bluuebunny/crossref_metadata_2025 huggingface dataset:
Methyl Mercuric Chloride Toxicokinetics in Mice. II: Sexual Differences in Whole‐Body Retention and Deposition in Blood, Hair, Skin, Muscles and Fat
Authors: Nielsen Jesper Bo , Andersen Ole
Published: March 2009

Abstract: This article reports the time course for deposition of methyl mercury administered as a single oral dose in whole body, total carcass, liver, kidneys, brain, blood, fat, muscle, bone, skin and hair of male and female Bom:NMRI mice. The whole‐body elimination initially approximated first order kinetics with half‐times around 7 days and 12 days for males and females respectively, although a decreased elimination rate was observed during the last 10 days. The elimination of mercury from carcass was slower than the elimination from the whole‐body, causing an increasing relative carcass deposition with time in both male and female mice and explaining the observed deviation from first order elimination kinetics. Thus, first order kinetics is observed only during 2‐3 weeks after dosage. Throughout the experimental period, male mice had significantly lower levels of mercury in both blood, brain and muscles than had female mice, whereas renal deposition of mercury in male mice was significantly higher than in female mice. At day 30 the females had about twice as much mercury in liver, brain and hair (median values) as had male mice. Despite the fact that comparable whole‐body retention and carcass deposition were observed in male and female mice, the blood concentrations in male mice was only about half that in female mice. Furthermore, half‐times for mercury in blood did not differ much between male and female mice and were close to whole‐body half‐time in male mice, although the absolute amounts of mercury in both blood and whole‐body at day 20 were significantly different. The large sexual differences in mercury levels in tissues compared with the more limited differences in half‐times and the fact that several organs have different mercury levels already at day 3 after dosage, although the whole‐body levels are more or less equal, indicate extensive differences in the methyl mercury toxicokinetics between male and female Bom:NMRI mice.
Impact of Structural Differences on thein VitroGlucuronidation Kinetics of Potentially Dopaminergic Hydroxy‐2‐Aminotetralins and Naphthoxazines Using Rat and Human Liver Microsomes
Authors: Swart P. J. , Jansman F. G. A. , Drenth B. F. H. , de Zeeuw R. A. , Dijkstra D. , Horn A. S.
Published: March 2009

Abstract:Thein vitroglucuronidation of seven monohydroxy‐2‐aminotetralins and two naphthoxazines has been determined using human and rat liver microsomes. All these compounds stimulate the D2dopamine receptor. The influence of the position of the phenolic hydroxyl group was studied with rat microsomes in monohydroxy‐2‐(N,N‐dipropylamino)‐tretralins. The highest activity and intrinsic clearance was found for 7‐OH‐DPAT, but the latter values for 5‐OH‐DPAT and 6‐OH‐DPAT were much lower by a factor of 9 and 30, respectively. The 8‐OH‐isomer was not glucuronidated at all. Substitution of a propyl side chain by a thienylethyl‐, or phenylethyl side chain, in 5‐hydroxy‐DPAT, or in (+)‐4‐propyl‐9‐hydroxyhexahydronaphthoxazine (PHNO, N‐0500), showed a large increase of the UDPGT affinity and intrinsic clearance especially for N‐0437. It also resulted for N‐0437 in a much higher affinity towards the dopaminergic D2 receptor. Although the glucuronidation activity of human microsomes was found to be considerably lower than that of rat microsomes, the latter phenomenon was clearly visible with human microsomes as well. These findings may have serious implications for the ability of these drugs to adequately reach the brain.
Modulation of Ouabain Binding in Beating Ventricular Myocardium from Guinea‐Pigs: Effects of Lidocaine and Monensin
Authors: Borst Christoph , Hempelmann Ralf , Herzig Stefan , Mohr Klaus
Published: March 2009

Abstract:To further elucidate the interdependence between digitalis sensitivity and the cellular Na+load, the influence of two Na+load modifying drugs, monensin and lidocaine, on the concentration‐dependence of ouabain binding and ouabain effects was studied inbeating ventricular stripsfrom guinea‐pig heart. Monensin (3 × 10−6M), a Na+ionophore known to elevate Na+influx, enhanced3H‐ouabain binding (by approximately 40%) as well as the ouabain effect at nontoxic ouabain concentrations, and it shifted the threshold for toxicity towards threefold lower ouabain concentrations. Lidocaine (2 × 10−4M), a Na+channel blocker, lowered ouabain binding by about one third, and it extended the ouabain concentration range tolerated without toxicity by a factor of three. In the concentrations used, neither compound exerted any direct effect on ouabain binding studied inisolated cardiac membranes.The binding data obtained in the muscle strips were well fitted by a mathematical model which quantifies the dependence of ouabain binding on the underlying (Na++ K+)‐ATPase activity. These findings provide evidence for an indirect drug‐induced modulation of ouabain binding via the interference with the cellular Na+load.
Improvement of Glucose Homeostasis by Oral Vanadyl or Vanadate Treatment in Diabetic Rats is Accompanied by Negative Side Effects
Authors: Domingo José L. , Gómez Mercedes , Llobet Juan M. , Corbella Jacinto , Keen Carl L.
Published: March 2009

Abstract:Vanadate and vanadyl, two forms of vanadium, have been reported to exert insulin‐like effectsin vivoandin vitro.In the present study we compared the effectiveness of oral sodium metavanadate (NaVO3), sodium orthovanadate (Na3VO4) and vanadyl sulphate pentahydrate (VOSO4·5H2O) treatment in alleviating some signs of diabetes in streptozotocin‐induced diabetic rats. Vanadium compounds were administered in aqueous solutions of NaCl (80 mM) at concentrations of 0.20 mg/ml (NaVO3), 0.50 mg/ml (Na3VO4), and 1.1 mg/ml (VOSO4·5H2O) for two weeks. Control rats, either diabetic or non‐diabetic, drank solutions of NaCl (80 mM). Although some signs of diabetes (hyperglycaemia, hyperphagia, polydipsia) were significantly ameliorated by the vanadium treatment, negative side effects were also observed in all of the vanadium‐treated diabetic rats. Those effects included some deaths, decreased weight gain, and tissue vanadium accumulation, which are consistent with the reported toxicity of vanadium in non‐diabetic rats. Vanadyl sulphate was the most effective compound of those tested in normalizing blood glucose levels. However, the results here reported suggest that chronic administration of vanadyl or vanadate in the drinking water is not a viable alternative treatment to insulin in human diabetes.
Increased Urinary Calcium and Magnesium Excretion in Rats Injected with Mercuric Chloride
Authors: Liu Xiaoyan , Jin Taiyi , Nordberg Gunnar F.
Published: March 2009

Abstract:Mercuric chloride (HgCl2) is a classic nephrotoxic agent. While it is well established that HgCl2can induce metallothionein synthesis in the kidney and also cause damage to the pars recta region of the renal tubule, the urinary losses of essential elements like calcium (Ca) and magnesium (Mg) probably related to this process, have not been described. In this study, calcium, magnesium, metallothionein (MT), as well as sodium (Na) and potassium (K) in urine, kidney cortex and liver were measured in male Wistar rats after two daily injections of HgCl2(0.5 or 1.0 mg Hg/kg body weight intraperitoneally). As compared with controls, there was a significant 3‐4‐fold increase in calcium excretion which reached its maximum at 8‐12 and 32‐36 hr after treatment with 1.0 mg Hg/kg. Urinary magnesium excretion was also increased in a similar way as the calcium excretion. At 12‐16 hr, urinary magnesium in the 1.0 mg Hg/kg dose group was 3.4 times higher than that of the controls. Urinary MT level in HgCl2treated rats was much higher than that in the controls, the maximum excretion was between 24‐28 and 32‐36 hrs preceeded by the peak of Hg in urine. Na and K concentrations in urine decreased significantly in rats treated with HgCl2. The present study thus demonstrates that increases of urinary calcium and magnesium excretion are early toxic effects of HgCl2on the kidney. It gives support to the hypotheses implying these ion imbalances in the mechanism of elicitation of renal toxicity by mercury. These findings are also of interest because they indicate the possibility that perturbations of Ca and Mg metabolism as a result of environmental (including occupational) mercury exposure might occur; such ion imbalances might subsequently increase risks of adverse health effects.
Different Inhibitory Potencies of Various ANF‐Analogues in the Isolated Aorta from Four Rodent Species
Authors: Weis Jan
Published: March 2009

Abstract: Five ANF (atrial natriuretic factor) analogues were tested under similar conditions for their inhibitory potency against noradrenaline induced contractions in the isolated aorta from rabbits, rats, mice and guinea‐pigs. The test compounds were: rat ANF 99‐126, rat ANF 103‐123, [Mpr105‐Ala107] rat ANF 105‐126‐NH2 (PL‐058), human ANF 105‐126 and human ANF 99‐126 oxidized at Met110. The potencies of the test peptides were compared to that of the reference peptide α‐human ANF 99‐126, the potency of which was set to 1. The EC50 values for the reference peptide varied between 2.4 (rabbit) and 6.6 (rat) × 10−10 M. The highest and lowest relative potencies of the test peptides were: rat ANF 99‐126: 2.6 (rat) and 1.4 (guinea‐pig); rat ANF 103‐123: 1.0 (rat) and 0.005 (rabbit); PL‐058: 47 (mouse) and 5 (rabbit); human ANF 105‐126: 2.1 (guinea‐pig) and 0.5 (rabbit); oxidized human ANF 99‐126: 0.3 (guinea‐pig) and 0.02 (rat). The species related differences in the relative potencies of the peptides are probably due to structural dissimilarities of the vascular ANF receptors in the different species.
Heterogeneous Binding of Sigma Radioligands in the Rat Brain and Liver: Possible Relationship to Subforms of Cytochrome P‐450
Authors: Ross Svante B.
Published: March 2009

Abstract:The binding of four sigma receptor ligands,3H‐(+)‐N‐allyl‐N‐normetazocine (3H‐(+)‐SKF 10,047),3H‐(+)‐3‐(3‐hydroxyphenyl)‐N‐(1‐propyl)piperidine (3H‐(+)‐3‐PPP),3H‐haloperidol and3H‐N,N'‐di(o‐totyl)guanidine (3H‐DTG), and the cytochrome P450IID6 ligand and dopamine uptake inhibitor3H‐1‐[2‐(diphenylmethoxy)ethyl]‐4‐(3‐phenylpropyl)piperazine (3H‐GBR 12935) to membranal preparations of rat liver or whole rat brain was examined regarding kinetical properties and inhibition by various compounds with affinity for sigma binding sites or cytochrome P‐450. In rat brain the density of binding sites was increased in order (+)‐SKF 10,047 <(+)‐3‐PPP<DTG<<GBR 12935. In liver the corresponding order was (+)‐SKF 10,047 <DTG<haloperidol<(+)‐3‐PPP<GBR 12935. The inhibition pattern of each ligand was similar in brain and liver, indicating that the binding sites were similar in the two tissues. With the exception of3H‐(+)‐SKF 10,047 which appears to bind to a homogeneous haloperidol‐sensitive site, there were quite marked differences between the ligands studied, suggesting heterogeneous binding sites. For instance, (+)‐SKF 10,047 and progesterone were potent inhibitors of the binding of3H‐(+)‐SKF 10,047,3H‐(+)‐3‐PPP and3H‐haloperidol but inhibited only a minor fraction of the binding of3H‐DTG to the brain and liver preparations. Multiple binding sites were also indicated by the low Hill coefficients found for most of the compounds studied. It was found that the cytochrome P‐450 inhibitor proadifen (SKF 525A), like haloperidol, was a potent inhibitor of the binding of3H‐(+)‐SKF 10,047,3H‐(+)‐3‐PPP and3H‐haloperidol to the liver and brain preparations, less active in inhibiting the binding of3H‐DTG and least effective on the binding of3H‐GBR 12935. Another cytochrome P‐450 inhibitor, L‐lobeline, was particularly potent in inhibiting the binding of3H‐DTG but was also quite potent inhibitor of the binding of the other sigma ligands. It was less potent in inhibiting the binding of3H‐GBR 12935. The binding of the latter ligand was potently inhibited by the analogous compound GBR 12909 but of the other compounds examined only L‐lobeline, proadifen, haloperidol, DTG and (+)‐3‐PPP had IC50 values below 10 μM. The possibility that the sigma binding sites are identical with some subforms of cytochrome P‐450 is discussed.
In Vitro Effect of Mercury on Aryl Hydrocarbon Hydroxylase, Quinone Reductase, Catecholamine‐O‐methyltransferase and Glucose‐6‐phosphate Dehydrogenase Activities in Term Human Placenta
Authors: Boadi William Y. , Urbach Jacob , Barnea Eytan R. , Brandes Joseph M. , Yannai Shmuel
Published: March 2009

Abstract: The effect of HgCl2 on human term placental aryl hydrocarbon hydroxylase (AHH), quinone reductase (QR), catecholamine‐O‐methyltransferase (COMT), and glucose‐6‐phosphate dehydrogenase (G‐6‐PD) enzyme activities was studied after incubation of placental explants with the salt for either a 6 or 24 hr period. Mercury (Hg) increased the activities of AHH, QR and COMT, but decreased that of G‐6‐PD. The increases in enzyme activities, as well as the decrease in G‐6‐PD activity observed were in all cases time‐ and dose‐dependent. The data suggest that Hg exerts an enhancing effect on the activity of placental phase I enzyme (AHH) and phase II enzymes (QR and COMT). This enhancement may be due to increased de novo synthesis, elimination of some suppressing agent(s), or the decreased breakdown of enzyme protein. Also, the inhibitory effect of Hg on G‐6‐PD activity appears to indicate that this enzyme is appreciably more sensitive to Hg than the other three enzymes. These findings may imply increased cellular resistance to Hg toxicity. The altered state of activity may also be used as a tool for monitoring exposure to this metal.
Cefmenoxime and Bilirubin: Competition for Albumin Binding
Authors: Onks David L. , Harris Ja‐Fana G. , Robertson Alex F.
Published: March 2009

Abstract:Certain drugs are known to compete with bilirubin for albumin binding; therefore, all drugs administered to neonates should be tested to determine the degree of competition. The effect of cefmenoxime on bilirubin‐albumin binding was determined by comparing the oxidation rate of free bilirubin in the presence and absence of drug. The reserve albumin concentration (RAC) of pooled cord serm was also measured using the MADDS dialysis rate method. We show that cefmenoxime competes with bilirubin for albumin binding with a displacement constant, of 3.1 × 103l/mol. The maximal displacement factor (MDF) is used to determine the clinical effect of the drug at usual serum concentrations. The MDF for cefmenoxime is 1.10, representing approximately a 10% increase in free bilirubin concentration. In comparison, the MDF for a known bilirubin displacing drug, sulfisoxazole, is 2.43. The MADDS method showed an estimated 28% decrease in the RAC at 150 μmol/l, the mean peak serum concentration (MPSC) of cefmenoxime. These results show while cefmenoxime affects bilirubin‐albumin binding, the degree of the effect is relatively small. However, cefmenoxime may pose a hazard to very sick, premature infants, especially if the infant is jaundiced.
Evaluation of a New Computerized Psychomotor Test Battery: Effects of Alcohol
Authors: Nuotto Esko J. , Korttila Kari T.
Published: March 2009

Abstract: In order to better evaluate the effects of centrally active drugs, a new computer based set of psychomotor tests was developed. Compared to the older apparati, the new set is very flexible and easy to operate allowing the measurement of hand/eye coordination, attention and several types of reaction skills. To evaluate the sensitivity and usefulness of the new tests, the effects of alcohol (oral doses of 0.5 g/kg and 1.0 g/kg) were studied in twelve healthy volunteers. The peak blood alcohol concentration after the larger dose was 0.86 g/l, and the effects were clearly seen with all new tests. The smaller dose of alcohol gave 0.33 g/l peak blood alcohol concentration and it impaired significantly only coordination at 1 hr after drinking. The results suggest that the new tests are at least as sensitive and reliable as older psychomotor tests detecting the effects of central depressant agents. The advantage of the new tests is that they are easy to operate and easy to modify without any specific programming skills. Because they can be used with a computer which is easy to transport, these tests are suitable for use in clinical areas to conduct studies with patients.
Drug Interaction Effects on Antitumour Drugs (X): Exacerbation of Cisplatin Lethality by Bacterial Lipopolysaccharide in Mice
Authors: Ishikawa Masaaki , Takayanagi Yoshio , Sasaki Ken‐ichi
Published: March 2009

Abstract:To determine whether bacterial endotoxin (lipopolysaccharide, LPS fromEscherichia coli) could modulate the lethality of cisplatin (CDDP) in mice, animals were treated with LPS (1 mg/kg, intraperitoneally) 24 hr and 1 hr before administration of cisplatin. A 1.6‐fold increase in 8‐day cumulative mortality was observed in LPS‐treated mice compared to the mortality of those injected with saline before CDDP administration. The duration of previous exposure time to LPS appeared to be an important determinant of the potentiating effect, as many more mice died after 24 hr pretreatment than after 1 hr. Because renal toxicity remains a serious limitation to the effective use of CDDP, we determined whether LPS could also enhance CDDP‐induced renal injury. CDDP markedly induces an increase in blood urea nitrogen (BUN) levels in LPS‐treated mice. Treatment with LPS did not affect urinary excretion or renal tissue levels of total platinum, or the plasma pharmacokinetics of free and total platinum. Despite the potentiating effect of LPS on CDDP‐induced lethality, it appeared that LPS can provide some enhancement of kidney function, because pretreatment of LPS enhanced an increase in BUN values.
Regioselective Induction of Liver Glutathione Transferase by Ethanol and Acetone
Authors: Sippel Helmuth , Penttilä Kai E. , Lindros Kai O.
Published: March 2009

Abstract:Both ethanol and acetone are substrates and inducers of the cytochrome P450 IIE1. This isoenzyme is induced in the perivenous region, which may explain the centrilobular damage elicited by several hepatotoxins being substrates for P450 IIE1. Here we demonstrate that induction of glutathione S‐transferase after ethanol and acetone treatment is also restricted to the perivenous region, suggesting regiospecific enhancement of the transferase associated cellular defence capacity. The total glutathione peroxidase activity does not increase after the induction.
Effects of Cilazaprilat and Enalaprilat on Experimental Dermatitis in Guinea Pigs
Authors: Rosenqvist Ulf , Persson Karin , Lindgren Björn R. , Andersson Rolf G. G.
Published: March 2009

Abstract:Two non‐sulfur containing ACE‐inhibitors were tested concerning their local effect on experimental dermatitis in ovalbumin‐sensitized guinea pigs. Enalaprilat but not cilazaprilat potentiated the ovalbumin‐evoked inflammatory response. Futhermore, enalaprilat clearly enhanced the erythema evoked by substance P, whereas cilazaprilat did not. Concerning, the bradykinin‐evoked erythema, enalaprilat significantly potentiated the response, whereas cilazaprilat only caused a slight increase. Our results suggest that different affinities for peptidases involved in degradation of inflammatory peptides can explain differences between the pro‐inflammatory properties of enalaprilat and cilazaprilat.
Applications of Autometallography to Heavy Metal Toxicology
Authors: Danscher Gorm
Published: March 2009

Abstract: Application of autometallography (AMG) to histological material from humans and animals exposed to gold, silver and mercury has made it possible to localize these heavy metals at light and electron microscopic levels. Because of high sensitivity of the technique, traces of the three metals have been demonstrated in tissues and cells that had previously not been suspected of containing metals. A chelatable pool of zinc in the synaptic vesicles of the zinc‐positive neurones can be demonstrated by AMG in the brain. The well defined staining pattern can be used to estimate volumes of cortical subdivisions. Volumetric studies based on autometallographic differentiation of cortical regions have provided valuable information about the effects of different toxicants. AMG can be combined with new quantitative methods, such as electron energy loss spectroscopy (EELS), electron probe X‐ray microanalysis (EPMA) and laser microprobe mass analysis (LAMMA), to enhance detection of AMG metal catalysts with these techniques.
Modifications of Cell Signalling in the Cytotoxicity of Metals
Authors: Rossi Anna , Manzo Luigi , Orrenius Sten , Vahter Marie , Nicotera Pierluigi
Published: March 2009

Abstract: Many metals act on biological systems at low concentrations and recent epidemiological and experimental research indicates that toxic effects of certain metals occur at levels only marginally higher than those found in healthy subjects. Despite a large number of studies describing metal cytotoxicity, the molecular mechanisms involved are still poorly understood. However, it now seems evident that several metals can interact with enzyme functional groups and that proteins involved in signal transduction, including Ca2+ channels and pumps, may be especially sensitive to this interaction. Impairment of the ability of cells to adequately respond to the stimulation by hormones and growth factors may result in the loss of important cell functions or activation of mechanisms that compromise cell survival. In the following sections we will briefly describe the effects of various metals on cell signalling and present our recent findings on the mechanism by which inorganic mercury affects signal transduction.
Mitogenicity and Metallothionein Induction: Two Separate Effects of Zinc Ions on Human Mononuclear Blood Cells
Authors: Steffensen I.‐L. , Mesna O. J. , Melhuus A. , Hjertholm H. , Heier H. E. , Andersen R. A.
Published: March 2009

Abstract: The mitogenic effect of elevated concentrations of zinc ions on human lymphocytes was found to be inhibited by the glucocorticoid hormone dexamethasone. The effect decreased progressively from complete block to partial inhibition when the culture period before the addition of dexamethasone was prolonged. In contrast, dexamethasone did not inhibit an induced formation of metallothionein in mononuclear cells. Furthermore, dexamethasone itself was found to induce small amounts of metallothionein. Apparently, the mitogenic effect and the induction of metallothionein by zinc ions in mononuclear cells occur by mutually independent mechanisms.
The Importance of Metallothionein for the Accumulation of Copper, Zinc and Cadmium in Environmentally Exposed Perch, Perca fluviatilis*
Authors: Hogstrand Christer , Lithner Göran , Haux Carl
Published: March 2009

Abstract: A field study of the role of metallothionein (MT) in the binding of heavy metals in perch (Perca fluviatilis), exposed to moderate levels of copper, zinc and cadmium, was performed. Perch were sampled at four sites in Sweden in September during two consecutive years. Two sites were located in the vicinity of a brassworks and two outside the emission range. The first year, fish from the two brassworks sites and from one of the uncontaminated sites were collected. The second year, fish from the most contaminated site and from the two uncontaminated sites were caught. The levels of hepatic copper, zinc and cadmium reflected the concentrations of these metals in water and were increased in fish from the two contaminated sites. The level of cadmium in liver was relatively low. MT was induced in liver of perch caught at the most contaminated site. The hepatic MT content in individual livers correlated well to the accumulation of copper (r=0.85, P<0.001) and zinc (r=0.75, P<0.001). There was a low but significant correlation between the levels of MT and cadmium in the liver (r=0.48, P<0.001). The relationship between MT and metals was very similar both years. Subcellular fractionation of the metals in the liver revealed that an induction of MT was followed by an increased amount of copper, zinc and cadmium bound to the protein. The relative fraction of the total hepatic copper and cadmium bound to MT was increased at the most contaminated site, whereas there was no difference in subcellular distribution of zinc between the sites. In perch from the most contaminated site, the portions of hepatic copper, zinc and cadmium found in the cytosolic fraction were 70, 57 and 81%, respectively. Seventy‐one % of the copper, 29% of the zinc and 84% of the cadmium found in hepatic cytosol of fish from the same site, eluted together with MT after gel filtration chromatography. The analysis of the subcellular distribution of copper, zinc and cadmium demonstrates that MT is responsible for the binding of a large amount of the total hepatic cellular content of copper and cadmium in perch.
The Effect of Medetomidine on GABA and Benzodiazepine Receptors in Vivo: Lack of Anxiolytic but some Evidence of Possible Stress‐Protective Activity
Authors: Rägo Lembit , MacDonald Ewen , Saano Veijo , Airaksinen Mauno M.
Published: March 2009

Abstract: Medetomidine, a new selective α2‐adrenoceptor agonist, potentiated bicuculline seizures in mice. In vivo pretreat‐ment with medetomidine in mouse cerebral cortex reduced dose‐dependently (2.5‐100 μg/kg) GABA‐potentiated 3H‐flunitrazepam binding. The affinity of 3H‐muscimol was also reduced by medetomidine. This effect of medetomidine on GABA‐potentiated benzodiazepine binding was reversed by pretreatment with atipamezole (1 mg/kg), a specific α2‐antagonist. In an elevated plus‐maze model of anxiety medetomidine (0.5‐10 μg/kg) was inactive both in rats and mice and did not antagonize the behavioural effects of an anxiogenic β‐carboline, DMCM. However, at lower doses medetomidine (10 but not 50 μg/kg) antagonized the swimming stress caused increase of central benzodiazepine binding sites (labeled with 3H‐Ro 15‐1788) in mouse cerebral cortex. The increase of peripheral benzodiazepine binding sites on brain and heart cryostat cut slices caused by stress was also antagonized by pretreatment with medetomidine. The behavioural and biochemical data obtained in this study are evidence that medetomidine does not have anxiolytic effect but may have, in lower doses, stress‐protective activity.
Effect of Repeated Treatment with Antidepressant Drugs and Electroconvulsive Shock (ECS) on the D2 Dopaminergic Receptor Turnover in the Rat Brain*
Authors: Nowak Gabriel , Zak Joanna
Published: March 2009

Abstract: The effect of repeated treatment with citalopram, (+)oxaprotiline, (—)oxaprotiline, imipramine and ECS on the turnover of dopamine D2 receptors in the rat brain was measured using an N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ)‐induced irreversible receptor inactivation method. Repeated treatment with citalopram and ECS, but not with (+) and (—) enantiomers of oxaprotiline and imipramine, significantly decreased the turnover of D2 receptors in the striatum. Neither of the applied repeated treatments changed the turnover of D2 receptors in the limbic system. The results suggest that changes in the turnover of D2 dopamine receptors in striatum may participate in the mechanism of antidepressant action of ECS and citalopram, but not that of (+) or (—)oxaprotiline or imipramine.
Enhancement of Memory Retrieval and Attenuation of Scopolamine‐Induced Amnesia Following Administration of 5‐HT3 Antagonist ICS 205‐930
Authors: Chugh Yati , Saha N. , Sankaranarayanan A. , Datta H.
Published: March 2009

Abstract: Experimental evidence suggests an important role of serotonin in the process of learning and memory. The present study investigated the effect of 5HT3‐receptor antagonist (ICS 205‐930) on retrieval of a previously learned aversive habit in the mouse. The effect of ICS 205‐930 on scopolamine (3 mg/kg) induced amnesia was also studied. ICS 205‐930 (1, 10 & 100 μg/kg) produced a dose‐dependent increase in latency to cross into the dark chamber. The scopolamine induced memory impairment was significantly attenuated by ICS 205‐930 (10 μg/kg). These results suggest that memory deficits may be susceptible to attenuation with non‐cholinergic treatments.
Time Course Study of Lipid Peroxidation Induced by N2‐Methyl‐9‐hydroxyellipticinium Acetate or Celiptium in Rat Renal Cortex
Authors: Thomas Nathalie , Raguenez‐Viotte Gilda , Dieber‐Rotheneder Martina , Esterbauer Herman , Fillastre Jean Paul
Published: March 2009

Abstract: Celiptium is an ellipticine derivative with renal toxic side effects. It has recently been characterized as a lipid overload in proximal tubular cells where loss of total phospholipids (in particular phosphatidylethanolamine) and of polyunsaturated fatty acids are linked to the accumulation of unsaturated free fatty acids and aldehydes. A time course study of celiptium‐induced peroxidative damage showed that a single dose of 40 mg/kg of celiptium induced no change in total or individual phospholipids of rat renal cortex. On the other hand, free fatty acids and thiobarbituric acid reactive substances increased as early as 1 hr after celiptium injection. 4‐Hydroxynonenal (4‐HNE) also increased whereas polyunsaturated fatty acids levels decreased at 6 and 24 hr. After 24 hr no change was detected in microsomal phospholipids. In contrast, the brush‐border membranes showed alterations such as decrease in total phospholipids and polyunsaturated fatty acids levels accompanied by increase in aldehydes. It appears that peroxidative damage occurs in brush‐border membranes of celiptium‐treated rat kidneys with preferential losses of phosphatidylethanolamine (PE, 30%) and phosphatidylcholine (PC, 14%).
Cellular Effects of Some Metabolic Oxidation Products Pertinent to 4‐Ethoxyaniline
Authors: Lindqvist Thomas , Moldéus Peter , Lindeke Björn
Published: March 2009

Abstract:The toxicity of some metabolic products pertinent to 4‐ethoxyaniline in isolated hepatocytes were investigated. The compounds investigated were 4‐ethoxynitrosobenzene (1), 4‐ethoxy‐4′‐nitrosodiphenylamine (2), 3,6‐bis(4‐ethoxy‐phenylimino)‐4‐ethoxy‐1,4‐cyclohexadienylamine (3), 4‐(4‐ethoxyphenylimino)‐2,3‐dimethyl‐2,5‐cyclohexadiene‐1‐one (4) and 4‐(4‐ethoxyphenylimino)‐2,6‐dimethyl‐2,5‐cyclohexadiene‐1‐one (5). Of these, 1, 2 and 3 are oxidation products of 4‐ethoxyaniline. Compounds 4 and 5 are dimethyl analogues of previously investigated oxidation product 4‐(4‐ethoxyphenyl‐imino(‐2,5‐cyclohexadiene‐1‐one (NEPBQI). Among the investigated compounds, 1 and 2 were the most toxic towards isolated hepatocytes. In hepatocytes treated with compounds 1, 2 and 4, loss of cell viability was also accompanied by surface bleb formation. All compounds except 3 reacted with GSH resulting in depletion of cellular GSH. No formation of GSSG was observed, however. Thus, the GSH depletion was apparently due to conjugate formation rather than oxidation. No superoxide dismutase inhibitable reduction of acetylated cytochrome c was observed, thus none of the compounds undergoes measurable redox cycling.
Cardiac Uptake Kinetics and Possible Dynamic Effects of a New Cerebral Antiischaemic Compound FG 9202 (NBQX) Studied in the Isolated Rabbit Heart
Authors: Nielsen‐Kudsk Folmer , Mellemkjær Søren , Bang Lone
Published: March 2009

Abstract:Accumulation of the putative drug FG 9202 in isolated rabbit hearts showed monophasic exponential kinetics with a half‐life of only 0.59 min. The disposition showed a three‐phasic exponential time course with half‐lives of 0.34, 1.51 and 15.8 min, respectively, which was interpreted as three‐compartment kinetics. FG 9202 accumulated only about 3 times in the myocardium at steady‐state with 51, 32 and 17% referable to a superficial and two deeper myocardial drug pools. The drug did not significantly affect contraction amplitude or velocity of contraction at increasing concentrations up to 40.6 μg‐ml−1(119 μM). Heart beating frequency decreased slightly but only significantly at some of the higher concentrations. Neither dromotropic, bathmotropic nor ischaemic ECG‐effects were observed. Coronary flow‐rate and myocardial oxygen consumption decreased at the highest drug concentrations. Myocardial efficiency expressed as the ratio of contractile parameters to oxygen consumption showed a minor but insignificant increase at the highest drug‐exposure levels. Our findings indicate that FG 9202 is not potentially toxic to the isolated, spontaneously beating rabbit heartin vitro.
Molecular Basis of Buspirone's Anxiolytic Action
Authors: Tunnicliff Godfrey
Published: March 2009

Abstract:Buspirone has been available in the United States for over four years for the treatment of anxiety. It was anticipated this drug would offer certain advantages over the established benzodiazepines. In contrast to diazepam, early studies found no evidence for the interaction of buspirone with GABAergic mechanisms. Behavioural, electrophysiological and receptor binding experiments gradually led to the idea that buspirone owes much of its anxiolytic activity to its ability to attenuate central 5‐hydroxytryptamine neurotransmission. Specifically, it appears to act as an agonist at presynaptic 5‐HT1Areceptors, particularly in the raphe nuclei. Although buspirone also shows an affinity for dopamine D2receptors, where it seems to behave as an antagonist, there is much doubt that this effect is related to its anxiolytic action. Even though buspirone and the benzodiazepines do not obviously share a common mode of action, the possibility is discussed that there is an underlying common mechanism of responsible for their antianxiety effects.
Methanol and Formic Acid Toxicity: Biochemical Mechanisms
Authors: Liesivuori Jyrki , Savolainen And Heikki
Published: March 2009

Abstract:Metabolism of methanol, methyl ethers, esters and amides give rise to formic acid. This acid is an inhibitor of the mitochondrial cytochrome oxidase causing histotoxic hypoxia. Formic acid is a weaker inhibitor than cyanide and hydrosulphide anions. The body burden of formate in methanol poisoning is high enough to cause acidosis, and other clinical symptoms. Part of the protons can be attributed to formic acid whereas the most significant acid load results from the hypoxic metabolism. The acidosis causes e.g. dilatation of cerebral vessels, facilitation of the entry of calcium ions into cells, loss of lysosomal latency and deranged production of ATP. The latter effect seems to impede parathormone‐dependent calcium reabsorption in the kidney tubules. Besides, urinary acidification is affected by formic acid. Its excretion causes continuous recycling of the acid by the tubular cell Cl−/formate exchanger. This sequence of events may partially explain an accumulation of formate in urine. Occupational exposure to vapours of methanol and formic acid can be quantitatively monitored by urinary formic acid determinations. Formic acid toxicity may prove a suitable model for agents causing histotoxic hypoxia.
Release of 2‐Thiobarbituric Acid Reactive Products from Glutamate, Deoxyuridine or DNA during Autoxidation of Dopamine in the Presence of Copper Ions
Authors: Rao Gondi S.
Published: March 2009

Abstract:Cytotoxic effects of catecholamine are thought to be caused by the formation of 0‐semiquinone and superoxide radicals. Dopamine in the presence of copper ions releases aldehydic products from glutamate, deoxyuridine or DNA capablae of reacting with 2‐thiobarbituric acid (TBA). The formation of TBA reactive products (TBAR) was concentration dependent of both dopamine and copper ion. Complete inhibition of formation of TBAR from glutamate, deoxyuridine or DNA was observed in the presence of thiourea and catalase. Mannitol, albumin and superoxide dismutase offered substantial protection. The present data indicate that dopamine in the presence of copper ions can lead to the formation of reactive hydroxyl radicals which can release aldehydic products from glutamate, deoxyuridine or DNA capable of reacting with TBA.
Interactions between Cultured Bovine Arterial Endothelial and Smooth Muscle Cells: Effects of Injury on the Release of Growth Stimulating and Growth Inhibiting Substances
Authors: Xu Cang‐Bao , Pessah‐Rasmussen Hélène , Stavenow Lars
Published: March 2009

Abstract: Dimethylsulfoxide‐soluble particles (DSP) from cigarette smoke and ultraviolet light caused a low degree (cell death < 30%) and high degree (cell death 60‐90%) injury to bovine arterial endothelial cells and smooth muscle cells in culture. Conditioned medium from low degree injured endothelial cells and smooth muscle cells generally inhibited DNA synthesis in new smooth muscle cells or endothelial cells while high degree injury increased DNA synthesis in new cells. Specifically, the growth stimulating activity from endothelial cells was decreased after low degree injury but increased after high degree. UV light released more growth stimulating substances from smooth muscle cells after both low and high degree injury. The release of growth inhibiting substances was dependent on both cell kind and degree of injury. In co‐culture low and high degree DSP injury to endothelial cells inhibited smooth muscle cell proliferation, which was in contrast to the effect of conditioned medium from high degree injured endothelial cells. Conditioned medium from endothelial cells treated with LDL and glucose inhibited DNA synthesis in smooth muscle cells. It is concluded that injury to endothelial cells or smooth muscle cells will modify the release of growth inhibiting and growth stimulating activity and that this release will depend on cell kind as well as degree and kind of the injurious stimulus.
The Concentration and Temporal Relationships of Acetaminophen‐Induced Changes in Intracellular and Extracellular Total Glutathione in Freshly Isolated Hepatocytes from Untreated and 3‐Methylcholanthrene Pretreated Sprague‐Dawley and Fischer Rats*
Authors: Willson R. A. , Hart J. , Hall T.
Published: March 2009

Abstract:Fischer rats are more sensitive to acetaminophen‐induced hepatotoxicity than Sprague‐Dawley rats, however, the mechanisms for this enhanced sensitivity remain unclear. The susceptability to hepatotoxicity is determined largely by the balance between acetaminophen toxification and detoxification. Since glutathione plays a critical role in the detoxification process, it would be of interest to compare the effects of acetaminophen on hepatic glutathione homeostasis in the Sprague‐Dawley and Fischer rat, and relate these effects to cytotoxicity. To this end, we measured the sequential changes of intracellular and extracellular total glutathione in freshly isolated hepatocytes from untreated and 3‐methylchol‐anthrene pretreated Fischer and Sprague‐Dawley rats, both in the absence (basal) and presence of acetaminophen. In the basal state, the intracellular total glutathione content was significantly (P < 0.01) increased in hepatocytes from untreated Fischer rats. Nevertheless, the sequential release of total glutathione into the medium and the sequential depletion of intracellular total glutathione were quantitatively similar in hepatocytes from untreated Fischer and Sprague‐Dawley rats. Following exposure to acetaminophen, there was a striking dose and time associated depletion of intracellular total glutathione in untreated hepatocytes from both rat strains, and quantitatively the depletion was similar in untreated hepatocytes from both rat strains. This degree of depletion of intracellular total glutathione was not associated with acetaminophen‐induced cytotoxicity in Sprague‐Dawley hepatocytes, whereas significant (P < 0.05) cytotoxicity was demonstrated in Fischer hepatocytes. In hepatocytes from 3‐methylcholanthrene pretreated rats, there was an even more marked dose and time associated depletion of intracellular total glutathione as compared with untreated hepatocytes from both rat strains. Although the magnitude of this depletion was also similar in hepatocytes from both rat strains, the acetaminophen‐induced cytotoxicity was significantly (P < 0.01) more prominent in hepatocytes from the Fischer rat. Our observations establish that basal hepatocellular glutathione concentrations are higher in Fischer than Sprague‐Dawley rats, however sequential changes in basal intracellular and extracellular glutathione are similar in hepatocytes of both strains. Moreover, the effect of acetaminophen on these glutathione measures was also similar in hepatocytes from both rat strains. Finally, our observations reveal a discordance between acetaminophen‐induced cytotoxicity and cellular glutathione content in the two rat strains, implying that the Fischer rats'enhanced susceptibility to hepatocellular injury may be related to a defective inherent cellular defense mechanism against attack by the reactive metabolite of acetaminophen.
Valproic Acid‐Induced Neural Tube Defects in Mouse and Human: Aspects of Chirality, Alternative Drug Development, Pharmacokinetics and Possible Mechanisms
Authors: Nau Heinz , Hauck Ralf‐Siegbert , Ehlers Katharine
Published: March 2009

Abstract:Administration of the antiepileptic drug valproic acid (VPA) during early pregnancy can result in a 1–2. incidence of spina bifida aperta, a closure defect of the posterior neural tube in the human. The predominant defect produced by VPA in the mouse is exencephaly, a closure defect of the anterior neural tube. Recent experiments demonstrate that an appropriate dosing regimen (consecutive doses of VPA on day 9 of gestation) can also result in a low incidence of spina bifida aperta, and a high incidence of spina bifida occulta in the mouse as a potential animal model. Relatively high doses and concentrations of VPA are needed in the mouse to produce neural tube defects, the human appears to be more sensitive in this regard. Maximal concentrations and not AUC (area under the concentration‐time curve) values correlate with the incidence of neural tube defects in the mouse which could in part be explained by saturation of plasma protein binding, increased free drug available for placental transfer and the embryonic neuroepithelium acting as a “deep compartment”. It is likely that the parent drug and not a metabolite is the proximate teratogen. Structure‐activity relationships show a strict structural requirement for high teratogenic potency: the molecule must contain an α‐hydrogen atom, a carboxyl function, branching on carbon atom 2 with two chains containing 3 carbon atoms each for maximum activity. If these two carbon chains are different, then enantiomers are present such as the R‐ and S‐enantiomers of 2‐n‐propyl‐4‐pentenoic acid (4‐en‐VPA), 2‐n‐propyl‐4‐pentynoic acid (4‐yn‐VPA) and 2‐ethylhexanoic acid. These enantiomers were synthesized and shown to be significantly different in regard to teratogenic potency. Pharmacokinetic studies indicate that both enantiomers of each compound reach the embryo to the same degree. Therefore, the intrinsic teratogenic activity of the enantiomers differ, suggesting a stereoselective interaction between the drugs and a chiral structure within the embryo, is involved in the mechanism of action. In sharp contrast to the teratogenic effect, the anticonvulsant activity and neurotoxicity of this compound class show broad structural specificity, opening the possibility for development of novel antiepileptic agents with low teratogenic potency such as 2‐n‐propyl‐2‐pentenoic acid (2‐en‐VPA). The molecular mechanism of the teratogenicity of VPA is quite unknown; of the several hypothesis suggested, the interaction of VPA with embryonic folate metabolism is discussed here.
The Cardiovascular Effects of Thyrotropin‐Releasing Hormone (TRH) are Attenuated by Cimetidine in Rats
Authors: Nurminen Marja‐Leena , Paakkari Ilari , Järvinen Asko , Vonhof Stefan
Published: March 2009

Abstract:The modulation of cardioventilator effects of thyrotropin‐releasing hormone (TRH) by histaminergic mechanisms was studied in anaesthetized rats pretreated with histamine receptor antagonists. TRH (1–10. nmol/kg) into the lateral cerebral ventricle dose‐dependently elevated mean arterial pressure, heart rate and stimulated respiration. The respiratory stimulating effect of TRH remained unchanged after pretreatments with histamine H1‐receptor antagonist diphenhydramine or H2‐receptor antagonists cimetidine and ranitidine, while the TRH‐induced hypertension and tachycardia were attenuated by cimetidine. This antagonism was not due to an interation between TRH and cimetidine at their central binding sites, since there was no displacement of [3H]MeTRH binding in the presence of cimetidine nor did TRH displace [3H]cimetidine in rat brain homogenates. Inability of diphenhydramine to modify the cardiovascular effects of TRH indicates that these effects are not due to histamine liberation, as cardiovascular stimulation after central administration of histamine is mainly mediated via H1‐receptors. The antagonism of the cardiovascular responses to TRH by cimetidine was not due to blockade of H2‐receptors, since another potent H2‐receptor antagonist ranitidine was unable to affect the cardiovascular effects of TRH. Therefore, we suggest that cimetidine exerted antagonism of TRH by some non‐specific action.
Rat Spinal Cord α2‐Adrenoceptors are of the α2A‐Subtype: Comparison with α2A‐ and α2B‐Adrenoceptors in Rat Spleen, Cerebral Cortex and Kidney Using3H‐RX821002 Ligand Binding
Authors: Uhlén Staffan , Wikberg Jarl E. S.
Published: March 2009

Abstract:Binding of the α2‐adrenoceptor antagonist radioligand3H‐RX821002 was investigated in membranes from rat spinal cord, spleen, cerebral cortex and kidney. The ligand was found to bind to saturable binding sites with apparent uniform affinities within each tissue. Seven compounds, some of which have previously been reported to be selective for either α2A‐ or α2B‐adrenoceptors, were used in competition with3H‐RX821002. By using computer modelling, competition curves generated for three of these compounds (ARC 239, prazosin and oxymetazoline) could be resolved into two site fits in the kidney, Kd's of the drugs being compatible with the notion that these sites corresponded to α2A‐ and α2B‐adrenoceptors. Moreover, rauwolscine and yohimbine were found to be about 14 and 9‐fold selective for α2B‐adrenoceptors in the kidney. In all other tissues studied drug competition curves were uniphasic and computer modelled into one site fits, drug Kd's being well correlated to those for the α2A‐adrenoceptor. In rat spinal cord 26 further drugs, which showed wide variation in structure, were evaluated in competition with3H‐RX821002. Of these compounds, competion curves of the agonists UK‐14,304, (—) and (+) adrenaline were modelled into two site fits whereas those of the remaining compounds could be modelled only into one site fits. Since the high affinity site for UK‐14,304, (—) and (+) adrenaline was eliminated when EDTA, Gpp(NH)p and 140 mM NaCl was present in the assay the heterogeniety observed in spinal cord was considered to be due to formation of high and low affinity conformations of the α2‐adrenoceptor for agonists. It is concluded that3H‐RX821002 is useful to label both α2A‐ and α2B‐adrenoceptors in the rat. Moreover, the binding sites labelled by3H‐RX821002 in the spinal cord appear to consist of a single population of α2‐adrenoceptors of the α2A‐type.