bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Portal Vein Responsiveness in Tris, HEPES or Bicarbonate‐Phosphate Buffered Media
Authors: Sigurdsson Stefan B.
Published: July 2010

Abstract:The effects of using Tris or HEPES buffered solutions instead of bicarbonate‐phosphate buffered solution on the spontaneous activity of the rat portal vein were studied. The effect of the solution buffered with Tris on the spontaneous contractile activity was a minor change in amplitude and frequency, increasing the integrated isometric force by about 20%. A small increase in the mechanical response to variations in [Ca2+]0(1.0–2.5 mM) was also observed. The response to field stimulation of intramural nerves was significantly lowered in Tris but the response to exogenous noradrenaline was not affected. HEPES buffer does not significantly affect the spontaneous activity, the concentration‐effect curve for Ca2+, the response to field stimulation or to exogenous noradrenaline. Transient changes in the spontaneous activity and the resting membrane potential were observed when the solution was changed from Krebs to Tris (or HEPES) solution or vice versa. These changes disappear if the Tris or HEPES solutions were aerated with 4% CO2in O2(at pH 7.4) instead of pure O2. A small change in extracellular pH ($pL0.2 pH units) significantly affects the spontaneous activity. A change in pH may be the reason for the observed effects in the different buffer media.
Effect of Daily Oral Intake of Manganese on Free Polysomal Protein Synthesis of Rat Brain
Authors: Magour S. , Mäser H. , Steffen I.
Published: July 2010

Abstract: The effect of manganese on free polysomal protein synthesis of immature rat brain (3 weeks old) has been determined after 1, 2, 3, and 4 weeks of daily intake of 55 μg manganese/ml of drinking water. The protein synthesis was inhibited up to 35% during the first 3 weeks and returned toward the control level during the fourth week of treatment. Cross‐incubation experiments with polysomes and pH 5 enzyme fractions indicated that the inhibition of protein synthesis is due to alteration of the pH 5 enzyme fraction. Furthermore, cerebral t‐RNA content was reduced by 20% during the first 3 weeks and also returned to the control level after 4 weeks. The data suggest that the previously reported retardation in learning and memory of manganese treated immature rats may partly be due to alteration of cerebral RNA and protein synthesis. It was also evident that an adaptation mechanism to the observed effect of manganese developes after three weeks of daily intake of 55 μg manganese/ml.
A Study of Hepatic Protein Synthesis, Three Subcellular Enzymes, and Liver Morphology in Chronically Ethanol Fed Rats
Authors: Smith‐Kielland A. , Blom G. P. , Svendsen L. , Bessesen A. , Marland J.
Published: July 2010

Abstract:Male Wistar rats were given ethanol chronically (20–30% of the energy as ethanol) in a nutritionally sufficient regimen. Controls received lipid as isoenergetic substitute for ethanol. Treatment lasted for 2 or 8 weeks. Hepatic protein synthesis was measured in fasted rats during a 32 min. continuous infusion of3H‐valine. After 2 weeks of treatment accumulation of hepatic protein was observed in the ethanol group, but there was no change in hepatic protein synthesis or morphology. After 8 weeks the rate of hepatic protein synthesis was decreased by 35% in the ethanol group, but there was no accumulation of protein and a slight accumulation of intracellular lipid droplets. Neither the subcellular distribution of incorporated3H‐valine, nor the activities and distributions of alcohol dehydrogenase and NADPH cytochromecreductase were changed. Mitochrondrial cytochromecoxidase activity was decreased in the ethanol group, and cytosolic and microsomal fractions showed higher cytochromecoxidase activity in this group. Chronic ethanol treatment for 8 weeks had an adverse effect on general protein synthesis as well as on a specific enzyme in the liver in the absence of serious morphologic abnormalities.
Antiarrhythmic Effects of Tocainide and Lidocaine in Dogs
Authors: Aberg Gunnar , Ronfeld Robert , Aberg Laurel , Fitzgerald Thomas , McCollom Kathleen , Moller Robert
Published: July 2010

Abstract:To compare the antiarrhythmic activities of tocainide and lidocaine in dogs, a protocol was designed where the drug plasma levels were increased stepwise. This was achieved by computerizing bolus doses and infusion rates, using pharmacokinetic equations with constants, derived from previous experiments in similar animals. In conscious coronary‐ligated dogs with ischaemic arrhythmias both compounds were active, causing a 50% reduction in VPB's at plasma concentrations of 5.0 μg/ml (tocainide) and 3.5 μg/ml (lidocaine). “Clearing” of catecholamine‐induced arrhythmias was not obtained in any of six dogs given tocainide and only in two out of six dogs given lidocaine.
Complete Programme for Acute Toxicity Testing — not only LD50 Determination.
Authors: Dayan A.
Published: July 2010

Abstract The objective of any experimenter should be to obtain the maximum amount of useful information in the most economical manner possible. In this context,‘useful’ means study both of the principal or anticipated actions of the compound under examination, and also detection of additional responses to it. For efficient evaluation, including greater statistical rigour, a continuous or graded response and quantitative measurement is preferable, although much can be done by simply analysis of the presence or absence of responses, even if these are complex or dependent upon subjective criteria. Consistency of experimental conditions, and of diagnostic criteria are essential, whether in single, exploratory or comparative tests.

Acute toxicity tests, like other experiments, should be designed pragmatically, therefore, confirming to the properties of the substance under examination, but also with general or holistic coverage, albeit less specific, to detect unanticipated actions. Greater or lesser weight may be given to these two classes of method, depending on whether the test is done as part of a general screen of a previously unknown substance, or as a specific control measure done to assay one particular property. Extrapolation of the results to man or other species is only possible with the caution proper to any experiment done under restricted and highly artificial conditions, but the value of acute toxicity data has often been shown by experience gained in man.
Shortcomings of LD50‐values and acute toxicity testing in animals.
Authors: Rowan A.
Published: July 2010

AbstractThe author argues that the standard practice of determining an LD50with 95% confidence limits is a waste of animals since the extra statistical precision is undermined by numerous other factors. For example, the LD50of a given chemical often varies by at least 10‐fold between different animal species and strains. Also, environmental factors can result in substantial differences in the LD50of a given chemical in a given animal strain. Therefore, the use of this measure as a general index of toxicity, as a guide to further pharmacological or toxicological studies, or as a guide to human toxicity involves unnecessary and needless taking of animal life. These points will be amplified and substantiated by actual examples. Finally, the author will make some suggestions as to what could constitute a satisfactory acute animal test given current scientific and regulatory needs.
Correlation between cytotoxicity in vitro and LD50‐values.
Authors: Ekwall B.
Published: July 2010

Abstract Previous studies of the correlation between cytotoxicity in vitro and LD50 in rodents have shown a good correspondence for small groups of substances, such as antibiotics, metals, and solvents, but a poor correspondence for other small groups of substances, such as drugs and pesticides, as well as for larger groups of heterogeneous chemicals. The generally poor correlation may be the result of the joint operation of three factors: 1. The existence of organ‐specific toxicity. 2. The pharmacokinetics in whole animals. 3. Methodological problems disturbing a basically equivalent in vitro/in vivo toxicity.

We have made further studies of the correlation for altogether 95 drugs. The type of human and mouse systemic lethal poisoning was compared with the cytotoxicity divided by the i.v. LD50 in the mouse and approximate i.v. LD in man, called Specific Indices (SI1d). A minority of the drugs had an organ‐specific lethal action which was corresponding to high SI1d of 100 or more for all drugs. A majority of the drugs (80%) had a known or possible lethal interference with basal functions of animal and human tissues correlated to low SI1d of 1–10. At lethal dosage most of the latter drugs induce a non‐specific CNS depression, which was interpreted as the systemic reaction to basal cytotoxicity of chemicals reaching brain cells.

Tissue culture tests of cytotoxicity seem to be relevant for the lethal action of most chemicals in man. Comparisons of in vitro/in vivo toxic dosage (SI1d) and concentrations might be used to screen the selectivity of lethal action of chemicals, and to select chemicals interfering with basal cell functions for further studies in vitro.

It will be difficult to replace animal testing by cell tests in toxicity evaluation because of the organ‐specific toxicity and characteristic pharmacokinetics of many substances. However, initial standard in vitro cytotoxicity tests combined with subsequent approximative LD50 tests coupled to pharmacokinetic studies in the animals could produce data discriminating organ‐specific from basal cell toxicity. The toxic mechanisms of the probable majority of common chemicals with a basal cytotoxicity at lethal dosage could then be analysed in tissue culture, which would increase the precision of analysis, as well as saving animal lives.
Acute toxicity testing in cultures of mouse neuroblastoma cells.
Authors: Walum E. , Peterson A.
Published: July 2010

AbstractCultured mouse neuroblastoma cells (C1300) may be used as models for nerve cells since they have a number of properties in common with their normal counterpartsin vivo.In order to test the possibility of using C1300 cells as alternativeto experimental animals when testing for acute toxicity, cells (clone 41A3) were exposed to a number of common chemicals (CH3HgCl, CdCl2HgCl2ppDDT, n‐butanol, benzene, dioxan, n‐propanol, aceton and t‐butanol). The toxic effect was quantified by measuring the degree of cell detachment in the cultures. The concentrations of chemicals that caused 25% of the total cell number to detach (TD25) were used for comparison with LD50values.

In spite of the very simplified situation in culture, where the toxicity of a substance is little or not at all influenced by factors like penetration, storage, metabolism and excretion a good correlation (corr. coeff. 0,98) was obtained between TD25values and LD50values. Good correlations betweenin vitroandin vivotests have also been reported by others. One possible explanation to these findings could be simplifiedin vivotoxicokinetics of these substances when tested in high doses for general effects like animal death. If so, simplein vitrotests may be used for predicting acute toxicity of certain groups of substances.
Pharmacokinetics and Bioavailability of Intravenous and Intramuscular Lorazepam with an Adjunct Test of the Inattention Effect in Humans
Authors: Nielsen‐Kudsk F. , Jensen T. Staehelin , Magnussen I. , Jakobsen P. , Jensen P. B. , Mondrup K. , Petersen T.
Published: July 2010

Abstract: Single dose pharmacokinetics and bioavailability of intravenous and intramuscular lorazepam were investigated in 6 younger healthy human volunteers of either sex. The plasma concentration profile after intravenously administered lorazepam could in all cases be fitted by NONLIN to a biexponential function of time with a mean terminal (biological) half‐life of 14.10 hrs ± 2.94 S.D. (range 9.68–18.42 hrs). The mean half‐life of the initial α‐phase of distribution was 0.31 hrs ±0.11 S.D. The mean apparent volume of distribution derived from AUC, Vd‐area (= Vdβ), was 1.24 1 kg−1 ±0.17 S.D. Mean plasma clearance of the drug was 62.17 ml kg−1 hr−1 ± 8.85 S.D. The apparent central volume of distribution characterizing the open two‐compartment pharmacokinetic model was 0.59 1 kg−1 ±0.19 S.D. After intramuscular administration to the same subjects the plasma concentration time lapse could be described by either tri‐ or bi‐exponential kinetics, which are representative of open two‐ and one‐compartment models with absorption phases, respectively. Mean biological half‐life was 14.01 hrs±2.31 S.D. and Vd‐area 1.24 1 kg−1 ±0.14 S.D., both values in full agreement with the findings based on intravenous administration. Half‐life of the absorption phase varied from 0.08 to 1.76 hrs. Mean systemic availability of the drug was 88.8% ±8.3 S.D. The inattention effect of lorazepam was assessed by exposing the subjects during the intravenous pharmacokinetic experiments to a binaural stimulation test, which revealed various degrees of acute reduced attention in only three of the subjects.
Effects of Trifluoperazine on β‐Adrenergic Responses of Rat Papillary Muscle: Related to Calmodulin?
Authors: Aass Halfdan , Skomedal Tor , Osnes Jan‐Bjørn
Published: July 2010

Abstract:The β‐adrenergic stimulation of cardiac contraction and relaxation is related to an augmented Ca++oscillation mediated by cAMP. This Ca++mobilization may secondarily involve calmodulin in a way modulating the mechanical responses. We tested this possibility by studying interferences of trifluoperazine (which is able to block Ca++‐calmodulin) with β‐adrenergic responses in rat heart papillary muscles. Trifluoperazine up to 10−5mol/l did not change the basal function. 10−5mol/l trifluoperazine augmented the contractile response to isoprenaline above 10−7mol/l. The inotropic effects of isoprenaline below 10−7mol/l and of the partial β‐agonist prenalterol were not influenced by trifluoperazine. 10−5mol/l trifluoperazine attenuated the stimulation of initial relaxation by isoprenaline in the entire concentration range. Thus this β‐adrenergic response was more sensitive to trifluoperazine than the contractile response. But trifluoperazine only slightly and non‐significantly attenuated the stimulation of initial relaxation by prenalterol. From experiments on broken cell preparations the present results can be explained in terms of calmodulin blockade and thus inhibition of Ca++efflux across the sarcolemma and of Ca++uptake by the sarcoplasmic reticulum. Trifluoperazine effects unrelated to calmodulin can hardly account for the results. Thus a full β‐agonist can apparently mobilize enough Ca++to activate calmodulin systems important for the final effects on the contraction‐relaxation cycle.
Differences between Binding Affinities of some Antimuscarinic Drugs in the Parotid Gland and those in the Urinary Bladder and Ileum
Authors: Nilvebrant Lisbeth , Sparf Bengt
Published: July 2010

Abstract:Possible differences between the muscarinic receptors in the guinea pig urinary bladder and those in the ileum and the parotid gland were investigated, using a receptor binding technique. The affinities of 18 antimuscarinic drugs were indirectly derived from the ability to inhibit the receptor‐specific binding of the radioligand (–)3H‐QNB. The Hill coefficients were close to unity which indicated that the drugs were bound to apparently uniform populations of receptors within each tissue. In contrast to traditional muscarinic antagonists, four drugs – namely, oxybutynine, dicyclomine, benzhexol and pirenzepine – bound with a significantly higher affinity in the parotid gland than in the urinary bladder and ileum. A tendency towards reversed selectivity was found for secoverine. Thus, the present results further support the hypothesis that differences in muscarinic receptors between tissues exist, e.g. smooth muscle compared with parotid gland, which can be detected only by certain antimuscarinic drugs.
The Effect of Long‐term Lithium Treatment on the Incorporation and Distribution of32P‐Orthosphosphate into the Phospholipids from Rat Synaptosomes
Authors: Edelfors Sven
Published: July 2010

Abstract:Rats were treated with lithium added to their diet for five weeks (40 mmol LiCl/kg diet). Mean plasma concentration was 0.45 mmol Li+/plasma. The investigation was divided into two sections. I) In anin vivoexperiment in which the rats were injected with32P‐orthosphosphate for 20 hours, and with carbamoylcholine for 20 min. prior to their death, the distribution of32P in the synaptosomal phospholipids, phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and phosphatidylcholine (PC), was investigated. II) Anin vitroexperiment which was carried out in order to establish the effect of carbamoylcholine on the incorporation of32P into total phospholipids from extracted synaptosomes. In I) the incorporation of32P‐orthosphosphate into PI from carbamoylcholine‐stimulated rats was significantly lower than from unstimulated rats, whereas there was no difference between the incorporation of32P into PI from synaptosomes from control animals and lithium‐treated animals. In II) the incorporation of32P‐orthosphosphate was significantly lower in unstimulated synaptosomes from lithium‐treated rats than from control rats, while the increase in the32P‐incorporation after stimulation followed the same pattern with regard to synaptosomes from control rats and lithium‐treated rats. The results support the idea of lithium exerting an effect on basal synaptosomal activity but not on stimulated synaptosomal activity.
Cyclic AMP Phosphodiesterase Activity in Rat Brain Following Chronic Treatment with Lithium, Imipramine, Reserpine, and Combinations of Lithium with Imipramine or Reserpine
Authors: Andersen P. H. , Klysner R. , Geisler A.
Published: July 2010

Abstract:The adaptability of the cyclic AMP phosphodiesterase (PDE) following chronic treatment (4–6 weeks) with lithium, reserpine, imipramine, and combinations of lithium with imipramine or reserpine has been studied in rat brain tissue. All drugs, except lithium, were given intraperitoneally once a day. Control animals received only vehicle. Lithium was given in the diet in a concentration yielding a plasma level of 0.5–0.6 mmol/l. The PDE activity was measured in homogenates from cerebral cortex and “limbic” forebrain. These two brain areas were both found to contain three types of PDE activity. One was mainly associated with the pellet after a 10,000Xg centrifugation for 10 min. This enzyme hydrolyzed both cyclic AMP and cyclic GMP with a Kmvalue of 130±48 μM for cyclic AMP, but was insensitive to calcium and calmodulin. Two types were mainly found in the supernatant after the centrifugation with Kmvalues for cyclic AMP of 300±108 μM and 4±3 μM, respectively. The former hydrolyzed both cyclic AMP and cyclic GMP and was stimulated 7‐fold by calcium and calmodulin, while the latter only hydrolyzed cyclic AMP and was insensitive to calcium and calmodulin. None of the treatments affected the “pellet” enzyme or the low affinity enzyme from the supernatant. However, lithium treatment, even combined with reserpine or imipramine, increased the high affinity enzyme. This increase was also apparent in the DEAE‐ion exchange chromotographic profile of the PDE enzymes.
Spinal 5‐HT or NA Uptake Inhibition Potentiates Supraspinal Morphine Antinociception in Rats
Authors: Larsen Jens‐Jørgen , Arnt Jørn
Published: July 2010

Abstract: Spinal injection of the specific uptake inhibitor of 5‐hydroxytryptamine (5‐HT), citalopram, or of noradrenaline (NA), desipramine, potentiated the antinociception following intracerebroventricular injection of morphine in rats tested on the hot plate. Combined spinal injection of citalopram and desipramine caused a synergistic potentiation. The unselective and less potent inhibitor of both 5‐HT and NA uptake, amitriptyline, did not cause potentiation. The results support the suggested involvement of both 5‐HT and NA pathways in supraspinal morphine antinociception.
The Interaction between Atropine and some Lipid‐soluble Barbiturates in Rats
Authors: Bolander Hans G. , Wahlström Goran
Published: July 2010

Abstract:The effect of atropine pretreatment on the CNS sensitivity to five lipid‐soluble barbiturates was studied in rats. Atropine in a dose of 8 mg/kg intraperitoneally or saline was given 1.5 hr before an EEG‐threshold determination with the tested barbiturates. The barbiturate was infused by constant rate through a tail vein. The dose of barbiturate needed to induce a burst suppression period in the EEG which is one second or longer was used as the threshold dose. Atropine pretreatment decreased the threshold dose significantly for two N‐methylated barbiturates, hexobarbital (enhexymalum NFN) and methohexital (enallynymalum NFN), but not for thiopental (thiomebumalum NFN), pentobarbital (mebumalum NFN) or amobarbital (pentymalum NFN). No clear effects of atropine pretreatment could be found in the ensuing anaesthesia times after threshold determinations. These results indicate that there are differences in mechanisms of action between barbiturates. One of these mechanisms is related to the cholinergic system in the CNS.
Studies on the Effect of Histamine in Isolated Human Pulmonary Arteries and Veins
Authors: Mikkelsen E. , Sakr A. M. , Jespersen L. T.
Published: July 2010

Abstract:The effect of histamine (0.01–200 μM) was studied in isolated human pulmonary vessels. Histamine induced concentration dependent contractions in both arteries and veins. In veins the maximal response to histamine was lower than in arteries. Histamine and 2‐methyl‐histamine had a dual action in both arteries and veins clearly demonstrated in vessels precontracted with potassium. In these vessels histamine and 2‐methyl‐histamine induced relaxation at low concentrations and contractions at high concentrations. Veins were more sensitive to the relaxant effect of histamine than arteries. Mepyramine eliminated the dual action of 2‐methyl‐histamine and histamine and unveiled a mepyramine resistant relaxation at the highest histamine concentrations used which was resistant to the effect of cimetidine and metiamide. The H2receptor agonist dimaprit (10–400 μM) induced a slight relaxation in both arteries and veins that could be eliminated by metiamide (100 μM). The results show that histamine has a dual action in human pulmonary vessels which includes a contractile effect mediated via H1receptors and a relaxant response partly mediated through H1receptors and partly via unspecific mechanisms. However, an H2mediated relaxant effect cannot be excluded.
The Disposition and Metabolism of N‐Nitrosodiethylamine in Adult, Infant and Foetal Tissues of the Syrian Golden Hamster
Authors: Löfberg Boël , Tjälve Hans
Published: July 2010

Abstract:Low‐temperature whole‐body autoradiography in Syrian golden hamsters, 11 and 15 days pregnant, given N‐14C‐nitrosodiethylamine, indicated an ability of the non‐metabolized substance to freely pass the cellular membranes of the maternal, placental and foetal tissues. Experimentsin vitrowith tissues of adult hamsters showed a capacity of the nasal olfactory and respiratory mucosa, the trachea, the lung, the lateral nasal gland, the liver and the kidney to degrade the N‐nitrosodiethylamine. Autoradiography showed a localization of non‐volatile N‐14C‐nitrosodiethylamine metabolites in these tissuesin vivo.Since the mentioned tissues are the targets for the N‐nitrosodiethylamine‐induced neoplastic or preneoplastic lesions in the hamster, our results indicate that the ability of the sensitive tissues to perform the degradation of the substance is correlated to the tumour organotrophy. The main targets for the N‐nitrosodiethylamine carcinogenicity ‐ the nasal olfactory and respiratory mucosa and the trachea ‐ were found to be very active in degrading the substance, and it was shown that cytochrome P450 is present in these tissues. Microautoradiography of the nasal mucosa showed the highest labelling over the subepithelial glands (Bowman's glands) in the olfactory region, but other areas were also labelled. In the 15 day pregnant hamster, autoradiography showed a markedin vivolocalization of non‐volatile metabolites in the foetal nasal and tracheo‐bronchial mucosa and liver, which was not observed in the 11 day pregnant hamster. Thein vivodata were shown to correlate to anin vitrocapacity by the nasal mucosa, the lung and the liver of the 15 day old foetus to metabolize the substance. N‐nitrosodiethylamine is a transplacental carcinogen only when administered on one of the last four days of pregnancy (day 12–15), and our results are in accord with the assumption that only at this late stage of pregnancy has the differentiation of the sensitive tissues reached a stage at which the substance can be metabolized to its ultimate carcinogen.In vitroexperiments in 4, 10, and 20 day old infant hamsters showed a high capacity of the nasal mucosa, the lung and the liver to metabolize the N‐nitrosodiethylamine at these early stages of life.
Tissue Disposition of Carbon Disulfide: I. Whole‐body Autoradiography of35S‐ and14C‐labelled Carbon Disulfide in Adult Male Mice
Authors: Bergman Kerstin , Danielsson Bengt R. G. , D'Argy Roland
Published: July 2010

Abstract:Occupational exposure to carbon disulfide (CS2) is associated with several adverse effects such as neurotoxicity, atherosclerosis, liver injury and endocrinal disturbances. In the present study, the distribution of CS2and its metabolites after inhalation of35S‐ or14C‐labelled CS2was studied in adult male mice with whole‐body autoradiography. CS2itself was registered in body fat and in well‐perfused tissues at survival times up to 2 hours. Very little CS2was taken up by the brain. The distribution patterns of CS2metabolites were very different after administration of C35S2or14CS2.35S‐Labelled metabolites were initially concentrated in the liver and kidney, but were rapidly eliminated from the body. There was evidence of an extensive metabolic incorporation of sulfur split off from CS2 during its biotransformation.14C‐Labelled metabolites were likewise concentrated in the liver and kidney, but were also observed in large amounts in the nasal mucosa, bronchi, bone, pancreas, thyroid, adrenal cortex and testis. A marked retention of non‐extractablel4C‐labelled metabolites was seen in the liver and thyroid. The results point to several sites of specific CS2‐induced toxicity due to the tissue disposition of metabolites of CS2.
Comparative Studies of the Hepatic Effects of Di‐ and Mono‐n‐Octyl Phthalates, Di‐(2‐Ethylhexyl) Phthalate and Clofibrate in the Rat
Authors: Lake Brian G. , Rijcken W. Robert Pels , Gray Tim J. B. , Foster John R. , Gangolli Sharat D.
Published: July 2010

Abstract:The oral administration of di‐n‐octyl phthalate (DNOP), mono‐n‐octyl phthalate (MNOP), di‐(2‐ethylhexyl) phthalate (DEHP) and clofibrate to young male Sprague‐Dawley rats for 14 days resulted in liver enlargement. Morphological examination of liver sections from DEHP and clofibrate treated rats, but not from either DNOP or MNOP treated animals, revealed increased numbers of peroxisomes (microbodies). Both DEHP and clofibrate treatment markedly stimulated the activities of certain peroxisomal marker enzymes whereas DNOP and MNOP produced only marginal effects. Similarly both DEHP and clofibrate, but not DNOP or MNOP, increased microsomal cytochrome P‐450 content and markedly stimulated microsomal lauric acid hydroxylation activity. The results thus demonstrate that whilst the branched chain phthalate ester DEHP induced peroxisomal proliferation, the straight chain analogue DNOP and its metabolite MNOP were essentially inactive. In addition, DEHP treatment appeared to induce similar form(s) of cytochrome P‐450 in rat liver to those previously described after clofibrate administration.
Detergent Extraction from Rat Synaptosomal Plasma Membranes Reveals Difference inμand δ Opioid Receptor Binding
Authors: Grynne Birthe H. , Bock Elisabeth , Holmen Aase T. , Slange Kirsten
Published: July 2010

Abstract:Rat synaptosomal plasma membranes were extracted with a detergent (CHAPS, a zwitterionic derivative of cholic acid), μ and δ opioid receptor binding and adenylate cyclase activities were tested in the intact membranes and in the supernatants from detergent treated membranes. The 6000 x g/8 min. supernatant contained μ receptor binding equal to 33% of the μ receptor binding measured in the untreated membranes. When the detergent treated membranes were sedimented at (50,000 x g/10 min.), 23% of the μ receptor binding was recovered in the supernatant. After a 100,000 x g/30 min. centrifugation the supernatant contained 10% of the μ receptor binding when compared to untreated membranes. Of the 5 receptor binding found in intact membranes, 10% or less was recovered in the 3 supernatants described above. Furthermore, the μ and δ receptor binding were distributed differently among particles in the supernatants. This indicates differences in the chemical properties of the μ and δ opioid receptors. Adenylate cyclase assays showed that the G/F site of this enzyme complex was inactivated in the supernatants from detergent treated membranes parallel to the δ receptor binding decrease. However, the catalytic part of adenylate cyclase was present in the supernatants and seemed resistant to the detergent.
Tissue Disposition of Carbon Disulfide. II. Whole‐Body Autoradiography of 35S‐ and 14C‐labelled Carbon Disulfide in Pregnant Mice
Authors: Danielsson Bengt R. G. , Bergman Kerstin , D'Argy Roland
Published: July 2010

Abstract: Occupational exposure to carbon disulfide (CS2) has been associated with an increased rate of spontaneous abortions. Animal experiments have shown that CS2 is embryotoxic and teratogenic. In the present study, the embryonal and foetal distribution of CS2 and its metabolites was studied after administration of 35S‐ or 14C‐labelled CS2 to pregnant mice in different stages of gestation. CS2 and its metabolites passed the placenta at all stages of gestation. High levels of metabolites of CS2 were registered in the embryonic neuroepithelium. In mid and late gestation CS2 itself accumulated in the cerebrospinal fluid (CSF) of the brain. 14C‐labelled metabolites of CS2 showed affinity for bone and were retained in the liver even at long survival times (24 hours). These localizations may be of significance for some of the reported teratogenic effects of CS2, such as hydrocephalus, ossification defects and foetal liver injury, and support the idea that CS2 and/or its metabolites are embryotoxic and teratogenic by acting directly on embryonal and foetal structures.
Reduced Synthesis of Hepatic and Plasma Proteins in Rats during Diethyl Ether Anaesthesia
Authors: Bessesen Atle , Smith‐Kielland Anne , Gadeholt Gaut , Mørland Jørg
Published: July 2010

Abstract: The effect of diethyl ether anaesthesia on in vivo hepatic protein synthetic rates was tested in male Wistar rats. Protein synthesis was measured by an isotope technique after correction for measured levels of precursor specific radioactivity. It was shown that usual anaesthetic levels of diethyl ether reduced the rate of synthesis of liver proteins with 20% compared to a group receiving no anaesthesia. The synthesis/secretion of plasma proteins was much more inhibited, with approximately 70–80%, compared to animals either receiving no anaesthesia or pentobarbital. Monitoring of ether concentrations therefore seems necessary in experiments in which the hepatic capacity for protein synthesis/secretion is measured.
A New Method for Studying the Distribution of Drugs in Spinal Cord after Intrathecal Injection
Authors: Post Claes , Freedman Jacob
Published: July 2010

Abstract: The pharmacological effect of local anaesthetic solutions in mice including their distribution within the spinal cord, were assessed following intrathecal injection at the L5‐L6 interspace. A solution of 5 μl radioactively labelled lidocaine at a concentration of 50 mg/ml or bupivacaine at 7.5 mg/ml, was used. Both drugs blocked the motor function of the hindlegs in less than 1 min. This persisted for 15.1×0.8 min. (X̄ ± S.E.M.) after lidocaine and 15.2 ± 2.7 min. after bupivacaine. The highest spinal cord concentration was adjacent to the site of injection, even if traces were present up to the lower cervical cord. The tissue concentration of bupivacaine was considerably less than that of lidocaine, despite a similar motor blockade. When the injected volume was doubled from 5 to 10 ±l, there was a tendency to a more cephalic distribution of lidocaine. When the speed of injection was increased from 2.5 sec. to 30 sec., no difference in results was seen. The drug concentration at the injection site tended to fall in animals alive until 5 min. after the injection, whereas it persisted in animals sacrificed before the intrathecal injection, suggesting that the circulatory transport is the major route of redistribution from the cord.
Effects of Two New Ca‐Entry Blockers Bepridil and Nitrendipine on Isolated Vessels
Authors: Mikkelsen Erich , Jespersen Lennard Tang , Pedersen Ole Lederballe
Published: July 2010

Abstract:The effects of nitrendipine and bepridil were studied in isolated rings of human crural veins contracted by noradrenaline (NA) or potassium (K). Both drugs had a concentration dependent inhibitory effect on active tone and shifted the NA and K concentration‐response curves to the right in a non‐parallel manner and reduced the maximum contractile response. Both drugs had a more potent inhibitory effect on K. than on NA‐induced contractions. Nitrendipine was far more potent in inhibiting the K‐induced contractions than bepridil while the drugs were equipotent in inhibiting NA‐induced contractions. Human veins were less sensitive than rat aorta to the inhibitory effect of nitrendipine. In contrast to nitrendipine the effect of bepridil was gradual and slow in onset. The inhibitory effect of both drugs was strong and long‐lasting and resistant to washout procedures. Both drugs effectively eliminated spontaneous mechanical activity and reduced K‐induced contractions in rat portal veins. The results support that nitrendipine and bepridil are effective vasodilators in arteries as well as in veins. The main action of both nitrendipine and bepridil seems to be attributed to an inhibitory effect on cellular Ca‐entry.
Characterization of the β‐Adrenergic Receptor on the Human Platelet: A β2‐Subtype
Authors: Klysner R. , Andersen P. H. , Geisler A. , Winther K.
Published: July 2010

Abstract:The human platelet β‐adrenergic receptor was characterized by using the ability of different drugs to stimulate the adenylate cyclase activity and the effects of various β‐antagonists to block the isoprenaline‐stimulated adenylate cyclase activity. Isoprenaline was found 10 times more potent than adrenaline and 1000 times more potent than noradrenaline in stimulating the adenylate cyclase activity in these cells. Isoprenaline‐stimulated activity was blocked by the non‐selective β‐antagonists propranolol and alprenolol and by the β2‐selective antagonist IPS 339 and prenalterol. Metoprolol, a β1‐selective blocker, was without effect on the isoprenaline‐stimulated adenylate cyclase activity. We conclude from our findings that the β‐adrenergic receptor type on the human platelet is mainly of the β2‐subtype.
Embryotoxicity of Arsenite and Arsenate: Distribution in Pregnant Mice and Monkeys and Effects on Embryonic Cellsin Vitro
Authors: Lindgren Arne , Danielsson Bengt R. G. , Dencker Lennart , Vahter Marie
Published: July 2010

Abstract:The distribution of74As‐labelled arsenate and arsenite in pregnant mice and a monkey has been studied by autoradiography and gamma counting of isolated tissues, and theirin vitrotoxicity to a chondro‐genic system has been investigated. With both arsenic forms, given as single intravenous injections to the mother, the74As‐arsenic appeared to pass the mouse placenta relatively freely and approximately to the same extent. The retention time in maternal tissues including the placenta was, however, around three times longer with arsenite than with arsenate. In early gestation, high activity was registered in the embryonic neuroepithelium, which correlates well with reported CNS malformations in rodents. In late gestation, the distribution pattern was more like that in the adults. Accumulation in skin and squamous epithelia of the upper gastrointestinal tract (oral cavity, oesophagus and oesophageal region of stomach) dominated the distribution picture, especially at a long survival interval. Arsenate, but not arsenite, showed affinity for the calcified areas of the skeleton. A marmoset monkey in late gestation receiving arsenite showed a somewhat lower rate of placental transfer than the mice. Skin and liver had the highest concentrations (at 8 hrs), both in mother and foetuses. This species is known not to methylate arsenic, resulting in stronger binding and longer retention times of arsenic as compared with other species. The stronger binding in maternal tissues may possibly explain the lower rate of placental transfer. Arsenite was shown to inhibit cartilage formation in a chick limb bud mesenchymal spot culture system (ED50~ 5‐10 μM), while arsenate seemed to be without effect at concentrations up to 200 μM (highest tested). Arsenate, however, showed a potentiation of the arsenite toxicity.
Disposition of Ethanol and its Effect on Rectal Temperature in Morphine‐dependent, Morphine‐abstinent and Morphine‐naive Rats
Authors: Jones A. W.
Published: July 2010

Abstract:Rats were treated chronically with twice daily injections of morphine hydrochloride in gradually increasing doses from 20 to 200 mg/kg for 22 consecutive days. Rats in a control group were injected with 0.9% NaCl. At 1 hour after the last injection of morphine (dependent state) and at 3 and 16 days after abrupt withdrawal (abstinent state) the animals were injected intraperitoneally with 2.0 g/kg ethanol. Blood ethanol concentrations (tail blood) and rectal temperatures were determined at 30–60 min. intervals for up to 7 hours. The absorption of ethanol was slower in rats treated with morphine and the time taken to reach the end of the blood concentration curve was increased. This implies a slower turnover of ethanol in morphine‐dependent and abstinent rats. At 16 days after withdrawal, the blood ethanol profiles were the same as in control rats not exposed to morphine. Injection of morphine (200 mg/kg) in tolerant animals caused a pronounced hyperthermia which lasted for about 4 hours. Ethanol treatment rapidly counteracted the rise in body temperature. Morphine abstinent rats showed a hypothermic response to ethanol. The altered disposition of ethanol in acute withdrawal may result from physiological disturbances such as impaired fluid balance, dehydration, altered peripheral blood flow and poor nutritional status. There was no evidence for a faster rate of ethanol metabolism in the hypermetabolic state associated with morphine tolerance and dependence.
Catecholamine Stimulation of Copper Dependent Haemolysis: Protective Action of Superoxide Dismutase, Catalase, Hydroxyl Radical Scavengers and Serum Proteins (Ceruloplasmin, Albumin and Apotransferrin)
Authors: Løvstad Rolf A.
Published: July 2010

Abstract:Copper induced lysis of washed rat erythrocytes was stimulated by catecholamines, the order of effectiveness being: adrenaline > noradrenaline ∼ dopamine > L‐DOPA. The degree of effectiveness is related to the rate of copper ion dependent oxidation of catecholamine, adrenaline being more rapidly oxidized than the other catecholamines investigated. Superoxide dismutase, catalase and different hydroxyl radical scavengers (mannitol, tris, formate and ethanol) markedly reduced the haemolytic effect of copper and catecholamine, suggesting the possibility that superoxide radicals and hydrogen peroxide, formed in the reaction system, cooperate in producing hydroxyl radicals, which are directly involved in the haemolytic action. The plasma proteins, ceruloplasmin, albumin and apotransferrin, also reduced the copper‐catecholamine induced haemolysis. The protective action is probably not related to the copper binding ability of these proteins.
Acute Effects of Atypical Antidepressants on Various Receptors in the Rat Brain
Authors: Hall Häkan , Sällemark Maria , Wedel Ilse
Published: July 2010

Abstract:Usingin vitroreceptor binding techniques, the effects of a number of different antidepressants on rat cerebral cortex receptors were investigated. In contrast to the tricyclic antidepressants, which potently inhibit several postsynaptic receptors, many atypical antidepressants have no or very little affinity for these receptors. Thus bupropion, amineptine, citalopram, fluoxetine, fluvoxamine and viloxazine are devoid of any activity, while amoxapine, doxepin and trazodone exert effects on a number of receptors. The implications of these receptor blocking effects are discussed.
No Change in Rat Cerebral Cortex Calmodulin Content Following Chronic Treatment with Lithium, Reserpine, Imipramine, and Lithium Combined with Reserpine or Imipramine
Authors: Andersen P. H. , Geisler A. , Klysner R.
Published: July 2010

Abstract:Rats were treated 2–3 weeks with lithium, reserpine, imipramine, and combinations of lithium with reserpine or imipramine. Lithium was given in the diet, while the other drugs were dissolved in 0.9% saline and given intraperitoncally twice daily. The control and lithium groups received only vehicle injections. Twenty‐four hours after the last injection the rats were decapitated and the cerebral cortex dissected. The tissue was sliced and the noradrenaline‐stimulated cyclic AMP accumulation determined or the tissue was homogenized and centrifuged at 10,000 μ g for 30 min. and the calmodulin content determined in the pellet and the supernatant. Reserpine treatment was found to cause an 50% increase in the noradrenaline‐stimulated cyclic AMP accumulation, while treatment with imipramine and the combination lithium‐imipramine decreased the noradrenaline‐stimulated cyclic AMP accumulation by 40%. The tissue content of calmodulin was, however, found unaltered by all treatments.
Bronchial Anaphylaxis in Actively Sensitized Sprague Dawley Rats: Studies on Mediators Involved**
Authors: Dahlbäck Magnus , Bergstrand Håkan , Sörenby Lars
Published: July 2010

Abstract:Previous experiments have shown that SD rats actively sensitized to ovalbumin (OA) undergo bronchial anaphylaxis at intravenous challenge with a specific antigen. The inhibitory effect of antiallergic drugs in this experimental system and the relation of the response to serum reaginic antibody levels, depend on sensitization conditions (Dahlbäck 1981; Dahlbäcket al. 1982). The present experiments indicate that the main primary mediators of the respiratory anaphylaxis are serotonin and product(s) of the cyclooxygenase pathway of arachidonic acid metabolism. This is the case whether the animals are sensitized with 10 or 100 μg OA together with 100 mg alum and whether they are examined 2–3 or 5–6 weeks after sensitization. However, the bronchoconstrictory efficacy of exogenously added 5‐HT varies with the immunization conditions of the animals: those given 100 μg OA together with alum are more reactive to 5‐HT at intravenous challenge than animals given 10 μg OA and alum. Moreover, compounds known to affect the lipoxygenase pathway of arachidonic acid metabolism influence the bronchial anaphylactic reaction in different ways depending on immunization and test conditions. These data suggest that 5‐HT and some not yet identified product(s) of cyclooxygenase/thromboxane synthetase are main mediators of allergen‐induced bronchial anaphylaxis in the rat and that products of the lipoxygenase pathway play a minor direct role but may modulate the response.
Effect of 5‐Chloro‐7‐iodo‐8‐hydroxy‐quinoline (Clioquinol) on the Uptake and Distribution of Nickel, Zinc and Mercury in Mice
Authors: Tjälve Hans , Ståhl Kenneth
Published: July 2010

Abstract:5‐Chloro‐7‐iodo‐8‐hydroxy‐quinoline (clioquinol) was found to induce a very marked increase in the concentration of63Ni2+in various tissues of mice when given orally together with the metal, compared with oral administrations of63Ni2+only. Markedly increased tissue concentrations, although less expressed than for the63Ni2+, were also observed for65Zn2+. Clioquinol increased the tissue levels of203Hg2+to a lesser extent. When clioquinol was given intraperitoneally and63Ni2+was given intravenously there were also very markedly increased tissue levels of the metal, compared with intravenous injections of63Ni2+only. It was also shown that the urinary excretion of63Ni2+was greatly increased in mice given the metal orally together with clioquinol, compared with mice given the63Ni2+only. Clioquinol and other 8‐hydroxy‐quinolines form lipophilic chelates with metallic cations and the observed effects on the tissue‐disposition of the metals are probably due to a facilitated penetration through the cellular membranes. Determinations of the chloroform:water partition coefficients showed the highest lipophilicity for the nickel‐clioquinol‐complex followed in decreasing order by the complexes with zinc and mercury. These data suggest that the ability of the clioquinol to affect the uptake of the metals in the cells may be related to the relative lipophilicity of the metal‐clioquinol‐complexes. Clioquinol and other halogenated 8‐hydroxy‐quinolines are linked with the SMON‐syndrom, which has been observed preferentially in Japan. It is suggested that the pathogenesis of SMON may involve an accumulation of toxic concentrations of metals in the tissues due to facilitated uptake by complex‐formation with halogenated 8‐hydroxy‐quinolines. The Japanese have been more heavily exposed to metals by environmental pollution than most people in other countries, explaining the prevalent occurrence of SMON in Japan.
Adrenaline Toxicity in Mice: Sensitization of α1 Adrenoreceptors by Nitroglycerin
Authors: Rydell Ewa L. , Axelsson Krister L.
Published: July 2010

Abstract:In mice, injected subcutaneously with nitroglycerin (GTN) for 12 days, adrenaline exhibited an increased toxicity. The LD50 value for adrenaline in control animals was 11.1 mg/kg b.wt. In GTN‐treated animals the LD50 value for adrenaline, measured 3 days after the last injection of GTN, was 9.1 mg/kg b.wt. (P = 0.05). In the animals sensitized with GTN, the adrenergic α‐receptor blocker phentolamine (1 or 10 mg/kg b.wt.) protected from the lethal action of adrenaline (P = 0.06 and P = 0.001, respectively). A low dose (1 mg/kg b.wt.) of the adrenergic β receptor blocker propranolol, was without effect while a higher dose (10 mg/kg b.wt.) potentiated the toxicity of adrenaline (P = 0.007). The α1adrenoreceptor antagonist, prazosin, (1 or 10 mg/kg b.wt.) was found to be highly effective in protecting the GTN‐sensitized mice towards adrenaline (P = 0.003 and P = 0.001, respectively). By contrast, the α2adrenoreceptor antagonist, yohimbine, (1 or 10 mg/kg b.wt.) was much less effective (P = 0.988 and P = 0.111, respectively). It is concluded that the lethal action of adrenaline was caused by stimulation of α1adrenoreceptors, and that long term treatment with GTN caused a sensitization of these receptors in mice. The possible relevance of this finding for the reported wihdrawal symptoms and sudden death phenomenon in nitroglycerin‐exposed industrial workers is discussed.