrier
Authors: PILETZ J E. , MAY P J. , WANG G , ZHU H
Published: March 2004

Abstract: The question of whether agmatine crosses the blood‐brain barrier has not been directly addressed, even though peripheral injection of this compound has produced behavioral responses in drug withdrawal, antidepressant, and anti‐anxiety paradigms. Two models were used in this investigation. In the first, mice were injected intraperitoneally (i.p.) with agmatine (10, 50, or 300 mg/kg body weight) or arginine (600 mg/kg). After 1 or 3 hours, the animals were killed under gas anesthesia by perfusing their brains with ice‐cold saline, and whole‐brain agmatine was measured by HPLC. In parallel studies, a rhesus monkey was injected under gas anesthesia either intravenously (i.v.) with agmatine (30 mg/kg) or arginine (150 mg/kg), or intracerebroventricularly (i.c.v.) with agmatine (0.3 mg/kg i.c.v.). At varying times thereafter, cisterna magna cerebrospinal fluid (CSF) and blood plasma were collected and analyzed for agmatine levels. A rise in mouse brain agmatine was apparent after doses of 50 and 300 mg/kg i.p. Monkey CSF agmatine peaked in parallel with plasma agmatine 15 minutes following intravenous (i.v.) agmatine injection and at one sixth the level of the plasma peak. Monkey CSF agmatine peaked 43 minutes after i.v. arginine injection. The ventricular injection of agmatine resulted in a threefold sustained rise in blood plasma agmatine for at least 24 hours after injection. Therefore, agmatine and its precursor, arginine, cross the blood‐brain barrier. CSF agmatine may be newly synthesized from peripherally injected arginine.
Identification and Pharmacological Characterization of a Specific Agmatine Transport System in Human Tumor Cell Lines
Authors: MOLDERINGS GERHARD J. , BRUSS MICHAEL , BONISCH HEINZ , GÖTHERT MANFRED
Published: March 2004

Abstract: Specific accumulation of [14C]agmatine in six human intestinal tumor cell lines and in the glioma cell line SK‐MG‐1 was inhibited by phentolamine, idazoxan, clonidine, 1,3‐di‐(2‐tolyl)guanidine, histamine, putrescine, spermine and spermidine. Corticosterone, desipramine, O‐methylisoprenaline, cirazoline, moxonidine, l‐arginine, l‐lysine, verapamil, nifedipine, CdCl2, ondansetron, and l‐carnitine failed to inhibit specific [14C]agmatine accumulation, thus excluding that it is mediated by amino acid or monoamine carriers, by the putrescine carrier, by 5‐HT3 receptor channels, by Ca2+ channels or by the organic cation transporters OCT1, OCT2, OCT3, OCTN1, or OCTN2. This conclusion is supported by the finding that transfection of HEK293 cells with cDNA encoding either hOCT1, hOCT2, or hOCT3 did not enhance specific [14C]agmatine accumulation compared to nontransfected cells. The data suggest that agmatine is accumulated by a specific agmatine transporter. Since incubation with exogenous agmatine for 24 hours increased intracellular agmatine content in all cell lines by a multiple of the basal endogenous content, the agmatine uptake system may be relevant for the regulation of the intra‐ and extracellular concentration of agmatine in humans.
Neuropharmacokinetic and Dynamic Studies of Agmatine (Decarboxylated Arginine)
Authors: NGUYEN H OANH X. , GORACKE‐POSTLE CORY J. , KAMINSKI LORI L. , OVERLAND AARON C. , MORGAN ANDREW D. , FAIRBANKS CAROLYN A.
Published: March 2004

Abstract: Agmatine has been previously proposed to represent a novel neurotransmitter. One of the criteria required to test that hypothesis is that the exogenously administered chemical produces pharmacological effects similar to the physiological effects of the putative neurotransmitter. Since agmatine was first identified in brain, approximately sixty studies of the in vivo effects of exogenously administered agmatine have been reported. Despite the assertion that agmatine functions as a neuromodulator/neurotransmitter, the vast majority of experiments have administered agmatine through systemic (rather than central) routes of administration. Systemic delivery of agmatine for studies of centrally mediated phenomenona (e.g., pain, spinal cord injury, cardiovascular responses) relies on the presumption that agmatine (a polar compound) gains appreciable access to the CNS. The mechanism by which agmatine crosses the blood‐brain barrier is not well understood. A number of studies have examined the in vivo effects of agmatine following central administration (e.g., intracerebroventricular and intrathecal). This paper summarizes and provides a comparison between the systemic versus central routes of administration for delivery of agmatine in experimental subjects.
Spinal and Supraspinal Agmatine Activate Different Receptors to Enhance Spinal Morphine Antinociception
Authors: ROERIG SANDRA C.
Published: March 2004

Abstract: The endogenous clonidine‐displacing substance, agmatine, enhances morphine‐induced antinociception and inhibits development of tolerance to morphine. Because agmatine binds with relatively high affinity to both a2 adrenergic and inidazoline (I) receptors, the following studies were designed to determine which receptor type is involved in the morphine‐enhancing activity. Mice were injected by various routes with agmatine, clonidine or norepinephrine as well as selective antagonists, and tail flick antinociception was measured. Agmatine administered subcutaneously (s.c.), intracerebroventricularly (i.c.v.), or intrathecally (i.t.) had no antinociceptive activity, but enhanced the antinociception produced by i.t. morphine. The morphine‐enhancing activity of i.c.v. agmatine (and clonidine) was attenuated by coadministered yohimbine, idazoxan and SK&F 86466 (a2 antagonists). When given i.t., agmatine, yohimbine and SK&F 86466 attenuated the antinociception produced by coadministered i.t. clonidine. In contrast, i.t. yohimbine and SK&F 86466, but not agmatine, attenuated antinociception produced by i.t. norepinephrine. These results suggested that agmatine actions were different at brain and spinal sites. Thus, agmatine may act at both a2 and I receptors in the brain and I receptors in the spinal cord.
Is Agmatine an Endogenous Factor Against Stress?
Authors: ARICIOGLU FEYZA , REGUNATHAN SOUNDAR , PILETZ JOHN E.
Published: March 2004

Abstract: Agmatine is an endogenous amine synthesized from the decarboxylation of arginine. A proposed intracellular role of agmatine is to balance the production of polyamines (a promitotic process) and nitric oxide (an inflammatory process). Agmatine is also released from neurons upon depolarization. We previously reported that agmatine concentrations are increased in rat pups' brains shortly after hypoxic‐ischemia and in the plasma of depressed patients. Herein, male rats (270–290 g) were divided into four groups receiving different degrees of known stress: 2‐hour restraint at 21°C, 4‐hour restraint at 21°C, 4‐hour restraint at 4°C, and control rats only handled at 21°C. Cortex, cerebellum, medulla, hippocampus, hypothalamus, and blood plasma samples were collected for determination of endogenous agmatine levels. No changes in agmatine levels were detected after 2‐hour and 4‐hour restraint at room temperature, but concentrations of agmatine were increased in all brain regions except cerebellum after 4‐hour restraint in the cold. Plasma agmatine levels (ng/mL) were 6.8 6 0.6 in controls versus 58.1 6 12.8 in the 4‐hour restraint‐plus‐cold group. Cortical agmatine levels (ng/g wet tissue) were 15.3 6 2.4 in controls versus 57.4 6 19.6 in the 4‐hour restraint‐plus‐cold group. Therefore, endogenous agmatine was increased in response to cold‐restraint stress, possibly as a neuroprotective agent.
Agmatine‐Morphine Interaction on Nociception in Mice
Authors: RUIZ‐DURÁNTEZ EDUARDO , LLORENTE JAVIER , ULIBARRI ISABEL , PINEDA JOSEBA , UGEDO LUISA
Published: March 2004

Abstract: The aim of this study was to investigate the possible participation of nitric oxide in the agmatine‐mediated potentiation of morphine‐induced analgesia in mice. Agmatine and L‐NAME (a nitric oxide synthesis inhibitor) enhanced morphine‐induced analgesia in the tail flick test, but not in the hot plate test. L‐NAME did not block the agmatine‐induced potentiation of morphine effect. Our results indicate that agmatine potentiates morphine‐induced spinal but not supraspinal analgesia, and that this effect is not mediated by a nitric oxide‐dependent mechanism.
Agmatine Inhibits Naloxone‐Induced Contractions in Morphine‐Dependent Guinea Pig Ileum
Authors: ARICIOGLU FEYZA , ERCIL ESER , DULGER GUL
Published: March 2004

Abstract: This study investigates the effects of agmatine on naloxone‐precipitated withdrawal syndrome in morphine‐dependent guinea pig ileum. Male guinea pigs that were starved for 24 hours were decapitated after cervical dislocation, and terminal portions of the ilea were removed. Segments were fixed at a resting tension of 1 g in an organ bath containing 1 3 1026 M morphine in Tyrode solution at 378C, which was bubbled with 95% O2 and 5% CO2. Tissues were incubated in morphine containing Tyrode solution for 4 hours before agmatine was added. Naloxone and agmatine had no effect on naive ilea. Naloxone (1 3 1026 M) contracted morphine‐dependent ilea. Agmatine significantly inhibited the contractile response to naloxone in a dose‐dependent manner (1 3 1027 M, 44%; 1 3 1026 M, 80%; 1 3 1025 M, 95%). This effect of agmatine was partly abolished by pretreatment with yohimbine and was almost completely abolished by idazoxan.
Effect of Agmatine on the Time Course of Brain Inflammatory Cytokines After Injury in Rat Pups
Authors: FENG YANGZHENG , LeBLANC MICHAEL H.
Published: March 2004

Abstract: Pro‐inflammatory cytokines play an important role in brain injury. Agmatine reduces brain injury. Does agmatine act by reducing cytokines? Seven‐day‐old rat pups had the right carotid artery ligated and then were subjected to 2.5 hours of 8% oxygen. Agmatine (100 mg/kg) or vehicle was administered at 5 minutes after reoxygenation. Cytokines were measured in the cortex by enzyme‐linked immunosorbent assay. Interleukin (IL)‐6, IL‐1b, and tumor necrosis factor‐alpha (TNF‐a) were significantly increased after reoxygenation. Agmatine had no effect.
Characterization of [3H]Harmane Binding to Rat Whole Brain Membranes
Authors: ANDERSON N J. , ROBINSON ES J. , HUSBANDS S M. , DELAGRANGE P , NUTT D J. , HUDSON A L.
Published: March 2004

Abstract: This study investigates the binding of [3H]harmane to rat whole brain homogenates. Saturation studies revealed [3H]harmane labels a single, saturable, high‐capacity population with high affinity. All the test compounds displaced [3H]harmane completely and in an apparently monophasic manner. The displacement profile of the test ligands indicated labeling of MAO‐A. Given the high level of MAO‐A binding, it is unlikely that a low‐capacity I2 site would be distinguishable from the total [3H]harmane population.
Effect of Harmane on Mononeuropathic Pain in Rats
Authors: ARICIOGLU FEYZA , KORCEGEZ EYLEM , OZYALCIN SULEYMAN
Published: March 2004

Abstract: This study was designed to investigate the effect of the endogenous b‐carboline, harmane, on neuropathic pain produced by chronic constriction injury (CCI) of the sciatic nerve. Thermal allodynia evaluations were made preoperatively, postoperatively on the fifteenth day, and after harmane administration. Harmane (1, 2.5, 5, 10, or 20 mg/kg) was administered intraperitoneally for 5 days beginning from postoperative day 15. Treatment with harmane had a profound anti‐allodynic effect in a dose‐dependent manner. In conclusion, harmane might provide a new approach to treatment of neuropathic pain.
Effect of Harmane on the Convulsive Threshold in Epilepsy Models in Mice
Authors: ARICIOGLU FEYZA , YILLAR OKAN , KORCEGEZ EYLEM , BERKMAN KEMAL
Published: March 2004

Abstract: The study investigated the activity of harmane on maximal electroshock seizures (MES) and seizures induced by pentilentetrazole (PTZ) in mice. Initial studies established convulsive current 50 (CC50) values or MES and effective dose 50 (ED50) for PTZ to produce seizures. Harmane (2.5, 5.0, or 10 mg/kg intraperitoneally) increased the threshold of seizures in MES dose‐dependently. The convulsions produced by PTZ were decreased by the low dose of harmane (2.5 mg/kg), but the high dose of harmane (10 mg/kg) resulted in worse grade V convulsions followed by more lethality compared with PTZ alone. Therefore, harmane seems to be protective against grand mal seizures in the MES model but not against a petit mal seizure model (PTZ) in mice.
Harmane Induces Anxiolysis and Antidepressant‐Like Effects in Rats
Authors: ARICIOGLU FEYZA , ALTUNBAS HALE
Published: March 2004

Abstract: A forced swim test (FST) and an elevated plus maze (EPM) were used to determine antidepressant and anxiolytic effects of harmane in rats in comparison with a known antidepressant, imipramine (30 mg/kg i.p.). Harmane (2.5, 5.0, or 10 mg/kg, i.p.), saline, or imipramine were given 30 minutes before the tests. Administration of harmane decreased the time of immobility in the FST dose‐dependently and increased the time spent in open arms in the EPM, as compared with the saline group. As an endogenous substance, harmane therefore has anti‐anxiety and antidepressant effects.
The Role of I1‐Imidazoline Receptors and a2‐Adrenergic Receptors in the Modulation of Glucose and Lipid Metabolism in the SHROB Model of Metabolic Syndrome X
Authors: KOLETSKY RICHARD J. , VELLIQUETTE RODNEY A. , ERNSBERGER PAUL
Published: March 2004

Abstract: Hypertension is commonly accompanied by obesity, hyperlipidemia, and insulin resistance in humans, a cluster of abnormalities known as metabolic syndrome X. With the notable exception of inhibitors of the renin‐angiotensin system, which have mildly beneficial effects on insulin resistance, most antihypertensive agents worsen one or more components of metabolic syndrome X. Second‐generation centrally acting antihypertensive agents such as rilmenidine and moxonidine have mixed effects on components of metabolic syndrome X, which might reflect in part actions on two different receptors: I1‐imidazoline and a2‐adrenergic. Using a rat model of metabolic syndrome X, we sought to separate the influence of these two receptors on glucose and lipid metabolism by using selective antagonists. Rilmenidine and moxonidine acutely raised glucose and lowered insulin, thereby further worsening glucose tolerance. These effects were entirely mediated by a2‐adrenergic receptors. Rilmenidine and moxonidine also lowered glucagon, an effect that was mediated solely by I1‐imidazoline receptors since it was potentiated by a2‐blockade, but eliminated in the presence of I1‐antagonists. Lowering of triglyceride and cholesterol levels followed the same pattern as glucagon, implicating I1‐imidazoline receptors in lipid‐lowering actions. Chronic treatment with moxonidine reproduced the beneficial effects on glucagon and lipids while the acute hyperglycemic response did not persist. Thus, a2‐adrenergic receptors mediate an acute deterioration of glucose tolerance, whereas in contrast I1‐imidazoline receptors appear to mediate the persistent long‐term improvements in glucose tolerance. The therapeutic action of I1‐imidazoline agonists may be primarily mediated through reduced glucagon secretion.
Involvement of Forebrain Imidazoline and a2‐Adrenergic Receptors in the Antidipsogenic Response to Moxonidine
Authors: ANDRADE CARINA A.F. , OLIVEIRA LISANDRA B. , MARTINEZ GIZELE , SILVA DANIELA C.F. , DE LUCA LAURIVAL A. , MENANI JOSÉ V.
Published: March 2004

Abstract: We investigated the participation of central a2‐adrenoceptors and imidazoline receptors in the inhibition of water deprivation‐induced water intake in rats. The a2‐adrenoceptor and imidazoline antagonist idazoxan (320 nmol), but not the a2‐adrenoceptor antagonist yohimbine, abolished the antidipsogenic effect of moxonidine (a2‐adrenoceptor and imidazoline agonist, 20 nmol) microinjected into the medial septal area. Yohimbine abolished the antidipsogenic effect of moxonidine intracerebroventricularly. Therefore, central moxonidine may inhibit water intake acting independently on both imidazoline receptors and a2‐adrenoceptors at different forebrain sites.
Alpha2A‐Adrenergic Versus Imidazoline Receptor Controversy in Rilmenidine's Action: Alpha2A‐Antagonism in Humans Versus Alpha2A‐Agonism in Rabbits
Authors: MOLDERINGS GERHARD J. , BÖNISCH HEINZ , BRUSS MICHAEL , GÖTHERT MANFRED
Published: March 2004

Abstract: At the a2A‐autoreceptors on the sympathetic nerve terminals of the human atrial appendages and rabbit pulmonary artery, rilmenidine and oxymetazoline exhibit different properties (antagonism and agonism, respectively). These opposite pharmacodynamic properties of a2‐adrenoceptor ligands seem to be due to substantial differences in the nucleotide and amino acid sequences between human and rabbit a2A‐adrenoceptors. Hence, the rabbit a2A‐adrenoceptor is not reliably predictive for the action of ligands at the human a2A‐adrenoceptor.
Atypical [3H]Clonidine Binding Sites in Human Caudate and Platelets on Cryostat‐cut Sections
Authors: ZHU H , HALARIS A , PILETZ JE
Published: March 2004

Abstract: Pharmacological characterization is described for a human imidazoline binding site (I‐site) labeled by [3H]clonidine using standard autoradiographic method. Under conditions that mask a2‐adrenergic sites, only a single high affinity site was observed in human caudate and blood platelet sections. Affinity constants (Ki) were highly correlated between the two tissues (r 5 0.90, P 5 0.0003). This site is dissimilar to classical I1 and I2 sites, even though both tissues possess abundant I1 and I2 sites by filtration binding methods. It is suggested that the isotonic buffer conditions inherent to the procedure alter drug affinities to the classical I1 site.
The Effects of Chronic Administration of Inhibitors of Flavin and Quinone Amine Oxidases on Imidazoline I1 Receptor Density in Rat Whole Brain
Authors: HOLT ANDREW , TODD KATHRYN G. , BAKER GLEN B.
Published: March 2004

Abstract: Many imidazoline ligands have been shown to bind to the active sites of several amine oxidases, and endogenous ligands such as agmatine and tryptamine are amine oxidase substrates. In order to ascertain whether concentrations of endogenous imidazoline receptor agonists might be regulated by amine oxidase activities, rats were administered saline, clorgyline, deprenyl, MDL 72274A, aminoguanidine, or a combination of clorgyline, deprenyl, and aminoguanidine, for 14 days, and then binding parameters for [3H]clonidine at imidazoline I1 receptors were determined in whole brain. Several EC 1.4.3.4, 1.4.3.6, and 1.5.3.11 amine oxidase activities were also measured ex vivo in tissues from treated animals. Results showed that drug treatments did not alter the affinity of clonidine for imidazoline I1 receptors. There was a tendency toward a reduction in receptor density when monoamine oxidase (MAO)‐A 1 MAO‐B, MAO‐B 1 semicarbazide‐sensitive amine oxidase (SSAO), or SSAO 1 diamine oxidase (DAO) were inhibited, and a marked reduction in density when MAO‐A 1 MAO‐B 1 SSAO were inhibited. These data suggest that amines that are substrates both for MAO and for SSAO, such as tryptamine and other trace amines, may act as endogenous imidazoline I1 receptor agonists, at which they may have neuromodulatory efficacy. A role for b‐carbolines, which can form endogenously from tryptamine, is also supported by the present findings.
Restoration of First‐Phase Insulin Secretion by the Imidazoline Compound LY374284 in Pancreatic Islets of Diabetic db/db Mice
Authors: BRENNER MB , GROMADA J , EFANOV AM , BOKVIST K , MEST H‐J
Published: March 2004

Abstract: The effect of the imidazoline compound LY374284 has been studied in pancreatic islets of db/db mice, a progressive model of diabetes. In perifusion experiments, pancreatic islets of db/db mice showed a progressive deterioration of glucose‐induced insulin release with increasing age, whereby the first phase of insulin secretion was almost completely abolished and the second phase was substantially decreased by 15 weeks of age. LY374284 restored the first phase of glucose‐induced insulin secretion in islets of 16‐week‐old db/db mice to 70% of that observed in islets isolated from age‐matched nondiabetic db/1 mice. LY374284 did not affect insulin secretion at a low glucose concentration (3.3 mmol/L). A similar restoration of first phase insulin secretion was observed after application of glucagon‐like peptide‐1, whereas a sulfonylurea agent, tolbutamide, was inactive. LY374284 did not affect cytosolic Ca21 concentration or cellular ATP content. Furthermore, LY374284 strongly enhanced insulin secretion in islets of db/db and db/1 mice maximally depolarized by 30 mmol/L K1 and 250 mmol/L diazoxide. The present data suggest that the imidazoline compound LY374284 restores biphasic insulin secretion in islets of diabetic db/db mice by amplifying glucose‐induced insulin secretion at a site distal to Ca21‐influx.
Association Between I2 Binding Sites and Monoamine Oxidase‐B Activity in Platelets
Authors: ZHU H , PILETZ JE
Published: March 2004

Abstract: An I2 imidazoline binding site on monoamine oxidase‐B (MAO‐B) is known to be encoded by a noncatalytic part of the enzyme, different from that which recognizes mechanism‐based inhibitors. Herein, the relationship between I2‐imidazoline binding sites and MAO‐B activity has been assessed using a semi‐purified source of MAO‐B: platelet mitochondrial membranes. A positive correlation between I2 sites and MAO‐B activity was observed (r 5 0.61, P 5 0.0016) among 24 human subjects. Nevertheless, the variance in MAO‐B activity cannot be completely accounted for in relation to I2 sites. Therefore, I2 density and MAO‐B activity are only weakly correlated in platelets.
Initial Evaluation of Novel Selective Ligands for Imidazoline2 Receptors in Rat Whole Brain
Authors: TYACKE RJ , SAZCZEWSKI F , TABIN P , SAZCZEWSKI J , NUTT DJ , HUDSON AL
Published: March 2004

Abstract: Indazim, the indazole analogue of 2BFI, and four methyl‐substituted analogues were tested for their affinity at the imidazoline2 binding site (I2‐BS), and this affinity was compared with their affinity at the α2‐adrenoceptor to determine their structure, affinity relationship, and selectivity at the I2‐BS. These studies showed that these ligands were highly selective for the I2‐BS compared with 2BFI and that substitution at the 4 and 7 positions increased affinity without affecting selectivity.
Cell Signaling by Imidazoline‐1 Receptor Candidate, IRAS, and the Nischarin Homologue
Authors: PILETZ JE , WANG G , ZHU H
Published: March 2004

Abstract: IRAS transfection into Chinese hamster ovary (CHO) or pheochromocytoma (PC‐12) cell lines leads to the appearance of nonadrenergic binding sites for radiolabeled‐clonidine. Nischarin is the mouse homologue of IRAS. IRAS seems to be a cytosolic protein that is anchored to the intracellular side of plasma membranes by a POX domain. Previous studies of IRAS‐transfected HEK293 cells, and Nischarin‐transfected 3T3 cells have shown this protein can intrinsically mediate cell growth and differentiation independent of imidazoline drugs through binding to insulin receptor substrates (HEK293 cells) and fibronectin receptors (3T3 cells). Herein, a growth‐arrested PC‐12 cell line stably transfected with IRAS is shown to express lower basal and nerve growth factor‐stimulated levels of the activated form of extracellular receptor kinase than found in a vector‐only transfected control cell line treated similarly. These findings suggest that IRAS is a membrane‐associated mediator of receptor signaling.
IRAS Is an Anti‐Apoptotic Protein
Authors: DONTENWILL MONIQUE , PILETZ JOHN E. , CHEN MICHAEL , BALDWIN JAMES , PASCAL GÉRALDINE , RONDÉ PHILIPPE , DUPUY LAURENCE , GRENEY HUGUES , TAKEDA KEN , BOUSQUETD PASCAL
Published: March 2004

Abstract: Active cell death, also known as apoptosis, has been implicated in the pathophysiology of diseases such as cancer, heart failure and neurodegenerative disorders. We report the anti‐apoptotic function of IRAS, which was previously shown to bind imidazoline ligands. The amino acid sequence of human IRAS (hIRAS) is unrelated to known proteins, except for rat IRAS and a mouse homologue named nischarin, which binds the alpha5 integrin subunit of the fibronectin receptor. When stably transfected into PC12 cells, hIRAS localizes to the cytosol as a 167 kDa immunoreactive protein. Clonal PC12 cell lines expressing hIRAS displayed normal serum growth responses. However, hIRAS expression led to prolonged cell survival against known apoptotic stimuli: serum starvation or thapsigargin or staurosporine treatments. The apoptotic population of hIRAS‐expressing cells was significantly reduced, and this protection was achieved by a decrease in caspase‐3 activity, phosphatidylserine translocation, and nuclear fragmentation. Similar protective effect was obtained in COS7 cells transiently transfected with hIRAS. A partial activation of the PI3 kinase pathway is possibly implicated in the anti‐apoptotic effect of IRAS. Thus, IRAS appears to represent a previously unknown anti‐apoptotic protein involved in the regulation of cell survival.
Assembly of PRR‐Containing Receptors on Scaffolds: A Model for Imidazoline I1‐Receptor Action
Authors: MUSGRAVE IF , DEHLE FC , PILETZ J
Published: March 2004

Abstract: IRAS, a putative clone of the I1‐imidazoline receptor, possesses a proline‐rich region (PRR) motif, which might interact with SH3 regions on tyrosine kinases, and an integrin‐binding motif. Receptors with a PRR motif can generally assemble onto multi‐element signaling complexes (eg., the b3‐receptor on the EGF receptor) and thereby modulate signal transduction. Integrins serve as scaffolds for multi‐element signaling complexes, similar to that assembled with the EGF receptor. It is therefore possible that IRAS signals through a complex with other receptors.
IRAS Splice Variants
Authors: PILETZ JE , DELEERSNIJDER W , ROTH BL , ERNSBERGER P , ZHU H , ZIEGLER D
Published: March 2004

Abstract: The human I1‐imidazoline receptor candidate gene, iras, has previously been cloned and mapped to locus 3p21.1–9 (also known as Nischarin; accession #AC006208). By comparison to a database of expressed sequence tags (ESTs), three alternatively spliced transcripts have been deduced. A map of 21 exons was constructed for the medium‐length transcript (IRAS‐M) containing 5,232 base pairs (bp) and encoding 1,504 amino acids (aas). Introns 13B and 13C are inserted into the two alternative transcripts, forming IRAS‐S and IRAS‐L mRNA (short and long isoforms). Northern blots confirmed the existence of these mRNA isoforms. In most brain regions the order of mRNA abundance was IRAS‐M > IRAS‐L > IRAS‐S mRNA. Although aas 1 through 510 are theoretically identical, truncated proteins could be derived from IRAS‐S (2,678 bp transcript yields 515 aas) and IRAS‐L (9,457 bp transcript yields 583 aas). Because exon‐16 of the iras gene has been proposed to encode the functional domains of imidazoline and a‐5 integrin binding, only IRAS‐M is expected to possess I1 receptor properties. Subtype‐selective cDNA expression constructs were therefore generated and used to transfect CHO cells. High‐affinity I1 binding was endowed by IRAS‐M and IRAS‐L, but not by IRAS‐S transfection.
Relationship between Platelet Imidazoline Receptor‐Binding Peptides and Candidate Imidazoline‐1 Receptor, IRAS
Authors: ZHU HE , HAYES JONATHAN , CHEN MICHAEL , BALDWIN JAMES , PILETZ JOHN E.
Published: March 2004

Abstract: A candidate human imidazoline‐1 receptor, designated imidazoline receptor antisera‐selected (IRAS) protein, was cloned based on immunoreactivity with antiserum against a purified imidazoline receptor binding peptide (IRBP antiserum). Human IRAS is 167 kD in size, different from 33‐ to 85‐kD IRBP bands previously linked to the human platelet I1 receptor. To explore the possible relationship between IRAS and these smaller proteins, seven different epitope‐specific antisera against IRAS were raised in rabbits for comparison with IRBP antiserum. Focus was on antiserum227–241, corresponding to amino acids #227 to 241 in IRAS, because this antiserum was found uniquely able to immunoprecipitate non‐denatured 85‐kD and 170‐kD forms of IRAS from a human megakaryoblastoma cell line (MEG01), a model of platelet‐producing cells. Human platelets lacked the 170‐kD form of IRAS, but 33‐kD and 85‐kD bands were detectable and seemed to be possible fragments of full‐length IRAS. The intensity of the 85‐kD band detected by antiserum227–241 was significantly correlated (r 5 0.62, P 5 0.04) with the intensity of the 33‐kD band across 11 human platelet samples. A positive correlation between the intensities of the 33‐kD and 85‐kD bands is consistent with both being fragments of IRAS.
Apparent Absence of Direct Renal Effect of Imidazoline Receptor Agonists
Authors: SMYTH DD , PIRNAT D , FORZLEY B , PENNER SB
Published: March 2004

Abstract: Imidazoline receptor agonists such as moxonidine and rilmenidine increase sodium excretion whether administered within the central nervous system, intravenously, or directly into the renal artery. To determine if this natriuresis was mediated by a direct renal effect and was independent of the renal sympathetic nerves, we used two different preparations in the pentobarbital‐anesthetized rat. In the first series of studies, rats were unilaterally nephrectomized 7 to 10 days before the experiment. On the day of the experiment, the remaining kidney was denervated (surgical and 10% phenol/ 95% ethyl alcohol) or sham treated. The effect of an intravenous infusion of rilmenidine was determined. Rilmenidine (10 nmol/kg/minute) decreased blood pressure and increased urine flow rate and sodium excretion in the sham‐ but not the denervation‐treated rats. The response to furosemide (5.05 nmol/kg/minute) remained intact following denervation. We then used a two‐kidney rat model that allowed for separate urine collection from each ureter. We used low infusion rates of moxonidine directly into the left renal artery. An increase in urine flow rate from the left but not the right kidney would suggest a direct renal action. Low infusion rates of moxonidine (10, 30 nmol/kg/minute) increased urine flow rate similarly from both ureters. A low infusion rate of furosemide (9.1 nmol/kg/minute) into the left renal artery increased urine flow rate only from the left ureter. The failure of moxonidine to increase urine flow rate selectively only in the left kidney indicated the agonist acts at an extrarenal site to increase urine flow rate from both kidneys equally. The complete attenuation of the response to rilmenidine indicates the importance of the renal nerves and suggests that the extrarenal site is most probably the central nervous system. Collectively, these studies do not support a direct renal action of imidazoline agonists in producing natriuresis.
MyoD enhances BMP7-induced osteogenic differentiation of myogenic cell cultures
Authors: Komaki M. , Asakura A. , Rudnicki M. A. , Sodek J. , Cheifetz S.
Published: March 2004

The muscle-specific, basic helix-loop-helix transcription factor MyoD can induce cells from other mesenchymal lineages to express a skeletal muscle phenotype. Interestingly, MyoD is initially upregulated in myogenic cells incubated with bone morphogenetic proteins (BMPs), a treatment that induces osteogenic differentiation, suggesting that MyoD has a role in BMP-induced osteogenesis of myogenic cells. This possibility is supported by our observations that muscle satellite cells derived from adult MyoD-/- mice show severely impaired osteogenic induction by BMP-7 (osteogenic protein 1; OP-1) as indicated by the decreased gene expression of the bone markers alkaline phosphatase, osteocalcin, Runx2/Cbfa1, and Osterix. Ectopic expression of MyoD increased alkaline phosphatase activity and Osterix mRNA expression in response to BMP treatment. Similarly, ectopic expression of MyoD in the pluripotent mesenchymal cell line C3H10T1/2 increased alkaline phosphatase activity induced by BMP-7. Transcription assays showed that transfection with a MyoD-expression vector, but not other myogenic basic helix-loop-helix transcription factors (Myf5, myogenin) increased Runx2/Cbfa1 transactivation of a reporter gene construct containing either six OSE sequences in tandem or a single OSE site. This effect was enhanced by BMP treatment. These studies, therefore, demonstrate that the muscle transcription factor MyoD is required for efficient BMP-induced osteogenesis of myogenic cells and indicate that MyoD might exert its effects through co-operative interactions with Runx2/Cbfa1.
Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts
Authors: Bilban Martin , Ghaffari-Tabrizi Nassim , Hintermann Edith , Bauer Sandra , Molzer Sylvia , Zoratti Cristina , Malli Roland , Sharabi Andrew , Hiden Ursula , Graier Wolfgang , Knöfler Martin , Andreae Fritz , Wagner Oswald , Quaranta Vito , Desoye Gernot
Published: March 2004

Trophoblast invasion of the uterine extracellular matrix, a critical process of human implantation and essential for fetal development, is a striking example of controlled invasiveness. To identify molecules that regulate trophoblast invasion, mRNA signatures of trophoblast cells isolated from first trimester (high invasiveness) and term placentae (no/low invasiveness) were compared using U95A GeneChip microarrays yielding 220 invasion/migration-related genes. In this `invasion cluster', KiSS-1 and its G-protein-coupled receptor KiSS-1R were expressed at higher levels in first trimester trophoblasts than at term of gestation. Receptor and ligand mRNA and protein were localized to the trophoblast compartment. In contrast to KiSS-1, which is only expressed in the villous trophoblast, KiSS-1R was also found in the extravillous trophoblast, suggesting endocrine/paracrine activation mechanisms. The primary translation product of KiSS-1 is a 145 amino acid polypeptide (Kp-145), but shorter kisspeptins (Kp) with 10, 13, 14 or 54 amino acid residues may be produced. We identified Kp-10, a dekapeptide derived from the primary translation product, in conditioned medium of first trimester human trophoblast. Kp-10, but not other kisspeptins, increased intracellular Ca2+ levels in isolated first trimester trophoblasts. Kp-10 inhibited trophoblast migration in an explant as well as transwell assay without affecting proliferation. Suppressed motility was paralleled with suppressed gelatinolytic activity of isolated trophoblasts. These results identifed Kp-10 as a novel paracrine/endocrine regulator in fine-tuning trophoblast invasion generated by the trophoblast itself.