bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of a Competitive Inhibitor (Mevinolin) of 3‐Hydroxy‐3‐methylglutaryl Coenzyme A Reductase on Human and Bovine Endothelial Cells, Fibroblasts and Smooth Muscle Cells in Vitro
Authors: Falke P. , Mattiasson I. , Stavenow L. , Hood B.
Published: March 2009

Abstract: Mevinolin, a competitive inhibitor of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase activity, is a potent inhibitor of cholesterol synthesis. We have tested the effects of mevinolin on cell replication (3H‐thymidine incorporation), prostacyclin production (6‐keto‐PGF1α) and cell death (51Cr release) in cell cultures (human umbilical vein endothelial cells, bovine endothelial cells, human fibroblasts and bovine smooth muscle cells). Mevinolin concentrations ranging from 0.05 μmol/l (reported therapeutic concentration) to 20 μmol/l were used. In human endothelial cells the replication was reduced by 11% at a concentration of 2.0 μmol/l (P<0.01). In fibroblasts and smooth muscle cells the reduction was significant already at 0.1 μmol/l (10%, P<0.01). The prostacyclin production was reduced in endothelial cells at 1.0 μmol/l (19%, P<0.01) and in smooth muscle cells at 2.0 μmol/l (15%, P<0.05). At 20 μmol/l both cell replication and prostacyclin production was markedly reduced by about 40% in all cell types. No effects on 51Cr release or trypan blue staining was seen at any concentration. It is concluded that mevinolin has an effect on DNA synthesis and prostacyclin production on the tested cell types in vitro. These effects were, however, observed only at concentrations higher than those recommended for therapeutical use.
Effects of Kynurenic Acid and Ketamine on Neonatal Sleep in Rats
Authors: Loikas P. , Hilakivi I.
Published: March 2009

Abstract: Kynurenic acid and ketamine are, besides non‐specific actions, antagonists of excitatory acidic amino acids in the rat brain. At intraperitoneal doses of 300 mg/kg (1.6 mmol/l) and 5 mg/kg (18 mmol/l), respectively, they are equipotent antagonists of N‐methyl‐D‐aspartate receptors. We studied the acute effects of ketamine and kynurenic acid, at these doses, on sleep patterns of rats during the second and third postnatal weeks with the so called static charge sensitive mattress (SCSB). Both kynurenic acid and ketamine decreased active sleep; ketamine additionally increased quiet state and kynurenic acid increased waking. The decrease in active sleep may be related to glutaminergic NMDA and serotonergic responses in the rat brain but non‐specific actions and interactions with other transmitter systems are also involved.
Diltiazem Enhances Gentamicin Nephrotoxicity in Rats
Authors: Gomez A. , Martos F. , Garcia R. , Perez B. , de la Cuesta F. Sanchez
Published: March 2009

Abstract:The effect of the calcium antagonist, diltiazem, was examined in gentamicin‐induced nephrotoxicity states in rats. Animals were injected for 5 days with diltiazem intraperitoneally (40 mg/kg/day), or gentamicin subcutaneously (100 mg/kg/day) or simultaneously with both preparations using the same doses. At the time of sacrifice, the urea and creatinine clearances, as well as urine osmolality were determined and the renal tissues were processed for examination by light microscopy. Gentamicin‐injected rats demonstrated the typical pattern of aminoglycoside nephrotoxicity characterized by poliuric renal failure and necrosis of the proximal tubular epithelium. Rats injected with diltiazem revealed only mild depression of urine osmolality. There was no elevation of blood urea nitrogen and serum creatinine or depression of urea and creatinine clearances, and no focal tubular cell necrosis was detected. However, concomitant administration of both compounds considerably increased nephrotoxicity by according both histological indications and renal function measurements. Thus, we conclude that the combination of diltiazem and gentamicin must be used carefully in human clinical practice.
Analysis of Methyl Mercury Binding Sites on Tubulin Subunits and Microtubules
Authors: Vogel Daryl G. , Margolis Robert L. , Mottet N. Karle
Published: March 2009

Abstract: We have studied the localization and affinity of methyl mercury hydroxide (MeHg) binding sites on microtubules. There is one class of binding sites for MeHg on tubulin, a high affinity class with fifteen sites. MeHg binds to tubulin stoichiometrically within microtubules, and does not induce microtubule disassembly at this low binding ratio. MeHg binds in microtubules either in the presence or absence of free tubulin subunits but free subunits act as uncompetitive inhibitors for MeHg binding to the polymer. These stoichiometric polymer surface binding sites for MeHg apparently do not interfere with subsequent polymerization, in contrast to the multiple sites in the free dimer whose occupation blocks subsequent assembly. In assembly cycles that follow MeHg binding to polymers, we continue to find MeHg bound to microtubules at substoichiometric ratios. Dimers with higher levels of MeHg binding are rendered assembly incompetent. These results show MeHg to have one class of binding site on tubulin, and the MeHg binding site, both to the polymer surface and to the free dimer, to be the same.
Effects of Acute Morphine Administration on Noradrenaline Turnover and Metabolism in Various Brain Parts of Control and Handled Rats
Authors: Attila L. M. J.
Published: March 2009

Abstract:The main purpose of these experiments was to study whether the morphine‐induced changes in cerebral noradrenaline (NA) turnover differ between various brain areas of male Wistar rats assessed by the α‐methyl‐p‐tyrosine (αMT)‐induced NA depletion. The effects of repeated saline injections (20 days) on the morphine‐induced changes in NA and also in free and sulphated 3‐methoxy‐4‐hydroxyphenylethylene glycol (MOPEG) concentrations were studied. 5 to 40 mg/kg of morphine reduced the αMT‐induced NA depletion in the cortical hemispheres, while 40 mg/kg of morphine enhanced it in the lower brain stem. 10 mg/kg of morphine lowered the NA concentration in limbic forebrain and hypothalamus and increased it in the cortical areas. It also elevated the MOPEG concentrations in all brain parts with the sole exception of sulphated MOPEG in the cortical hemispheres. Naltrexone antagonized the morphine‐induced changes in NA turnover and MOPEG concentrations. The only significant handling‐induced change was the elevation of NA concentrations in the hypothalamus. The increasing effect of morphine on the sulphated MOPEG concentration in the prefrontal cortex and the lower brain stem was attenuated in handled rats. In conclusion, these findings show that, the response of cortical NA neurones to acute morphine administration is retardation of turnover rather than activation which occurs most notably in the lower brain stem. Furthermore, the responses are modified by previous exposure of rats to handling.
The Role of Brain Serotonin in the Electroconvulsive Shock‐Induced Changes in Behavioural Effects of Intra‐Hippocampally Injected Clonidine
Authors: Tamborska Ewa , Plaznik Adam , Kostowski Wojciech , Hauptmann Miroslawa , Bidzinski Andrzej
Published: March 2009

Abstract: The influence of central serotonin depletion upon behavioural effects of intra‐hippocampally injected clonidine in the electroconvulsive shock‐treated rats (ECS), was studied. Repeated ECS significantly attenuated the depressive influence of clonidine upon the locomotor activity of the rats in the open field test. Chemical lesions to the median raphe nucleus (MR) did not significantly affect ECS‐induced changes in clonidine activity in this test. In the forced swimming the MR lesions revealed the stimulatory potency of clonidine microinjections upon rat active behaviour. In animals pretreated with repeated ECS, clonidine also significantly potentiated swimming activity, but no evident synergism of ECS and MR lesion could be observed. Taking into account these and other data it is concluded that central serotonin depletion might differentially affect the adaptive processes occurring in the α2‐adrenoceptors in the course of treatment with tricyclic antidepressants and ECS, but it does not seem to be a strong phenomenon. Moreover, it is suggested that clonidine effects in the open field and forced swimming tests may be mediated by different neuronal substrates within the rat hippocampus.
Effects of Dithiocarbamates on Intestinal Absorption and Organ Distribution of Cadmium Chloride in Mice
Authors: Andersen Ole , Nielsen Jesper B. , Jones Mark M.
Published: March 2009

Abstract: Earlier publications have demonstrated that diethyldithiocarbamate (DDC) antagonizes the acute toxicity of injected CdCl2 but enhances the acute toxicity of orally administered CdCl2, most likely due to the high lipophilicity of DDC and the complex formed with the Cd++ ion. This study demonstrates that the hydrophilic dithiocarbamates dihydroxyethyldithiocarbamate (DHE‐DTC) and N‐methyl‐N‐glucamyl dithiocarbamate (NMG‐DTC) also enhance the intestinal absorption of orally administered CdCl2 in mice, although less efficiently than DDC. After oral as well as intraperitoneal administration 15 min. after a single oral dose of CdCl2 the dithiocarbamates tested enhanced the intestinal cadmium uptake with a relative efficiency, DDC>DHE‐DTC>NMG‐DTC, which correlated to the lipophilicity of both the dithiocarbamates and the complexes formed with the Cd++ ion. Intraperitoneal administration of DDC induced extensive changes in the relative organ distribution of absorbed cadmium, compared to the distribution of CdCl2 administered alone. However, the only noticeable effect of administration of DHE‐DTC and NMG‐DTC was decreased gastrointestinal deposition of cadmium, irrespective of the administration route of the dithiocarbamates. Earlier studies have demonstrated that DDC and various other dithiocarbamates are capable of mobilizing intracellular cadmium deposits, presumably due to some lipophilicity. This study demonstrates that these dithiocarbamates may also enhance the intestinal absorption of cadmium.
Effect of Short‐Term Ammonia Inhalation on Selected Amino Acids in Rat Brain
Authors: Manninen Alli T. A. , Savolainen H.
Published: March 2009

Abstract: Increased brain and plasma glutamine after ammonia inhalation had an effect on the concentrations of selected amino acids in rats. Rats inhaled ammonia vapour of 25 and 300 p.p.m. for 5 days 6 hr daily. Brain glutamine increased from the control level, 10.9±2.6 (S.D.) μmol/g to 15.5±5.2 (S.D.) μmol/g (P<0.05) in 25 p.p.m. NH3 and to 15.3±1.1 (S.D.) μmol/g (P<0.01) in 300 p.p.m. NH3. The blood glutamine was also increased so that the brain/plasma ratio was not changed. A slight elevation in the brain threonine was found, from 0.6±0.1 (S.D.) μmol/g (controls) to 0.8±0.2 (S.D.) μmol/g in 25 p.p.m. and to 0.8±0.1 (S.D.) μmol/g in 300 p.p.m. NH3. The brain/plasma ratio of threonine was increased at the 300 p.p.m. level. The increasing brain threonine linearly correlated to the increased plasma glutamine the general correlation co‐efficient being 0.59 according to a linear regression analysis. The effects on other amino acids, e.g., glycine, alanine, serine, aspartate, glutamate, were less clear. It seems that the elevated blood glutamine impaired the threonine export or augmented its uptake from the blood stream. Exposure to NH3 vapour by inhalation proved to be an alternative model to portocaval shunting or urease injections in the study of hyperammonemia in the brain.
Extracorporeal Complexation and Haemodialysis for the Treatment of Cadmium Poisoning. I. Effects of Four Chelators on thein VitroElimination of Cadmium from Human Blood
Authors: Sheabar Fayad Z. , Yannai S.
Published: March 2009

Abstract:The effect of ethylenediamine tetraacetic acid (EDTA), glutathione (GSH), citrate and 2, 3‐dimercaptosuccinic acid (DMSA) on the elimination of cadmium (Cd) from human blood, by complexing haemodialysis, was investigatedin vitro.A significant increase in elimination rate was observed with all four chelators compared to that observed without chelators. EDTA was found to be the most effective agent, which at a level of 0.01M in the dialysate facilitated elimination of 80% of the blood Cd originally present.
The Absorption and Distribution of14C‐Bacitracin in Rainbow Trout (Salmo gairdneri) after a Single Oral Dose, as Observed by Whole Body Autoradiography
Authors: Høy T. , Horsberg T. E. , Nafstad I. , Berge G. N.
Published: March 2009

Abstract:This study was performed to investigate the absorption, distribution and elimination of orally given radiolabelled bacitracin methylene disalicylate (BMD) in rainbow trout kept in salt water. The level of radioactivity in skeletal muscle tissue remained low, but stable throughout the experiment, while radioactivity in bile and liver tissue increased for about 48 hr, before decreasing. There was a trapping of BMD and/or its metabolites in excretory kidney tissue, where the amount of radioactivity continued to increase when radioactive material was being removed from other tissues. The maximum concentration found in excretory kidney tissue was about 7 times as high as the maximum concentration found in the liver. Even though there is no appreciable absorption of BMD from the gastrointestinal tract in homoiotherms, we found the absorption in rainbow trout to be significant.
The Levels of Somatostatin in the Brain and CSF of Rat after Carbamazepine Administration
Authors: Pitkänen Asia , Hyttinen Juha‐Matti , Sirviö Jouni , Jolkkonen Jukka , Sarlund Helena , Riekkinen Paavo
Published: March 2009

Abstract: Previous studies have suggested that carbamazepine (CBZ), a potent antiepileptic drug, affects the somatostati‐nergic system in humans and animals; but the results have been contradictory. In the present study we further evaluated the effect of CBZ administration on somatostatin‐like immunoreactivity (SLI) in cisternal cerebrospinal fluid (CSF) and in different areas of the rat brain. Somatostatin receptor binding in the cortex of CBZ‐treated rats was also studied. Two hours after administration of CBZ at a dose of 30 mg/kg intraperitoneally, which resulted in a serum CBZ concentration of 64 μM, the SLI in CSF was lower than in vehichle‐injected controls (P = 0.024, MANOVA). In the hippocampus SLI was elevated to 132% that of vehicle‐injected controls (P = 0.016, Mann‐Whitney U‐test). At a dose of 15 mg/kg a slight decrease in SLI was seen in CSF compared to vehicle‐injected controls (P = 0.034, MANOVA) but no change was observed in the hippocampus. After administration of CBZ for 7 days (30 mg/kg intraperitoneally twice a day) we were not able to demonstrate any definitive change in SLI of rat CSF (MANOVA). In these rats the SLI in the hypothalamus was elevated compared to vehicle‐injected controls (132%, P = 0.016, Mann‐Whitney U‐test). In experiments with both acute and chronic administration of CBZ, the somatostatin receptor binding was unchanged. The present study suggests that administration of CBZ only slightly affects the somatostatinergic system in the rat brain.
Effect of Repeated Administration of Berenil on Urinary Enzyme Excretion with Corresponding Tissue Pattern in Rats
Authors: Akanji Musbau A. , Ngaha Edwin O.
Published: March 2009

Abstract:The effect of repeated administration of berenil, a trypanocide, on urinary excretion of some enzyme activities in rat and their corresponding levels in the kidney and serum was investigated. Daily administration of this drug to rats resulted in increased urinary volume, excretion of protein, alkaline phosphatase and lactate dehydrogenase activities. However, the level of acid phosphatase activity was not significantly increased while muramidase activity disappeared completely during the period of drug administration. In the kidney tissue, there was a significant loss of lactate dehydrogenase activity immediately after the first dose and this trend continued until the end of drug administration. In the same tissue, there was an increase in alkaline phosphatase activity while the lysosomal enzymes were not significantly affected. In the serum, except for the increase in alkaline phosphatase activity, all other enzymes were not significantly affected. All these results indicate that there is cellular damage to rat kidney as a result of repeated berenil administration, and that the plasma membrane and the soluble portion of the cytoplasm are the primary site of injury to the cells. They also suggest that urinary enzyme excretion could be useful in determining the site of cellular damage by chemical agents in kidneys.
Investigation of Lipid Peroxidation Induced by Hydrazine Compoundsin Vivoin the Rat
Authors: Preece Nicholas E. , Timbrell John A.
Published: March 2009

Abstract:Phenylhydrazine caused lipid peroxidation in ratsin vivoas detected by expiration of ethane but this was not due to lipid peroxidation in liver, as there was no associated MDA production in this tissue. Hydrazine did not cause either ethane expiration or MDA formation. Both hydrazine and phenylhydrazine caused a significant increase in propane expiration. Phenylhydrazine significantly decreased packed cell volume and haemoglobin levels but hydrazine had no effect on these parameters. These data indicate that the early toxicity of hydrazine does not involve peroxidation of lipids whereas phenylhydrazine causes lipid peroxidation possibly within the erythrocyte, perhaps by interaction with red cell haemoglobin.
Teratological Study of the Hypolipidaemic Drugs Etofylline Clofibrate (VULM) and Fenofibrate in Swiss Mice
Authors: Ujházy E. , Onderová E. , Horáková M. , Bencová E. , Ďurišová M. , Nosál R. , Balonová T. , Zeljenková D.
Published: March 2009

Abstract: Teratological studies of the hypolipidaemic drugs etofylline clofibrate (VULM) and fenofibrate were carried out in mice. Pregnant mice were given etofylline clofibrate and fenofibrate in doses 11.7, 117.1, and 585.5 mg/kg orally from day 7 to 16 of gestation. Terminal maternal body weight was significantly decreased after all doses of etofylline clofibrate in a non‐dose‐related fashion compared to the control group. The foetuses were examined on day 19 of gestation. They were weighed and inspected for external, skeletal and visceral abnormalities. The low and middle doses of etofylline clofibrate and fenofibrate had no adverse effects on embryofoetal development. The highest etofylline clofibrate dose induced a significant decrease of foetal weight at term, likewise postimplantation loss was significantly increased after the highest dose of fenofibrate. The incidence of external, skeletal and visceral anomalies was not dose‐dependent. In this study no teratogenic effects were detected, yet with the highest etofylline clofibrate and fenofibrate doses some foetotoxic effects were observed.
Influence of Prenatal Administration of Cadmium on Postnatal Development and Inducibility of Hepatic Monooxygenases in Rats
Authors: Jahn Florentine , Klinger Wolfgang
Published: March 2009

Abstract:Cadmium inhibits hepatic monooxygenases in rats of different ages. But also in the offspring of dams which had received cadmium during pregnancy changes in biotransformation activities and their inducibilities could be observed. In the 30‐ and 60‐day‐old offspring a decrease in the inducibility of ethoxyresorufin O‐deethylation by the specific inducer β‐naphthoflavone could be demonstrated, whereas cytochrome P‐450 concentration, ethylmorphine N‐demethylation and ethoxycoumarin O‐deethylation were not influenced.
An Open Field Study of Antidepressant Drugs
Authors: Dahl Carl Bredo , Götestam K. Gunnar
Published: March 2009

Abstract: Eight psychotropic drugs, mainly acting on the catecholaminergic systems, were investigated in an open field setting. All drugs but one showed a significant reduction in overall activity over time. Only piribedil at 32 mg/kg showed an increase, while 2 mg/kg showed a decrease over time. Amineptine and nomifensine significantly increased and salbutamol significantly decreased both ambulation and rearing with dose. For viloxazine, metapramine, piribedil and piracetam no significant dose effects were revealed at the doses tested. It is concluded that no clear correlation between clinically reported antidepressant efficacy and the selected open field variables can be demonstrated. However, some of the dopaminergic drugs have substantial activating properties, which might render them dependence‐producing properties.
MPTP Toxicity in Relation to Age, Dopamine Uptake and MAO‐B Activity in Two Rodent Species
Authors: Jossan S. S. , Sakurai E. , Oreland L.
Published: March 2009

Abstract:The effects of single and multidose 1‐methyl‐4‐phenyl‐1,2,5,6‐tetrahydropyridine (MPTP) treatment on mice (NMRI and C‐57 bl) and rats of different ages have been investigated by using the reduction of striatal dopamine uptake rate as a measure of the neurotoxic effect. The possibility that differences in MAO‐B activity or in dopamine (DA) uptake rate might explain differences in MPTP toxicity between species, strains or animals of different age was investigated. Single dose MPTP treatment (45 mg/kg) had no effect on 10 day and 3 week old mice, while there was a significant reduction of DA uptake rate at the age of 12 and 40 weeks (both strains). No neurotoxicity of single dose MPTP treatment was observed in the rats, irrespective of their age. Multidose treatment with MPTP (3 × 20–45 mg/kg) caused a reduction of DA uptake rates both in the mice and in the rats at all dose regimens used. The effect of MPTP increased with increasing doses and was most pronounced in the C‐57 bl mice. Both DA uptake rate and monoamine oxidase B (MAO‐B) activity increased with age. The increase in MAO‐B activity was highest between 10 days and 3 weeks both in the mice and in the rats. Rats had higher (MAO‐B) activity than the mice, while the two species had about the same DA uptake rates. No obvious correlations were found either between MAO‐B activities or DA uptake rates and the neurotoxic effect of MPTP.
Inhibitory Effects of Nasal Drops Components on Granulocyte Chemotaxis
Authors: Håkansson Bo , Forsgren Arne , Tegner Hans , Toremalm Nils Gunnar
Published: March 2009

Abstract: A possible toxic effect of components in nasal drops on chemotaxis by human granulocytes was studied. The vasoactive substances oxymetazoline chloride and xylometazoline chloride gave a successive reduction of chemotaxis down to zero for a concentration of 500 mg/l which is around that used in commercial preparations. The preservative benzalkonium chloride which is used in nasal drops in a concentration of 200 mg/l was deleterious for chemotaxis at a concentration of 0.8 mg/l. Thiomersal was deleterious for chemotaxis at a concentration of 1 mg/l which should be compared with a concentration of 24 mg/l used as preservative in nasal drops. Together with previous studies the present results indicate that the addition of preservatives in nasal drops should be questioned especially as they can be safely distributed without any risk of bacterial contaminations nowadays.
Attenuation of Ischaemia‐Induced Regional Myocardial Acidosis by Bevantolol, a β1‐Adrenoceptor Antagonist, in Dogs
Authors: Hino Tomoko , Sakai Kenji , Ichihara Kazuo , Abiko Yasushi
Published: March 2009

Abstract:In dogs anaesthetized with pentobarbital, the left anterior descending coronary artery (LAD) was occluded for 90 min. so that about 1/2 of the original flow was allowed to flow (partial occlusion). Bevantolol (a β1‐adrenoceptor antagonist) or propranolol (a reference drug) was injected intravenously 30 min. after partial occlusion. Regional myocardial pH was measured by a micro glass pH electrode inserted in the LAD area. Partial occlusion decreased myocardial pH by 0.62 to 0.74. Bevantolol (1.0 mg/kg) or propranolol (1.0 mg/kg) significantly increased myocardial pH, that had been decreased by partial occlusion, within 60 min. after the injection. Restoration of myocardial [H+] (defined as return towards a lower [H+] to the preocclusion level) (calculated from the pH data) induced by bevantolol and that induced by propranolol were 64.0 and 66.4% (measured 60 min. after the injection), respectively. Bevantolol or propranolol decreased heart rate also. Even in the paced heart, bevantolol restored the myocardial [H+] that had been increased by partial occlusion. These results suggest that bevantolol has a favorable effect on the ischaemic myocardium as has propranolol, and that the pH effect of bevantolol is not primarily due to a decrease in heart rate.
Inhibition of Theophylline Elimination in Rabbits by Verapamil
Authors: Nielsen‐Kudsk Jens Erik
Published: March 2009

Abstract:Single intravenous dose pharmacokinetics of theophylline in 10 rabbits were investigated before and after 5 days oral administration of verapamil in daily doses of 6 mg/kg. Verapamil caused a significant inhibition of theophylline elimination. Theophylline clearance was reduced from 126 to 98 ml/hr/kg (22.2%) whereas the steady state volume of distribution of the drug increased from 461 to 550 ml/kg (19.3%). The terminal half‐life of theophylline increased from 2.7 to 4.0 hr (49.8%).
Interaction of L‐Ascorbic Acid on the Disposition of Lead in Rats
Authors: Dalley J. W. , Gupta P. K. , Lam F. C. , Hung C. T.
Published: March 2009

Abstract: L‐Ascorbic acid (As‐Ac) has been investigated for its potential in the prophylaxis of lead poisoning. Using rats as the animal model, the pharmacokinetics of As‐Ac was determined following a single intravenous dose (100 mg/kg) administered through a jugular vein. Plasma As‐Ac levels were monitored using an enzyme assisted UV spectrophotometric method. The pharmacokinetic parameters of As‐Ac obtained were used to establish a dosage regimen which could maintain its average plasma concentration of about 11 μg/ml at steady state in rats. The disposition of lead acetate (1 mg/kg) in rats was studied in the absence and presence of As‐Ac at steady state. Lead concentrations were monitored in femur, kidney, liver and plasma over a 120 hr period using flameless atomic absorption spectrophotometry. In presence of As‐Ac, femur, kidney and liver demonstrated 56, 22 and 41% respective reductions in their exposure towards lead. In addition, the half‐life of lead in femur and plasma was found to be reduced by 27 and 51% respectively.
Chelation in Metal Intoxication XXX: α‐Mercapto‐β‐aryl Acrylic Acids as Antidotes to Cadmium Toxicity
Authors: Tandon S. K. , Sharma B. L. , Kachru D. N.
Published: March 2009

Abstract: α‐Mercapto‐β‐(2‐furyl) acrylic acid (MFA), α‐mercapto‐β‐(2‐hydroxyphenyl) acrylic acid (MHA), β‐1,2‐phenylene di‐α‐mercaptoacrylic acid (1,2‐PDMA) and β‐1,4‐phenylene di‐α‐mercapto acrylic acid (1,4‐PDMA) were compared to sodium N‐benzyl‐D‐glucamine dithiocarbamate (NBG‐DTC) an effective cadmium chelator, for their ability to mobilize Cd and influence the Cd induced tissue metallothionein (MT) in rats administered 100CdCl2, 72 hr earlier. MFA was almost as effective as NBG‐DTC but more effective than MHA in enhancing urinary and faecal excretion of Cd, reducing tissue and blood levels of Cd and in lowering Cd induced increase in hepatic and renal MT contents. 1,2‐PDMA and 1,4‐PDMA were effective only in reducing the hepatic burden of Cd. The resuls do not indicate any direct relationship between the efficacy of α‐mercapto‐β‐aryl acrylic acids to decorporate body Cd and their lipophilic‐hydrophilic character or number‐arrangement of their sulfhydryl groups.
Effect of Antibiotics on Colony Formation from Mouse Granulocyte‐Macrophage Progenitors (CFU‐GM), Megakaryocyte Progenitors (CFU‐M) and Erythrocyte Progenitors (CFU‐E, BFU‐E) in Vitro
Authors: Maruyama Toshiyuki , Kobayashi Fumihiko , Uchida Kiyohisa , Hara Hiroshi
Published: March 2009

Abstract: Mouse bone marrow cells were cultured in vitro in semisolid medium containing various concentrations of β‐lactam antibiotics, moxalactam (LMOX), cefotetan (CTT), flomoxef (FMOX), ceftizoxime (CTZ), cefmenoxime (CMX), cefotasime (CTX), cefamandole (CMD), cefotiam (CTM), carbenicillin (CBPC) or sulbenicillin (SBPC). All of these antibiotics dose‐dependently suppressed colony formation from granulocyte or macrophage progenitors (CFU‐GM) and from megakaryocyte progenitors (CFU‐M). The suppressive potencies of these antibiotics for both progenitors, as evaluated from the drug concentrations that induced 50% suppression of colony formation (IC50), were ranked as the weakest for CBPC and SBPC, moderate for LMOX, CTT, CMX, FMOX and CTZ, and strongest for CMD, CTX and CTM. LMOX, FMOX, CTX, CBPC and SBPC also showed dose‐dependent inhibition of colony formation from erythroid progenitors (CFU‐E and BFU‐E). In the ranking of suppression of colony formation from CFU‐E, CMD and CTX showed comparatively strong inhibition but others showed a weak effect, and in that from BFU‐E, the effect was weakest for CBPC and SBPC, moderate for LMOX and FMOX, and strongest for CMD and CTX. The suppressive effect of LMOX and CMD on colony formation from each progenitor could almost be prevented by washing the cells after incubation with these antibiotics for 24 hr.
Glucagon‐Induced Refractoriness of Hepatocyte Adenylate Cyclase: Comparison of Homologous and Heterologous Components and Evidence Against a Role of cAMP
Authors: Refsnes Magne , Johansen Ellen J. , Christoffersen Thoralf
Published: March 2009

Abstract:Exposure of cultured hepatocytes to glucagon leads to a partial refractoriness of the adenylate cyclase both to glucagon (homologous desensitization) and to isoproterenol (heterologous desensitization). In contrast, isoproterenol produces a very strong homologous desensitization but almost no heterologous desensitization. The present study compared the pattern of the homologous and heterologous components of glucagon‐induced desensitization in these cells, particularly during the first 4 hours, and examined the role of cyclic 3′,5′‐adenosine monophosphate (cAMP) in the mechanism of refractoriness development. The decrease in glucagon‐sensitive and isoproterenol‐sensitive adenylate cyclase activities were closely parallel with respect to the extent, the time course and the dose required. 8‐Bromoadenosine 3′,5′‐monophosphate (8‐Bromo‐cAMP) also reduced the hormone‐responsive adenylate cyclase activity, but this effect developed more slowly than the desensitization after glucagon treatment. No consistent relationship was found between cAMP levels and induction of hormone refractoriness when the cells were exposed to glucagon, isoproterenol, cholera toxin or forskolin. Furthermore, addition of 0.5 mM 3‐isobutyl‐1‐methylxanthine) (IBMX) which strongly amplified the cAMP response, did not potentiate the glucagon‐induced desensitization of either glucagon‐sensitive or isoproterenol‐sensitive adenylate cyclase activity. Taken together, the results suggest that homologous and heterologous desensitization of the adenylate cyclase developing after glucagon exposure occur by similar (agonist‐non‐specific) mechanisms which do not involve cAMP.
Effects of Flunitrazepam and Triazolam in Man: Are They Influenced by the Time of Ingestion?
Authors: Wickstrem Egil , Bredesen Jan E. , Gordeladze Jan
Published: March 2009

Abstract: Five healthy young volunteers were given flunitrazepam 1 mg, triazolam 0.25 mg or placebo at 2 a.m. or 9 a.m. in a double blind, cross‐over study. The aim was to investigate the cyclic variations mainly in residual effects of the drugs, but also in sleep onset latency and pharmacokinetics. The study suggested cyclic variations in mood, psychometric tests and in sleep onset latency.
Fluoride‐Induced Cytoplasmic Acidification: Possible Role of Protein Kinase C in BCECF‐Loaded L929 Cells
Authors: Kawase Tomoyuki , Suzuki Akitoshi
Published: March 2009

Abstract: The effect of fluoride on cytoplasmic pH (pHi) in L929 cells was investigated by using a fluorescent pH indicator, BCECF. Fluoride decreased pHi in a dose‐dependent manner. This cytoplasmic acidification was composed of two phases: 1) a rapid decrease in pHi occurring within seconds, and 2) a slow decrease in pHi occurring 1–2 min. after stimulation with fluoride. The phase one decrease in pHi at external pH (pHe) 7.7 was more rapid than that at pHe 6.8, whereas the phase two decrease at pHe 7.7 was slower than that at pHe 6.8. In addition, both in the protein kinase C‐inhibited and depleted cells, the fluoride‐acidified pHi gradually returned to the resting pHi level in phase two, though the initial cytoplasmic acidification (i.e. phase one) was not affected. These results suggest that the fluoride‐induced cytoplasmic acidification is dependent upon pHe and is sustained by the protein kinase C‐dependent Na+/H+ exchange.
Effects of Amperozide in Two Animal Models of Anxiety
Authors: Engel J. A. , Egbe P. , Liljequist S. , Söderpalm B.
Published: March 2009

Abstract: The novel psychotropic agent amperozide (amp) was investigated in two different rat anxiety models, Vogel's conflict test (VT) and Montgomery's conflict test (MT). In the VT, amp in lower doses (0.2–0.6 mg/kg subcutaneously) increased the number of shocks accepted, as compared to controls. Pretreatment with the specific benzodiazepine receptor antagonist Ro 15–1788 (10.0 mg/kg orally) or the GABA‐A receptor antagonist bicuculline (2.0 mg/kg intraperitoneally) antagonized the anticonflict effect of amp (0.4 mg/kg subcutaneously). At the highest dose tried (2.0 mg/kg subcutaneously) amp instead decreased the number of shocks accepted. Both 0.4 mg/kg and 2.0 mg/kg of amp raised the shock threshold, as compared to controls. The latter dose also decreased the motivation to drink. Pretreatment with Ro 15–1788 (10.0 mg/kg orally) did not significantly change the shock threshold or the drinking motivation, as compared to the group receiving amp alone. In the MT, amp (0.05–0.1 mg/kg subcutaneously) increased the percentage time spent in the open arms, while no changes were seen in the number of entries made into these arms. After higher doses (0.4–0.8 mg/kg subcutaneously) no differences, as compared to controls, were observed. Amp (1 nM–10μM) exhibited no affinity for 3H‐flunitrazepam binding sites in mouse forebrain membranes in vitro. Taken together, the present data suggest that amp in low doses produces anticonflict (anxiolytic‐like) effects. These effects appear to be mediated through an indirect (via 5‐HT and/or DA systems?) activation of the GABA/benzodiazepine chloride ionophore receptor complex.
Effect of Growth Hormone Dosing on Ultimate Weight and Length of XO Mice
Authors: Jørgensen Karin Damm , Jensen Sigrid , Ørskov Hans
Published: March 2009

Abstract: Mice with the karyotype 39, XO and XX mice with the same genetic background were injected for a six month period with daily subcutaneous doses of 0.5 IU biosynthetic human growth hormone (hGH) or with placebo. The XO mice dosed with hGH obtained a significantly higher body weight and greater final length than the XO mice dosed with placebo (39.2 g versus 29.0 g and 21.1 cm versus 19.2 cm respectively). The body weight remained constant after cessation of dosing. The XX mice became significantly longer but not heavier as a result of hGH dosing. The placebo dosed XO mice became significantly longer than the placebo XX mice but their body weights were comparable. Dosing with hGH caused a significant increase in growth rate in both XO and XX mice, and the ultimate body weight was reached within a significantly shorter time period. In the XO mice the hGH injections increased significantly the length and thickness of the femoral bones and the length of the tibia bones. Stimulated endogenous plasma growth hormone levels were significantly higher in XX mice compared to XO mice. Plasma IGF‐I levels were significantly higher in XO compared to XX mice, but the levels were not affected by hGH dosing. XO mice may be useful in future metabolic and hormonal studies.
Relaxant Effects of the Selective Phosphodiesterase Inhibitors Milrinone and OPC 3911 on Isolated Human Mesenteric Vessels
Authors: Lindgren S. , Andersson K.‐E. , Belfrage P. , Degerman E. , Manganiello V. C.
Published: March 2009

Abstract:Several new positive inotropic drugs with vasodilating properties for which a major mechanism of action is believed to be inhibition of phosphodiesterase (PDE) have been introduced in the treatment of congestive heart failure. Hydrolysis of cyclic nucleotides is catalyzed by multiple forms of PDE, which may vary between organs and cell‐types. These enzymes can be selectively inhibited by various agents, theoretically making it possible to produce tissue‐selective responses. An enzyme, which belongs to a subclass of cGMP inhibited low KmcAMP PDE, was recently purified from rat adipose tissue. The enzyme was specifically and potently inhibited by the cilostamide derivative OPC 3911 (OPC) and milrinone (mil). We studied the relaxant effects of OPC and mil on isolated human mesenteric arteries and veinsin vitro.In preparations contracted by noradrenaline (NA), both agents produced about 60% maximum relaxation; OPC was 3–4 times more potent than mil. Both OPC and mil caused rightward displacement of the NA concentration‐response curve and depressed the maximum responses. Arteries, as compared to veins, were more sensitive to this inhibition of NA contraction. Both drugs relaxed arteries contracted by 30 mM K+, but not 127 mM K+; maximum relaxation was between 60 and 70%. OPC was 10 times more potent than mil. The interactions between mil/OPC and isoprenaline, forskolin and ouabain were also studied. In preparations pretreated with isoprenaline or forskolin, the relaxant effects of mil and OPC were additive to those of isoprenaline and forskolin. Ouabain pretreatment did not affect the actions of the phosphodiesterase inhibitors. The results suggest the presence of a low KmcAMP PDE in human mesenteric arteries and veins, and that selective inhibition of this enzyme causes relaxation of the vessels.
Chlorpromazine, Administered in Vivo and in Vitro, Inhibits the Efflux of Bile Acids in Freshly Isolated Rat Hepatocytes*
Authors: Willson R. A. , Hart J. R. , Hall T.
Published: March 2009

Abstract: Although it has been speculated that chlorpromazine may alter the transhepatic movement of bile acids from plasma to bile, the effect of chlorpromazine on various determinants of bile acid transport in isolated rat hepatocytes remains incompletely defined. In particular, there is little information about the effect of chlorpromazine on the release of bile acids from freshly isolated hepatocytes. Therefore, we examined the effect of chlorpromazine, administered in vivo and in vitro, on the efflux rate of radiolabeled bile acids in freshly isolated rat hepatocytes. In an isolated haptocyte system, it is not possible to distinguish the sinusoidal plasma membrane function of efflux (back diffusion) from the canalicular plasma membrane function of excretion. Therefore, efflux, as used in this manuscript, reflects both back diffusion and excretion. In vitro, chlorpromazine produced a rapid dose dependent significant (P<0.05) decrease of the bile acid efflux rate in freshly isolated hepatocytes. This decrease in bile acid efflux was observed at chlorpromazine concentrations which did not alter hepatocyte plasma membrane permeability (viability), as measured by intracellular potassium content, release of lactate dehydrogenase, and trypan blue exclusion. Moreover, in freshly isolated hepatocytes from chlorpromazine pretreated rats, a significant (P<0.05) decrease in the bile acid efflux rate was also observed, and this decrease in efflux was similar in magnitude to the decrease in bile acid efflux observed following exposure of freshly isolated hepatocytes to chlorpromazine in vitro. Our experimental findings indicate that chlorpromazine does alter the efflux of bile acids by the isolated hepatocyte, and this observed alteration of hepatocyte bile acid release may have a pathophysiologic role in the development of chlorpromazine‐induced bile secretory failute in the intact liver.
The Effects of Inorganic Lead on the Spontaneous and Potassium‐Evoked Release of 3H‐5‐HT from Rat Cortical Synaptosome Interaction with Calcium
Authors: Oudar Pascal , Caillard Liliane , Fillion Gilles
Published: March 2009

Abstract: Interaction of lead with the serotonergic system has been studied in vitro in rat brain synaptosomal fraction prepared from cortical tissue. Synaptosomes were loaded with 3H‐5‐HT and spontaneous and K+‐evoked release of the amine was examined in the presence and the absence of calcium. It was shown that lead itself induced the release of 3H‐5‐HT (EC50 = 27 μM). This effect decreased (40%) in the presence of calcium without modification of the EC50. Moreover, lead markedly inhibited the K+‐evoked release of 3H‐5‐HT observed in the presence of calcium. This effect was obtained either in the presence of lead or using synaptosomes pretreated with lead and washed. These results indicate that lead interferes with neuronal 5‐HT release by mechanism(s) involving calcium.
Molecular Cloning of cDNA for Rat Brain Metallothionein‐II and Regulation of its Gene Expression
Authors: Saijoh Kiyofumi , Kuno Takayoshi , Shuntoh Hisato , Tanaka Chikako , Sumino Kimiaki
Published: March 2009

Abstract: A rat brain metallothionein‐II (MT‐II) complementary DNA (cDNA) clone was isolated from a cDNA plasmid library, which was prepared from non‐treated rat brain mRNA, by a colony screening procedure using 32P‐labeled synthetic oligonucleotide probes. It is deduced that the clone encodes for a protein of 61 amino acids comprising 20 cysteines, which is highly homologous to MT‐IIs in other species. Northern blot analysis demonstrated major mRNA species in the brain, liver and kidneys (approximately 350 b in size), which is induced in response to dexamethasone, zinc, cadmium and mercury but not to methyl mercury. These findings confirm that MT‐II genes are expressed and regulated both by steroid and heavy metals in the brain as well as in peripheral organs.
Attenuation of Water Intake and Operant Responding by Dopamine D2 Antagonists: Raclopride Provides Important Cues for Understanding the Functional Mechanism of Action
Authors: Ljungberg Tomas
Published: March 2009

Abstract: The selective dopamine (DA) D2 receptor antagonist raclopride was found to attenuate operant lever‐pressing with water as reward in a dose dependent manner and more potently than the corresponding consummatory act, i.e. the unconditioned water intake. This is the same way as previously reported for other DA D2 antagonists. In screening experiments raclopride has been selected on the basis of great separation between antagonism of DA‐agonist induced hyperactivity, stereotypies and production of catalepsy. We found that attenuation of lever‐pressing and water intake by raclopride were not more separated in dose than after, for example, haloperidol. We further found that attenuation of lever‐pressing and water intake occured in doses relatively lower than those producing catalepsy, thus excluding catalepsy as a cause for the attenuation. Decreased water intake in thirsty animals caused by a low dose of apomorphine (APO) was counteracted by raclopride. This has previously been found with DA D2, but not with D1, antagonists, which further supports that this apomorphine‐effect is mediated via D2 receptors. However, raclopride only showed this antagonism in a narrow dose‐range, like haloperidol. The selective profile previously found for sulpiride, proposed to be related to low incidence of extrapyramidal side‐effects in the clinic, was thus not replicated.
Brain, Kidney and Liver 203Hg‐Methyl Mercury Uptake in the Rat: Relationship to the Neutral Amino Acid Carrier
Authors: Aschner Michael
Published: March 2009

Abstract: To investigate the effect of L‐neutral amino acids on tissue levels of methyl mercury in the adult animal, rats were infused into the external jugular vein with solutions containing a) 0.05 mM 203Hg‐MeHgCl and saline, b) 0.05 mM 203Hg‐MgHgCl‐0.1 mM L‐cysteine, c) 0.05 mM 203Hg‐MeHgCl‐0.1 mM L‐cysteine‐0.1 mM L‐methionine, d) 0.05 mM 203Hg‐MeHgCl‐0.1 mM L‐leucine, or e) 0.05 mM 203Hg‐MeHgCl‐0.1 mM L‐cysteine‐0.1 mM L‐leucine. Groups of animals were sacrificed at 3 min. 7 hr, and 96 hr. Brain, kidney, and liver 203Hg radioactivity was measured by means of gamma‐scintillation spectrometry. Brain 203Hg concentrations L‐cysteine treated animals were significantly higher compared with saline treated animals (P<0.05) at 3 min., 7 hr and 96 hr. The coinjection or coinfusion of methyl mercury with L‐cysteine and L‐methionine abolished the L‐cysteine‐mediated brain 203Hg uptake (P<0.05), at each sacrifice time. Kidney and liver 203Hg concentrations were not significantly different in any of the treatment groups compared with controls, irrespective of the sacrifice time. Furthermore, the percentage of diffusible 203Hg (non‐protein bound) at each sacrifice time was not statistically different irrespective of the treatment assigned. These results suggest that methyl mercury L‐cysteine conjugates in the plasma may share a common transport step with the L‐neutral amino acid carrier transport system and indicate the presence in brain capillaries of a transport system capable of selectively mediating methyl mercury uptake across the capillary endothelial cell membrane.
Deuterium Isotope Effects as a Tool in the Study of Ethanol Oxidation in Rat Liver Microsomes
Authors: Lundquist Frank , Hansen Lillian Lund
Published: March 2009

Abstract: The apparent kinetic deuterium isotope effect (I) on the oxidation of ethanol to acetaldehyde by washed rat liver microsomes was measured with (1‐R)‐[1‐2H2, 1‐14C]‐ethanol (I1) and [1‐2H2, 2‐14C]‐ethanol (I2) as substrates by a competitive technique involving only measurements of radioactivity. The average values were for non‐induced rats, I1 = 1.57 and I2 = 2.23. When these two substrates were used with stereospecific enzymes (alcohol dehydrogenase and catalase) a small secondary effect was observed, causing I2 to be about 10% higher than I1. With non‐stereospecific systems I2 was much larger than I1, and the values were connected by a simple formula. This relation in combination with use of the inhibitors, sodium azide and thiourea, made it possible to calculate tentatively the contribution to microsomal ethanol oxidation of catalase, a non‐identified stereospecific enzyme, and non‐stereospecific catalytic systems, as well as the isotope effects of the latter two systems. Measurements were made in microsomes from normal, phenobarbital treated, and acetone treated rats. For the stereospecific component an isotope effect of 1.4‐1.5 was calculated for all three groups. For the non‐stereospecific enzyme in acetone treated rats a value of 4.0 was found. Both the other groups showed a value about 2.7. The activity of the non‐stereospecific system was about twice the normal in barbiturate treated, and 3 times the normal in the acetone treated group, where it contributed 70% of the total activity. The isotope effects on the changes in ethanol oxidation (the ‘differential isotope effect’) caused by inhibitors and activators were utilized to decide whether inhibitors were specific for a single reaction. Thus azide while inhibiting catalase completely, also inhibited other reactions. The large increase (5‐6 times) in rate caused by Fe‐EDTA had an I2 of 1.6, equal to that for oxidation of ethanol by hydroxyl radicals.