bluuebunny/crossref_metadata_2025 huggingface dataset:
Consistency of projected drought over the Sahel with changes in the monsoon circulation and extremes in a regional climate model projections
Authors: Sylla M. B. , Gaye A. T. , Jenkins G. S. , Pal J. S. , Giorgi F.
Published: August 2010

As a step toward an increased understanding of climate change over West Africa, in this paper we analyze the relationship between rainfall changes and monsoon dynamics in high‐resolution regional climate model experiments performed using the Regional Climate Model (RegCM3). Multidecadal simulations are carried out for present‐day and future climate conditions under increased greenhouse gas forcing driven by the global climate model European Center/Hamburg 5 (ECHAM5). Compared to the present day, the future scenario simulation produces drier conditions over the Sahel and wetter conditions over orographic areas. The Sahel drying is accompanied by a weaker monsoon flow, a southward migration and strengthening of the African Easterly Jet, a weakening of the Tropical Easterly Jet, a decrease of the deep core of ascent between the jets, and reduced African Easterly Wave activity. These circulation changes are characteristics of dry periods over the Sahel and are similar to the conditions found in the late twentieth century observed drought over the region. Changes in extreme events suggest that the drier conditions over the Sahel are associated with more frequent occurrences of drought periods. The projected drought over the Sahel is thus physically consistent with changes in the monsoon circulation and the extreme indices (maximum dry spell length and 5 day precipitation).
On the statistical modeling of persistence in total ozone anomalies
Authors: Vyushin D. I. , Shepherd T. G. , Fioletov V. E.
Published: August 2010

Geophysical time series sometimes exhibit serial correlations that are stronger than can be captured by the commonly used first‐order autoregressive model. In this study we demonstrate that a power law statistical model serves as a useful upper bound for the persistence of total ozone anomalies on monthly to interannual timescales. Such a model is usually characterized by the Hurst exponent. We show that the estimation of the Hurst exponent in time series of total ozone is sensitive to various choices made in the statistical analysis, especially whether and how the deterministic (including periodic) signals are filtered from the time series, and the frequency range over which the estimation is made. In particular, care must be taken to ensure that the estimate of the Hurst exponent accurately represents the low‐frequency limit of the spectrum, which is the part that is relevant to long‐term correlations and the uncertainty of estimated trends. Otherwise, spurious results can be obtained. Based on this analysis, and using an updated equivalent effective stratospheric chlorine (EESC) function, we predict that an increase in total ozone attributable to EESC should be detectable at the 95% confidence level by 2015 at the latest in southern midlatitudes, and by 2020–2025 at the latest over 30°–45°N, with the time to detection increasing rapidly with latitude north of this range.
Holocene geocentric dipole tilt model constrained by sedimentary paleomagnetic data
Authors: Nilsson Andreas , Snowball Ian , Muscheler Raimund , Uvo Cintia Bertacchi
Published: August 2010

Paleomagnetic data, although undeniably limited, have been used to constrain complex time‐varying geomagnetic field models. Here we present four different versions of a time varying geocentric dipole model for the past approximately 9000 years based on a limited selection of sedimentary paleomagnetic data with good spatial coverage. The robustness of the modeling approach is evaluated using modern magnetic observation station data provided by the World Data Centre for Geomagnetism in Edinburgh and we discuss the magnitude of the error introduced by insufficient data coverage. The prediction in terms of directional variations is tested against paleomagnetic data from 63 different sedimentary sites and compared to results from recently published spherical harmonic geomagnetic field models. We find that the dipole estimate can explain the paleomagnetic data almost as well as the more complicated spherical harmonic models. Specific areas and records are identified where there are significant differences between the performance of the dipole estimate and the spherical harmonic models. Our results suggest that many of the differences between the dipole model predictions and the paleomagnetic data can be related to poor paleomagnetic quality and/or the lack of accurate and precise time control inherent to some of the records. These results agree with Valet et al. (2008) who suggested that the CALS7K.2 model probably underestimates the dipole contribution in order to reduce the misfit between the inversion and the data. We conclude that better paleomagnetic data and associated time control are needed to improve global geomagnetic field models.
Anomalous negative excursion of carbon isotope in organic carbon after the last Paleoproterozoic glaciation in North America
Authors: Sekine Yasuhito , Tajika Eiichi , Ohkouchi Naohiko , Ogawa Nanako O. , Goto Kazuhisa , Tada Ryuji , Yamamoto Shinji , Kirschvink Joseph L.
Published: August 2010

Early Paleoproterozoic time (2.5–2.0 Ga) spanned a critical phase in Earth's history, characterized by repeated glaciations and an increase in atmospheric oxygen (the Great Oxidation Event (GOE)). Following the last and most intense glaciation of this period, marine carbonates record a large positive excursion of δ13C value (termed the “Lomagundi event”) between about 2.2 and 2.1 Ga coinciding with the global appearances of red beds and sulfates, which suggest an accumulation of high levels of atmospheric oxygen. Here we report the discovery of large negative excursions of δ13C in organic matter (down to −55‰) from quartzose sandstones (of the Marquette Range and the Huronian Supergroups, North America) intermediate in age between the last Paleoproterozoic glaciation and the possible onset of the Lomagundi event. The negative excursion is concomitant with the appearance of intensely weathered quartzose sandstones, which may represent hot and humid conditions. There are some interpretations that potentially explain the negative excursions: (1) redeposition of older 13C‐depleted kerogen, (2) later post‐depositional infiltration of oil, (3) active methane productions by methanogens in shallow‐marine environments, or (4) dissociation of methane hydrate. If the latter two were the case, they would provide clues for understanding the environmental change connecting the intense glaciation and an increase in oxygen.
Detachment depth revealed by rollover deformation: An integrated approach at Mount Etna
Authors: Ruch J. , Acocella V. , Storti F. , Neri M. , Pepe S. , Solaro G. , Sansosti E.
Published: August 2010

Flank instability is common at volcanoes, even though the subsurface structures, including the depth to a detachment fault, remain poorly constrained. Here, we use a multidisciplinary approach, applicable to most volcanoes, to evaluate the detachment depth of the unstable NE flank of Mt. Etna. InSAR observations of Mount Etna during 1995–2008 show a trapdoor subsidence of the upper NE flank, with a maximum deformation against the NE Rift. The trapdoor tilt was highest in magnitude in 2002–2004, contemporaneous with the maximum rates of eastward slip along the east flank. We explain this deformation as due to a general eastward displacement of the flank, activating a rotational detachment and forming a rollover anticline, the head of which is against the NE Rift. Established 2D rollover construction models, constrained by morphological and structural data, suggest that the east‐dipping detachment below the upper NE flank lies at around 4 km below the surface. This depth is consistent with seismicity that clusters above 2–3 km below sea level. Therefore, the episodically unstable NE flank lies above an east‐dipping rotational detachment confined by the NE Rift and Pernicana Fault. Our approach, which combines short‐term (InSAR) and long‐term (geological) observations, constrains the 3D geometry and kinematics of part of the unstable flank of Etna and may be applicable and effective to understand the deeper structure of volcanoes undergoing flank instability or unrest.
A plasmapause‐like density boundary at high latitudes in Saturn's magnetosphere
Authors: Gurnett D. A. , Persoon A. M. , Kopf A. J. , Kurth W. S. , Morooka M. W. , Wahlund J.‐E. , Khurana K. K. , Dougherty M. K. , Mitchell D. G. , Krimigis S. M. , Krupp N.
Published: August 2010

Here we report the discovery of a well‐defined plasma density boundary at high latitudes in Saturn's magnetosphere. The boundary separates a region of relatively high density at L less than about 8 to 15 from a region with densities nearly three orders of magnitude lower at higher L values. Magnetic field measurements show that strong field‐aligned currents, probably associated with the aurora, are located just inside the boundary. Analyses of the anisotropy of energetic electrons show that the magnetic field lines are usually closed inside the boundary and open outside the boundary, although exceptions sometimes occur. The location of the boundary is also modulated at the ∼10.6 to 10.8 hr rotational period of the planet. Many of these characteristics are similar to those predicted by Brice and Ioannidis for the plasmapause at a strongly magnetized, rapidly rotating planet such as Saturn.
Neurotoxic Effects of Three Fractions Isolated from Tityus serrulatus Scorpion Venom
Authors: Nencioni Ana Leonor A. , Carvalho Fátima F. , Lebrun Ivo , Dorce Valquiria A. Coronado , Sandoval Maria Regina L.
Published: August 2010

Scorpion venoms contain low molecular weight basic polypeptides, neurotoxins, that are the principal toxic agents. These toxins act on ion channels, promoting a derangement that may result in an abnormal release of neurotransmitters. In the present study we investigated some of the effects of the F, H and J fractions isolated from Tityus serrulatus scorpion venom on the central nervous system of rodents. The venom was partially purified by gel filtration chromatography. The neurotoxic effect of these fractions was studied on convulsive activity after intravenous injection, and on electrographic activity and neuronal integrity of rat hippocampus when injected directly into this brain area. The results showed that intravenous injection of the F and H fractions induced convulsions, and intrahippocampal injection caused electrographic seizures in rats and neuronal damage in specific hippocampal areas. Fraction J injected intravenously reduced the general activity of mice in the open field but induced no changes when injected into the brain. These results suggest that scorpion toxins are able to act directly on the central nervous system promoting behavioural, electrographic and histological modifications.
Protective Effect of Ebselen on Aflatoxin B1‐Induced Cytotoxicity in Primary Rat Hepatocytes
Authors: Yang Cheng‐Feng , Liu Jin , Shen Han‐Ming , Ong Choon‐Nam
Published: August 2010

Recent studies have shown that aflatoxin B1 enhances reactive oxygen species formation and causes oxidative damage, which may ultimately contribute to the cytotoxicity and carcinogenic effect of aflatoxin B1. Ebselen, 2‐phenyl‐1,2‐benzoisoseleazol‐3(H)‐one, a synthetic seleno‐organic compound has been shown to possess glutathione peroxidase‐like activity and free radical scavenging ability. Thus present study was designed to investigate the protective effect of ebselen on aflatoxin B1‐induced cytotoxicity in primary rat hepatocytes. Aflatoxin B1‐induced cytotoxicity and lipid peroxidation were determined by lactate dehydrogenase leakage and malondialdehyde generation, respectively. Intracellular reactive oxygen species level was measured using the fluorescent probe 2′,7′‐dichlorofluorescin diacetate, and the intracellular reduced glutathione concentration was determined with a fluorometric method. Ebselen was found to display a dose‐dependent protective effect on lactate dehydrogenase leakage and malondialdehyde generation caused by aflatoxin B1 exposure. The results also demonstrate that ebselen efficiently inhibits the intracellular reactive oxygen species formation in aflatoxin B1‐treated hepatocytes in a dose and time‐dependent manner. It was also noted that ebselen was able to increase the intracellular reduced glutathione concentration, both in the control and in aflatoxin B1‐treated hepatocytes. The protection of ebselen against aflatoxin B1 cytotoxicity, however, was not affected by lowering the concentration of intracellular reduced glutathione. The overall data indicate that ebselen possesses a potent protective effect against aflatoxin B1‐induced cytotoxicity, and the main mechanism involved in the protection may be its strong capability in inhibiting intracellular reactive oxygen species formation and preventing oxidative damage.
Sensitivity to Nitrogen Mustard Relates to the Ability of Processing DNA Damage in Chinese Hamster Ovary Cells
Authors: Møller Peter , Wassermann Karsten , Damgaard Jesper , Nexø Bjørn A. , Wallin Håkan
Published: August 2010

The hallmark of the excision repair pathways is the removal of DNA adducts by excision of the damaged nucleotides. In the course of repair, transient DNA strand breaks occur, which can be measured by the Comet assay. We have investigated the processing of DNA damage, mediated by nitrogen mustard, in wild‐type AA8 Chinese hamster ovary cells, and in UV5, UV20 and UV41 DNA repair deficient cell lines. Whereas DNA repair could not be detected by unscheduled DNA synthesis at nitrogen mustard doses below 10 μM, processing of nitrogen mustard‐mediated DNA damage was observed by the Comet assay at a 100‐times lower concentration. Wild‐type Chinese hamster ovary AA8 cells were able to process nitrogen mustard‐mediated DNA damage within 4–24 hr depending on the dose of nitrogen mustard (0.1–10 μM). None of the repair‐deficient cell lines was able to completely process the DNA damage induced by 10 μM nitrogen mustard. At nitrogen mustard doses that conferred 10% colony forming ability, the repair‐deficient cells had an altered processing of nitrogen mustard‐mediated DNA damage: In the AA8, UV20, and UV41 cells, the amplitude of strand breaks peaked early (within 4 hr), the level of strand breaks in the nitrogen mustard exposed UV20 and UV41 cells did not return to the baseline of the unexposed reference culture, and the peak in strand breaks in the UV5 cell line occurred after 4 hr. Our results indicate that the single cell gel electrophoresis (Comet) assay is suitable for assessing repair capability of DNA alkylations.
Bioavailability and Pharmacokinetics of Isradipine after Oral and Intravenous Administration: Half‐Life Shorter than Expected?
Authors: Christensen Hanne Rolighed , Antonsen K. , Simonsen K. , Lindekær A. , Bonde J. , Angelo Helle Riis , Kampmann Jens P.
Published: August 2010

Isradipine is a calcium channel‐blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half‐life of 8–9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half‐life was observed, and the present trial was therefore conducted in order to estimate the half‐life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross‐over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10–12 hr after administration and half‐life and bioavailability were estimated. Mean terminal half‐life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half‐life of isradipine seems to be of much shorter than demonstrated in previous oral studies.
Influence of Ageing on Vasomotor Responses of Human Epicardial Coronary Arteries
Authors: Opgaard Ole Saetrum , Ytterberg Hoa T. , Saxena Pramod R. , Edvinsson Lars
Published: August 2010

Vasomotor responses to various agonists were studied on isolated circular segments of human epicardial coronary arteries from three different age groups; 23–38 years, 40–58 years and 63–86 years. Noradrenaline had no or only weak contractile effect on coronary arteries from younger patients but induced contraction of all artery segments from older patients. The Emax value was significantly (P<0.0001) higher in arteries from the oldest group compared to each of the two younger age groups, whereas the potency was similar in all three groups. Linear regression analysis of noradrenaline‐induced contraction in individual patients revealed a significantly positive age‐correlation (correlation coefficient 0.67, P<0.0001). Contraction induced by endothelin‐1 and relaxation induced by substance P, calcitonin gene‐related peptide and vasoactive intestinal peptide on arteries precontracted with U46619 showed no significant differences in maximum responses and potencies between the three age groups, and no significant linear age‐correlation. These data demonstrate a large variability in contractile responses to noradrenaline with contractions seen mostly in coronary arteries from older patients. It thus seems that sympathetic activation could contribute to coronary ischaemia in some patients.
Effect of ω‐Conotoxin GVIA on Noradrenaline Release from Postganglionic Sympathetic Neurones in Rabbit Aorta
Authors: Nedergaard Ove A.
Published: August 2010

Abstract: The aim of the present work was to examine the effect of the selective N‐type calcium blocking agent ω‐conotoxin GVIA on stimulation‐evoked release of noradrenaline from sympathetic nerves in rabbit isolated aorta with regard to stimulation frequency, extracellular Ca2+ concentration, and transmitter uptake. Rings of rabbit isolated aorta were preloaded with (‐)‐3H‐noradrenaline and the fractional 3H‐overflow evoked by electrical‐field stimulation was determined by liquid scintillation spectrometry. ω‐Conotoxin GVIA (3×10−10– 3×10−8 M) did not alter the spontaneous 3H‐outflow. ω‐Conotoxin GVIA (3×10−10– 3×10−8 M) caused a slowly developing reduction of stimulation‐evoked 3H‐overflow at 1 and 30 Hz. The Emax for the ω‐conotoxin‐induced inhibition was less (70%) at 30 Hz than that (96%) seen at 1 Hz. Short‐term incubation with ω‐conotoxin GVIA caused a subsequent steady‐state inhibition. The inhibitory action of ω‐conotoxin GVIA (3×10−10– 3×10−9 M) was inversely related to the extracellular Ca2+ concentration (6.5×10−4– 2.7×10−3 M). Cocaine (3×10−5 M) plus corticosterone (4×10−5 M), neuronal and extraneuronal uptake inhibitors, respectively, did not alter the inhibitory effect of ω‐conotoxin GVIA (3×10−9 M) on 3H‐overflow evoked by stimulation at a frequency of either 1 or 30 Hz. It is concluded that ω‐conotoxin GVIA acts on prejunctional N‐type calcium channels to inhibit stimulation‐evoked noradrenaline release from sympathetic neurone terminals in rabbit aorta. At a high frequency, another subtype calcium channel may possibly be involved. The action of ω‐conotoxin GVIA is independent of neuronal and extraneuronal uptake mechanisms for noradrenaline, but dependent on the amount of Ca2+ to be transported across the neurilemma from the extracellular space into the neurone.
Arterial Responses in vitro and Plasma Digoxin Immunoreactivity after Losartan and Enalapril Treatments in Experimental Hypertension
Authors: Kalliovalkama Jarkko , Kähönen Mika , Tolvanen Jari‐Petteri , Wu Xiumin , Voipio Juha , Pekki Anu , Doris Peter A. , Ylitalo Pauli , Pörsti Ilkka
Published: August 2010

Abstract: Treatment with the angiotensin‐converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin‐like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10‐week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar‐Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross‐sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium‐evoked contractions was similar and less marked in arterial preparations from Wistar‐Kyoto rats and losartan‐ and enalapril‐treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium‐free solution) were used to evaluate the function of vascular Na+,K+‐ATPase. The rate of potassium relaxation was faster in losartan‐ and enalapril‐treated spontaneously hypertensive rats and all Wistar‐Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain‐sensitive part of the potassium‐relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin‐like immunoreactivity were observed. In conclusion, the outward remodelling following long‐term AT1‐receptor blockade and angiotensin‐converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+‐ATPase, but this effect could not be attributed to changes in circulating sodium pump inhibitor concentration.
Cyclic Adenosine Monophosphate Inhibits Ursolic Acid‐Induced Apoptosis via Activation of Protein Kinase A in Human Leukaemic HL‐60 Cells
Authors: Choi Byung‐Min , Park Raekil , Pae Hyun‐Ock , Yoo Ji‐Chang , Kim Youn‐Chul , Jun Chang‐Duk , Jung Byung‐Hak , Oh Gi‐Su , So Hong‐Seob , Kim Young‐Myeong , Chung Hun‐Taeg
Published: August 2010

Abstract: This study was designed to investigate the effect of cAMP on ursolic acid‐induced apoptosis of HL‐60 cells. Ursolic acid decreased the viability of the cells in a dose‐dependent manner, which was revealed as an apototic process characterized by ladder‐pattern DNA fragmentation in agarose gel electrophoresis and segmented nuclei in DAPI‐sulpharhodamin 101 staining. Ursolic acid‐induced apoptosis of the cells was markedly inhibited by the addition of cAMP‐elevating agents including DB‐cAMP, CPT‐cAMP, 8‐Br‐cAMP and forskolin. These results were further evidenced by the fact that inhibitors of cAMP‐dependent protein kinase including H89 and KT5720 completely inhibited the cAMP‐mediated rescue of HL‐60 cells from ursolic acid‐induced apoptosis. In addition, differentiating agents of the cells such as dimethyl sulfoxide and retinoic acid did not affect the ursolic acid‐induced apoptosis of HL‐60 cells. These results suggest that signaling pathway of cAMP‐dependent activation of protein kinase A may affect the responsiveness of tumor cells upon ursolic acid.
The Influence of the Nitric Oxide Synthase InhibitorL‐NOARG on the Effects of Ethanol in Rats after Acute Ethanol Administration
Authors: Vassiljev Vitali , Mesila Ingrid , Väli Marika , Pokk Paavo
Published: August 2010

Abstract: The aim of this work was to study the effects of the nitric oxide synthase inhibitor NG‐nitro‐L‐arginine (L‐NOARG) on the sedative and toxic effects of ethanol in rats. Ethanol at a dose of 3 g/kg, intraperitoneally induced sleep in rats (sleep time: 111.2±10.3 min.). Administration of the nitric oxide synthase inhibitor L‐NOARG (20 and 40 mg/kg, intraperitoneally) 30 min. before ethanol significantly increased the duration of ethanol‐induced sleep. L‐NOARG at doses of 20 and 40 mg/kg reduced the exploratory activity of rats in the open‐field test and significantly enhanced the sedative effect of ethanol in this test. It is possible that this effect is not caused by the interaction of ethanol with nitric oxide pathways but by synergistic CNS depression caused by ethanol and L‐NOARG. L‐NOARG (20 and 40 mg/kg) had no effect on ethanol concentrations in blood after acute ethanol administration (2 and 3 g/kg). Moreover, the combined administration of ethanol (2 g/kg) and L‐NOARG (20 and 40 mg/kg) caused a decrease in the body weight of animals, observed for 14 days. Also, livers of these rats were studied for necrosis and connective tissue reaction. In histological studies L‐NOARG at a dose of 40 mg/kg had no effect on hepatic necrosis caused by the acute administration of ethanol but strenghtened connective tissue reaction. L‐NOARG is widely used in pharmacological studies, including those concerning the effects of ethanol. However, on the basis of our data the possibility of toxic interactions with ethanol should be considered.
β,γ‐Methylene ATP but Not α,β‐Methylene ATP Mimicsthe Inhibitory Effect of ATP on Ventricular Automaticity
Authors: Hernández Jesús , Laorden María L. , Ruiz Francisco , Ribeiro Joaquim A.
Published: August 2010

Abstract: The effects of α,β‐ and β,γ‐methylene ATP on ventricular automaticity induced by local injury in the right ventricle of rats pretreated with reserpine, were investigated and compared with the effects of ATP and adenosine. β,γ‐Methylene ATP but not α,β‐methylene ATP mimicked the inhibitory effect of both ATP and adenosine on the spontaneous automaticity. In low concentrations, adenosine was more effective than ATP. α,β‐Methylene ATP caused little or no effect on ventricular automaticity. The results suggest that the effect of ATP might depend on its hydrolysis into AMP/adenosine.
Hypotensive Activity of the Pineal Indoleamine Hormones Melatonin, 5‐Methoxytryptophol and 5‐Methoxytryptamine
Authors: Wang Hexiang , Ng Tzi Bun
Published: August 2010

Abstract: Injection of the pineal indoles melatonin, 5‐methoxytryptophol and 5‐methoxytryptamine via the external jugular vein elicited a dose‐dependent depression in mean arterial pressure. Melatonin and 5‐methoxytryptophol were approximately equipotent and a dose of 150 μmol/kg brought about a reduction of about 40 mmHg in mean arterial pressure. Methoxytryptamine exerted a much more potent hypotensive action. An abrupt decrement in mean arterial pressure by 30 mmHg ocurred when the dose was only 2 nmol/kg. Subsequent increases in the dose further lowered the mean arterial pressure, but more gently. The other pineal indoles tested including 5‐methoxyindoleacetic acid and 5‐hydroxyindoleacetic acid, as well as 6‐methoxy‐2‐benzoxazolinone, did not affect the mean arterial pressure when tested up to 80 μmol/kg. Methylene blue, a guanylate cyclase inhibitor, was not able to antagonize the hypotensive activity of melatonin, suggesting that the mechanism of action of melatonin does not involve guanylate cyclase. Lidocaine, which blocks sodium channels in perivascular nerves, antagonized the hypotensive action of melatonin.
Effects of Various Aluminium Compounds Given Orally to Mice on Al Tissue Distribution and Tissue Concentrations of Essential Elements
Authors: Długaszek Maria , Fiejka Maria A. , Graczyk Alfreda , Aleksandrowicz Janina Cz. , Słowikowska Maria
Published: August 2010

To evaluate the risk of gastrointestinal long‐term aluminium (Al) exposure, aluminium distribution and the levels of the following essential elements: Ca, Mg, Zn, Cu, and Fe in tissue were studied. Aluminium was administered in drinking water as aluminium chloride, dihydroxyaluminium sodium carbonate or aluminium hydroxide. Mice (strain Pzh:SFIS) were exposed to a total dose of 700 mg Al in long‐term treatment (for each Al compound n=15). Concentrations of Al, Ca, Mg, Zn, Cu, and Fe in stomach, kidneys, bone and liver were analyzed by atomic absorption spectrometry. After AlCl3 treatment, aluminium was found to accumulate in all tested tissues. A significant decrease in Fe concentration in liver and Zn in kidneys was observed in comparison to concentrations of these elements in the control group. In the Al(OH)3‐treated group, accumulation of aluminium was observed in bone only and decline of Fe concentration in stomach and Cu in liver and kidney. In the NaAl(OH)2CO3‐treated group the increase in Al concentration was significant in bone; there was no change in concentration of essential elements in the examined tissues. The observed aluminium accumulation was not accompanied by changes in Ca and Mg concentration except for bone. This study showed that oral administration as a route of Al exposure can result in diverging accumulation of aluminium in tissues, the concentration depending on the chemical form.
Involvement of CYP3A4 in the Metabolism of Bromperidol in vitro
Authors: Sato Satoshi , Someya Toshiyuki , Shioiri Toshiki , Koitabashi Tomomi , Inoue Yoshimasa
Published: August 2010

In this study, human cytochrome P450 isoenzymes (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) expressed in a cell line were used to elucidate their roles in the metabolism of bromperidol. We found that CYP3A4 catalyzes the N‐dealkylation of bromperidol and its metabolite, reduced bromperidol. CYP3A4 also catalyzes the dehydration of bromperidol to bromperidol 1,2,3,6‐tetrahydropyridine, metabolizes bromperidol to bromperidol pyridinium, and catalyzes the oxidation of reduced bromperidol back to bromperidol. CYP1A2, CYP2C19, and CYP2D6 do not catalyze these reactions.
Lesioning of Locus coeruleus Projections by DSP‐4 Neurotoxin Treatment: Effect on Amphetamine‐Induced Hyperlocomotion and Dopamine D2 Receptor Binding in Rats
Authors: Harro Jaanus , Meriküla Alar , Lepiku Martin , Modiri Ali‐Reza , Rinken Ago , Oreland Lars
Published: August 2010

DSP‐4 is a neurotoxin highly selective for the noradrenergic nerve terminals of the locus coeruleus projections. Data on the effect of DSP‐4 treatment on amphetamine‐induced hyperlocomotion are contradictory. In this study, DSP‐4 (50 mg/kg) caused reduction of noradrenaline levels by 70% in the cerebral cortex and by 79% in the cerebellum. This treatment resulted in upregulation of dopamine D2 receptors in the striatum as evidenced by [3H]‐raclopride binding. In an open field test, DSP‐4 reduced locomotor activity. D‐Amphetamine (1.5 mg/kg) caused a similar increase in locomotor activity in control and DSP‐4‐pretreated animals not familiar to the apparatus. However, when the rats were habituated to the test apparatus, the effect of amphetamine on horizontal activity was significantly larger in the DSP‐4‐pretreated animals. These data suggest that supersensitivity of D2 receptors develops after locus coeruleus denervation, but that the enhanced efficacy of amphetamine in DSP‐4‐treated rats is masked by neophobia.
Myrica nagi Attenuates Cumene Hydroperoxide‐Induced Cutaneous Oxidative Stress and Toxicity in Swiss Albino Mice
Authors: Alam Aftab , Iqbal Mohammad , Saleem Mohammad , Ahmed Salah‐uddin , Sultana Sarwat
Published: August 2010

In recent years, considerable efforts have been made to identify new chemopreventive agents which could be useful for man. Myrica nagi, a subtropical shrub, has been shown to possess significant activity against hepatotoxicity and other pharmacological and physiological disorders. We have shown a chemopreventive effect of Myrica nagi on cumene hydroperoxide‐induced cutaneous oxidative stress and toxicity in mice. Cumene hydroperoxide treatment at a dose level of 30 mg/animal/0.2 ml acetone enhances susceptibility of cutaneous microsomal membrane for iron‐ascorbate‐induced lipid peroxidation and induction of xanthine oxidase activity which are accompanied by decrease in the activities of cutaneous antioxidant enzymes such as catalase, glutathione peroxidase, glutathione reductase, glucose‐6‐phosphate dehydrogenase and depletion in the level of cutaneous glutathione. Parallel to these changes a sharp decrease in the activities of phase II metabolizing enzymes such as glutathione S‐transferase and quinone reductase has been observed. Application of Myrica nagi at doses of 2.0 mg and 4.0 mg/kg body weight in acetone prior to that of cumene hydroperoxide (30 mg/animal/0.2 ml acetone) treatment resulted in significant inhibition of cumene hydroperoxide‐induced cutaneous oxidative stress and toxicity in a dose‐dependent manner. Enhanced susceptibility of cutaneous microsomal membrane for lipid peroxidation induced by iron ascorbate and xanthine oxidase activities were significantly reduced (P<0.05). In addition the depleted level of glutathione, the inhibited activities of antioxidants, and phase II metabolizing enzymes were recovered to a significant level (P<0.05). The protective effect of Myrica nagi was dose‐dependent. In summary our data suggest that Myrica nagi is an effective chemopreventive agent in skin and capable of ameliorating cumene hydroperoxide‐induced cutaneous oxidative stress and toxicity.
Role of Cholecystokinin Receptors in Induction of Antinociception in Hot‐Plate Test
Authors: Rezayat Mehdi , Rahnavard Azita , Zarrindast Mohammad‐Reza
Published: August 2010

In the present study, the antinociceptive effect of cholecystokinin receptor agonists in the hot‐plate test in mice has been evaluated. Subcutaneous administration of cholecystokinin octapeptide (cholecystokinin‐8; 0.001, 0.005, 0.01, 0.05, and 0.1 mg/kg), unsulfated cholecystokinin octapeptide (cholecystokinin‐8U; 0.1 mg/kg) or caerulein (0.25 mg/kg) produced antinociception. Administration of the cholecystokinin tetrapeptide (cholecystokinin‐4; 0.25, 0.5 and 1.0 mg/kg) had no effect in the hot‐plate test. Subcutaneous injection of the selective cholecystokinin receptor antagonists, MK‐329 (0.125, 0.25 and 0.5 mg/kg) or L‐365,260 (0.125, 0.25 and 0.5 mg/kg), produced no antinociceptive response. When the animals were pretreated with the cholecystokinin receptor antagonists or naloxone (0.5 and 1 mg/kg), a significant decrease in the antinociceptive response induced by cholecystokinin‐8 and caerulein was obtained. The results indicate that single administration of cholecystokinin receptor agonists could produce an antinociceptive effect which is probably mediated via cholecystokinin receptors. With respect to the results obtained from morphine and naloxone administration, it is concluded that there may be an interaction between cholecystokinin and opiate mechanisms.
Uptake of Barbituric Acid Derivatives in Small Intestinal Brush Border Membrane Vesicles from Retinyl Palmitate‐Treated Rats
Authors: Tanii Hiromi , Horie Toshiharu
Published: August 2010

Brush border membrane was prepared from the small intestinal (jejunum) cells along the crypt‐villus axis. The fluorescence spectra of 1,8‐anilinonaphthalene sulfonic acid and the steady‐state fluorescence anisotropy of 1,6‐diphenyl‐1,3,5‐hexatriene were measured in the brush border membrane vesicle suspension. The hydrophobicity of brush border membrane was found to be in the order villus tip >mid villus >lower villus. The fluidity of brush border membrane was in the order villus tip <mid villus <lower villus. The uptake of barbituric acid derivatives by brush border membrane vesicles was well correlated with their partition coefficients (isopentyl acetate/water). No significant difference was observed between the uptake of hexobarbital by brush border membrane vesicles from the villus tip and lower villus. When retinyl palmitate was administered to rats, the fluidity of brush border membrane was found to be higher in the retinyl palmitate‐treated rats than in the control rats. However, no significant difference in the uptake of hexobarbital by brush border membrane vesicles was observed between the retinyl palmitate‐administered rats and the control rats. Thus, the retinyl palmitate treatment seems unlikely to affect the passively transported ligands like barbituric acid derivatives in brush border membrane vesicles.
Effects of Different Periods of Lithium Pretreatment and Aminoglycoside Antibiotics on Apomorphine‐Induced Yawning in Rats
Authors: Sharifzadeh Mohammad , Firooz Elham Khajvand , Abdollahi Mohammad
Published: August 2010

Interactive effects of intracerebroventricular administration of the aminoglycoside antibiotics, amikacin and gentamicin, and different duration of lithium pretreatment on apomorphine‐induced yawning were investigated in male rats. The study was designed to investigate whether the hypothesis that the aminoglycoside antibiotics, amikacin and gentamicin, via their effects on phosphoinositide pathways and calcium channel might influence dopaminergic mechanisms as manifested in the yawning effect. Lithium is known to interact with phosphoinositide metabolism and was also tested after chronic studies on the apomorphine yawning model. Subcutaneous administration of apomorphine (0.1, 0.2 and 0.4 mg/kg) to rats induced yawning in a biphasic manner. However the maximum response was obtained by 0.2 mg/kg of the drug. Intracerebroventricular administration of aminoglycoside antibiotics amikacin (25 μg/rat) increased and gentamicin (10 and 20 μg/rat) decreased apomorphine‐induced yawning. Pretreatment of animals with lithium (600 mg/l) in drinking water for 7, 14 and 21 days reduced yawning induced by apomorphine. Administration of lithium for 28 days did not induce any significant effect on yawning response. Amikacin and gentamicin function via the same mechanism on phosphoinositide cascade. Since amikacin and gentamicin did not affect the yawning response similarly, they apparently do not involve inositol trisphosphate level in the alterations of dopaminergic‐induced yawning. Probably, the effect of lithium pretreatment on the number of yawns is also time‐dependent and some tolerance to the inhibitory effect of lithium might occur after 28 days' treatment.
Copper, Ceruloplasmin and Superoxide Dismutase (SOD) in Amyotrophic Lateral Sclerosis
Authors: Tórsdóttir Gudlaug , Kristinsson Jakob , Gudmundsson Grétar , Snaedal Jón , Jóhannesson Torkell
Published: August 2010

In two previous studies we found copper dyshomeostasis in patients with Alzheimer's disease and in patients with Parkinson's disease. In this study, the levels of copper in plasma, of ceruloplasmin in serum, ceruloplasmin oxidative activity, ceruloplasmin specific oxidative activity (activity related to mass) as well as superoxide dismutase (SOD) activity in erythrocytes have been determined in 14 patients with amyotrophic lateral sclerosis and their healthy age‐ and gender‐mathced controls. Three of the patients had a familial form of the disease or were suspected of having it. The mean values of all parameters were found not to differ significantly between the patients and their controls (Student's t‐test; P>0.05). By testing the equality of variances (F distribution) we found that the variances of individual results for ceruloplasmin specific oxidative activity and SOD activity differed significantly between the patients group and the controls group (P=0.021 and P=0.003), but the individual results of these two activities were not correlated (P>0.05). We conclude that disturbances in ceruloplasmin specific oxidative activity and SOD activity could contribute to motor neurone death in amyotrophic lateral sclerosis, and since the two enzyme activities are not correlated it is uncertain which one is more closely related to the pathology of the disease.
Effect of Imipramine on Tolerance to Morphine Antinociception in the Formalin Test
Authors: Zarrindast Mohammad‐Reza , Shaverdian Shirin , Sahebgharani Mousa
Published: August 2010

In this study, the effect of imipramine on morphine antinociception in tolerant and non‐tolerant mice in the formalin test, was investigated. Subcutaneous administration of different test doses of morphine (3, 6 and 9 mg/kg) and intraperitoneal injection of test doses of imipramine (10, 20 and 40 mg/kg) induced a dose‐dependent antinociception in non‐tolerant mice, both in the first and second phases of the formalin test. The combination of morphine (1 mg/kg) with imipramine (10 mg/kg) showed a potentiated response in the second phase of the test. Combination of a single dose of morphine (1.5 mg/kg) with lower doses of imipramine (2, 4 and 8 mg/kg) did not show potentiation. The antinociceptive response of either morphine or morphine plus imipramine was reduced by the opioid receptor antagonist naloxone (2 mg/kg). In order to induce tolerance, mice were treated subcutaneously with morphine (50 mg/kg) once daily for 3 days. On day 4, the antinociceptive effect of test doses of morphine or imipramine were assessed. Tolerance to the responses of test doses of morphine (3, 6 and 9 mg/kg), but not imipramine (10, 20 and 40 mg/kg) in both phases of the test was observed. Administration of lower dose of imipramine (4 mg/kg) before the test doses of morphine (3, 6 and 9 mg/kg) was not able to alter the expression of morphine tolerance. When imipramine was used during development of tolerance, either on days 1 and 2 or on days 2 and 3, the morphine tolerance in the second phase of the test was reduced. It is concluded that opioid receptor mechanism(s) may mediate the antidepressant‐induced antinociception, however, imipramine may be useful in inhibiting morphine tolerance.
Lindane (γ‐Hexachlorocyclohexane) Induces Internal Ca2+ Release and Capacitative Ca2+ Entry in Madin‐Darby Canine Kidney Cells
Authors: Lu Cheng‐Hsien , Lee Kam‐Chung , Chen Yu‐Chih , Cheng Jin‐Shiung , Yu Ming‐Sun , Chen Wei‐Chuan , Jan Chung‐Ren
Published: August 2010

The effect of lindane (γ‐hexachlorocyclohexane), an organochlorine pesticide, on Ca2+ mobilization in Madin‐Darby canine kidney cells was examined by fluorimetry using fura‐2 as a Ca2+ indicator. Lindane (5–200 μM) increased [Ca2+]i concentration‐dependently. The [Ca2+]i signal comprised an immediate initial rise followed by a persistent phase. Ca2+ removal inhibited the [Ca2+]i signal by reducing both the initial rise and the sustained phase. This implies lindane‐triggered Ca2+ influx and Ca2+ release. In Ca2+‐free medium, 0.15 mM lindane increased [Ca2+]i after pretreatment with carbonylcyanide m‐chlorophenylhydrazone (CCCP; 2 μM), a mitochondrial uncoupler, and two endoplasmic reticulum Ca2+ pump inhibitors, thapsigargin and cyclopiazonic acid. Conversely, pretreatment with lindane abolished CCCP‐ and thapsigargin‐induced Ca2+ release. This suggests that 0.15 mM lindane released Ca2+ from the endoplasmic reticulum, mitochondria and other stores. La3+ (1 mM) partly inhibited 0.1 mM lindane‐induced [Ca2+]i increase, confirming that lindane induced Ca2+ influx. Addition of 3 mM Ca2+ increased [Ca2+]i after pretreatment with 0.15 mM lindane for 750 sec. in Ca2+‐free medium, which indicates lindane‐induced capacitative Ca2+ entry. Lindane (0.15 mM)‐induced Ca2+ release was not reduced by inhibiting phospholipase C with 2 μM U73122, but was inhibited by 70% by the phospholipase A2 inhibitor aristolochic acid (40 μM).
Anticipation of Acute Stress in Isoprenaline‐Sensitive and – Resistant Rats: Strain and Gender Differences
Authors: Yamamotová Anna , Starec Miroslav , Holeček Václav , Racek Jaroslav , Trefil Ladislav , Rašková Helena , Rokyta Richard
Published: August 2010

The effect of stress anticipation was studied in two inbred Wistar rat strains with high and low sensitivity to isoprenaline. The animals were exposed to tail‐flick and 4‐hr water immersion restraint stress on two consecutive days. On the first day stress was applied to one group and the next day to the anticipation group. The changes in adrenal, heart and spleen weights, tail‐flick latency, incidence of gastric ulcers, and the antioxidant defense system in the sensorimotor cortex were compared with two non‐stressed control groups. Anticipatory stress decreased adrenal weights. The content of thiobarbituric acid reactive substances (TBARS) was increased both in acute and anticipatory stress; superoxide dismutase, glutathione peroxidase, and antioxidative capacity were increased in anticipatory stress only. Stress anticipation decreased the pain threshold in the isoprenaline‐sensitive and increased in the isoprenaline‐resistant rats and led to more frequent gastric ulcers in the isoprenaline‐resistant group. Significant sex differences were observed both in adrenal weights and TBARS content. The relative adrenal weights were negatively correlated with the TBARS content. We suggest that the outcome of anticipatory stress may depend upon the relation between the hormonal and antioxidant functions of the adrenals and that anticipation‐induced activation of antioxidant enzymes may ameliorate the acute stress response. Anticipation itself was found to be a stronger stressor than physical acute stress.
Expression Changes of CYP2A and CYP3A in Microsomes from Pig Liver and Cultured Hepatocytes
Authors: Skaanild Mette T. , Friis Christian
Published: August 2010

The P450 enzymes of the liver are responsible for the metabolism of a wide range of chemical compounds, and hepatocytes are used in pharmacological and toxicological in vitro tests. Thus, it is important to know how stable these enzymes are in culture. We measured the activity of CYP2A and CYP3A in microsomes isolated from both pig liver and primary pig hepatocyte cultures, together with the apoprotein concentration using Western blotting. The CYP2A activity and apoprotein concentration decreased rapidly; only about 5 percent remained after 48 hr incubation, whereas the CYP3A activity and apoprotein concentration was constant. CYP3A was induced 3 times after exposure to rifampicin, whereas neither rifampicin nor pyrazole could induce CYP2A. The hepatocytes were also incubated with varying concentration of FCS and autologous serum, however without effect on the stability of CYP2A, nor did different concentrations of growth hormone and testosterone added to the cultures have any effect.
Mycophenolate Mofetil Pharmacokinetics in Transplant Patients Receiving Cyclosporine or Tacrolimus in Combination Therapy
Authors: Vidal Elena , Cantarell Carmen , Capdevila Luis , Monforte Victor , Roman Antonio , Pou Leonor
Published: August 2010

Mycophenolate mofetil is a highly effective immunosuppressant drug used in the prophylaxis of organ rejection in combination with cyclosporine or tacrolimus and corticosteroids. The present study is a retrospective data analysis of the routinely estimated mycophenolic acid plasma trough levels in 60 transplant patients (kidney, n=49; lung, n=11) receiving mycophenolate mofetil in combination with prednisone and cyclosporine (n=45) or tacrolimus (n=15). Co‐administration of cyclosporine instead of tacrolimus resulted in a significant increase of median (range) of the ratio of dose‐to‐concentration 0.92 (0.11–8.33) (n=167) versus 0.38 (0.11–14.28) (n=66); P<0.0001. No correlation was seen between mycophenolate mofetil dose and mycophenolic acid trough concentrations. The dose‐to‐concentration in cyclosporine‐treated patients increased significantly (P<0.0001) as the cyclosporine level increased, suggesting a possible interaction between mycophenolate mofetil and cyclosporine. No correlation was seen between dose‐to‐concentration and tacrolimus blood levels (P×0.215). Further studies are necessary to investigate this issue.