bluuebunny/crossref_metadata_2025 huggingface dataset:
Deuterium Isotope Effects on Ethanol Oxidation in Perfused Rat Liver and in Rats and Rabbits in Vivo: Application to Determine the Contribution of Various Pathways
Authors: Lundquist Frank , Quistorff Bjørn , Huang Ming‐ta
Published: March 2009

Abstract: The kinetic deuterium isotope effect, D(V/K), on ethanol oxidation was measured by the radiometric, competitive method using 14C‐labelled ethanol containing deuterium in the (1‐R) position. Acetate was isolated and used for the determination. Experiments were performed on rats either anaesthetized and laparotomized, or provided with indwelling catheters in a. carotis, v. cava and v. portae. Experiments were also made on perfused liver from rats pretreated with acetone, or a mixture of acetone and phenobarbital. Finally, intact non‐anaesthetized rabbits were used. The apparent isotope effect in all in vivo experiments decreased rapidly in the presence of acetaldehyde as a consequence of the reversibility of the ADH reaction. In the case of rabbits and catheterized rats this problem was tackled by taking blood samples in quick succession, thus permitting extrapolation of the apparent isotope effect to the time of injection of the labelled ethanol. In anaesthetized rats injection of the ADH inhibitor isobutyramide was used to reduce the concentration of acetaldehyde and thereby the rate of decline of the apparent isotope effect. At high doses of isobutyramide the isotope effect was constant with time at about 1.9 suggesting the presence of non‐ADH activity. In all three kinds of in vivo experiments the isotope effect ranged from 2.66 to 2.93. In the case of anaesthetized rats the mean value was 2.89±0.05 (S.D.). This figure is significantly different from that of rat liver ADH, P<0.001. As the figures for the initial isotope effects are minimum values the contribution of non‐ADH ethanol oxidizing systems is likely to be small, probably less than 10 percent.
Protective Effect of Anethol Dithiolthione Against Acetaminophen Hepatotoxicity in Mice
Authors: Warnet J.‐M. , Christen M. O. , Thevenin M. , Biard D. , Jacqueson A. , Claude J.‐R.
Published: March 2009

Abstract:Anethol dithiolthione (ADT), usually prescribed as a choleretic drug, when given orally 1 hour prior to acetaminophen (AAP) (450 mg/kg intraperitoneally) in Swiss female mice, exhibited an hepatoprotective potency at doses as low as 10 mg/kg relative to serum aminotransferase activities and hepatic glutathione related enzyme system (glutathione reductase, peroxidase, transferase). These preliminary results are relevant with the use of pharmacologic dosage of ADT in hepatotoxicity prevention.
Cardiotoxic Effects and the Influence on the β‐Adrenoceptor Function of Doxorubicin (Adriamycin®) in the Rat
Authors: Rasmussen I. M. N. , Schou H. S. , Hermansen K.
Published: March 2009

Abstract:The possible relationship between the effect of the anthracycline‐cytostatic doxorubicin (Dox) on the cardiac β‐adrenoceptor functionin vitroand the development of delayed cardiotoxicityin vivohas been investigated in the rat. Dox (10−5‐10−4M) blocked the chronotropic effect of isoprenaline on isolated atria in a competitive manner. Treatment with a single dose of Dox 5 mg/kg intravenously caused marked ECG changes manifested by progressive prologations of the QαT and SαT‐intervals, which amounted to 37% and 58% respectivity 5 weeks after the medication. At this time no β‐blocking action was detectable when tested on the isolated atria in the same rats. The results indicate that the delayed cardiotoxicity induced by Dox is not mediated by an interference with the cardiac β‐adrenoceptor function.
Effect of Cadmium on Lipid Peroxidation and Antioxidant Enzymes in Undernourished Weanling Rat Brain
Authors: Gill K. D. , Pal R. , Nath R.
Published: March 2009

Abstract: The effect of early postnatal cadmium exposure on lipid peroxidation and antioxidant enzymes in undernourished weanling rat brain has been studied. The results suggest that undernutrition makes the weanling rat brain more susceptible to the neurotoxic effects of cadmium. Cadmium at a low dose of 1 mg/kg body weight did not produce any changes in lipid peroxidation and antioxidant enzymes in normal weanling rat brain, but caused a significant increase in lipid peroxidation and markedly decreased the activities of antioxidant enzymes like glutathione peroxidase, superoxide dismutase and catalase when subjected to undernutrition.
The Inhibition of Granulocyte Phagocytosis by Various Components of Nasal Drops
Authors: Håkansson Bo , Linder Carina , Ohlsson Kjell , Tegner Hans , Toremalm Nils Gunnar
Published: March 2009

Abstract: The effect of two decongestive substances and two preservatives used in nasal drops on phagocytosis by human granulocytes was studied. The vasoactive substances oxymetazoline chloride and zylometazoline chloride incubated with human granulocytes during 20 min. gave a reduction of phagocytosis to almost zero when using concentrations found in commercially used nasal drops (500 mg/l respectively 1000 mg/l). However, a dilution of 1:100 was consistent with an almost normal phagocytic function. The preservatives benzalkonium chloride and thiomersal gave a dose related reduction of phagocytosis down to zero. A dilution of 1:100 of the benzalkonium chloride solution used commercially (200 mg/l) and a dilution of 1:10 of the thiomersal solution used commercially (24 mg/l) were needed to get an almost normal phagocytic function. These results together with previous studies indicate that the addition of preservatives in nasal drops should be questioned, excluded or replaced with other less harmful substances.
Prostaglandin F2α Binding to Bovine Ocular and Synthetic Melanins in Vitro
Authors: Aula Pirjo , Kaila Timo , Huupponen Risto , Salminen Lotta , Iisalo Esko
Published: March 2009

Abstract: The binding of 3H‐prostaglandin F2α to bovine iris and synthetic melanin was studied in vitro using a ligand binding assay. Prostaglandin F2α was reversibly bound to both types of melanin. The binding was saturable and the Scatchard analysis revealed the existence of at least two binding sites with the corresponding KD values of 3.71 nM and 1.99 μM for natural and 4.99 nM and 0.19 μM for synthetic melanin, respectively. The high affinity Bmax values were 3.4 nM/g for natural and 2.5 nM/g for synthetic melanin. The dissociation of prostaglandin F2α from melanin after dilution of the complex was rapid and uniform.
EEG in Anaesthetized Rats
Authors: Sim M. K. , Chua M. E.
Published: March 2009

Abstract: The constancy of rat EEG during surgical anaesthesia induced by phenobarbital, cholorose, paraldehyde, and inactin was investigated. The results showed that intraindividual variations and spontaneity of EEG were not abolished in the anaestheized animals. However, at the higher of the two doses used, the EEG was less variable. Our findings thus indicate that in the study of drug actions on the EEG of anaesthetized animals, the results obtained not only represent the interaction of the anaesthetic and the drug on the animal EEG but is also a reflection of the dosage of the anaesthetic employed.
Changes in Catalase, Glutathione Peroxidase and Glutathione‐S‐transferase Activities in the Liver of Newts Exposed to 2‐Methyl‐4‐chlorophenoxyacetic Acid (MCPA)
Authors: Santagostino Angela , Colleoni Mariapia , Arias Elio , Zaffaroni Nicoletta Pacces , Zavanella Teresa
Published: March 2009

Abstract: Activities of catalase, glutathione peroxidase (GSH‐Px) and glutathione‐S‐transferase (GST) were measured in livers of the crested newt (Urodele Amphibian) after 16 days of percutaneous exposure to the herbicide Agroxone 3, a commercial formulation of 2‐methyl‐4‐chlorophenoxyacetic acid (MCPA) containing 25% MCPA as sodium salt and 75% wetting and dispersing ingredients. Animals of both sexes were exposed to 800 p.p.m. of the active ingredient. There was a three‐fold increase in catalase and a clear enhancement of GSH‐Px in the MCPA‐exposed animals of both sexes. A sex‐dependent effect of MCPA was observed on GST activity, which increased significantly in female newts only. Similar liver enzyme changes were observed in female newts, and not in males, given the hypolipidaemic drug clofibrate (13 mg/animal/day, by gavage, for 8 days), which is structurally related to phenoxyherbicides. These findings indicate that the crested newt is sensitive to the hepatic effects of the peroxisome proliferators.
Adaptive Changes in α‐2 Adrenoceptor Mediated Responses: Analgesia, Hypothermia and Hypoactivity
Authors: Minor Bruce G. , Danysz Wojciech , Jonsson Gösta , Mohammed Abdul K. , Post Claes , Archer Trevor
Published: March 2009

Abstract:The acute effects of the α‐2 adrenoceptor agonists, clonidine and guanfacine, upon antinociception, hypothermia and motor activity were compared under conditions of receptor antagonism, denervation, and chronic administration of a tricyclic antidepressant compound. The analgesic actions of clonidine and guanfacine were antagonised by idazoxan, an α‐2 receptor antagonist, but potentiated by pretreatment with the noradrenaline neurotoxin DSP4, and attenuated by chronic treatment with desipramine (DMI). Clonidine‐ and guanfacine‐induced hypothermia was antagonised by idazoxan, potentiated by prior treatment with DSP4 and attenauted by chronic administration with DMI. Both clonidine and guanfacine produced decreases in motor activity that were attenuated by idazoxan but unaffected by prior DSP‐4 treatment. Chronic DMI administration also attenuated clonidine‐induced hypoactivity but potentiated guanfacine‐induced hypoactivity. These diverse results describe both similar and differential adaptive mechanisms modulating the functional effect of α‐2 receptor systems in the central nervous system.
Comparison of the Effects of Intraventricular Taurine, GABA and Homotaurine on Serum Prolactin Levels in Male Rats
Authors: Panula‐Lehto Elina , Ahtee Liisa , Tuominen Raimo K. , Männistö Pekka T.
Published: March 2009

Abstract:The effects of taurine (2‐aminoethanesulphonic acid), γ‐aminobutyric acid (GABA) and homotaurine (3‐aminopropanesulphonic acid), a structural analogue of both taurine and GABA, on serum prolactin (PRL) levels were compared in conscious, unrestrained male rats. Taurine, injected into the lateral brain ventricles at doses of 6 and 10 μmol per rat, elevated serum PRL level by 52% (P<0.01) and 90% (P<0.001), respectively. GABA elevated serum PRL level (41%, P<0.05) only at the lowest dose (1 μmol) tested. Homotaurine was the most effective compound, eliciting increases of 353% and 449% (P<0.001) at 6 and 10 μmol per rat, respectively. The rank order of the three amino acids in elevating serum PRL level bears some similarity to their known rank order of potency in altering cerebral dopamine metabolism.
Studies of Glucocorticoid Enhancement of the Capacity of Hepatocytes to Accumulate Cyclic AMP
Authors: Thoresen G. Hege , Gjone I. Helene , Gladhaug Ivar P. , Refsnes Magne , Østby Eva , Christoffersen Thoralf
Published: March 2009

Abstract:Pretreatment of cultured rat hepatocytes with dexamethasone markedly enhanced the acute cAMP response to glucagon, isoproterenol or forskolin. The effect of dexamethasone was apparent within 3‐6 hr and was maximal after 20‐30 hr. The amplification of the cAMP response to glucagon could also be produced by other glucocorticoids, with relative potency dexamethasone >> methylprednisolone > hydrocortisone. The increased cAMP response was associated with a reduced cAMP phosphodiesterase activity in cell lysates and a reduced effect of the phosphodiesterase inhibitor 3‐isobutyl‐1‐methylxanthine in intact cells, indicating that the glucocorticoid pretreatment reduced cAMP degradation. However, the increase in response to glucagon in glucocorticoid‐treated cells was relatively larger than the increase in forskolin response and also larger than the decrease in phosphodiesterase activity, suggesting that other factors in addition to down‐regulation of phosphodiesterases was responsible for the effect. Cycloheximide abolished the difference in phosphodiesterase activity and cAMP response between dexamethasone‐treated and control cells. The results suggest that the glucocorticoids increase the ability of hepatocytes to accumulate cAMP due to protein synthesis‐dependent processes which at least in part involve reduced degradation of cAMP.
Role of Carboxylesterase in Soman, Sarin and Tabun Poisoning in Rats
Authors: Jokanović Milan
Published: March 2009

Abstract:TOCP (triorthocresyl phosphate) inhibits carboxylesterase (CarbE) activity in rat plasma and liver and significantly increases soman, sarin and tabun toxicity. Application of these agents after TOCP caused strong additional inhibition of CarbE and cholinesterases (ChE) in rat red blood cells, plasma, liver, brain, diaphragm and intercostal muscle. After phenobarbital pretreatment, which induced CarbE activity in plasma and liver by 80% and that of plasma ChE by 33%, acute toxicity of soman and tabun was greatly decreased, while that of sarin remained unaffected.
Alaproclate Increases the Excitability of Hippocampal CA1 Pyramidal Cells and Blocks the Slow After‐hyperpolarization
Authors: Hedlund Britta , Andersen Per
Published: March 2009

Abstract: Effects of alaproclate, an antidepressive substance and 5‐HT uptake blocker, was studied using intracellular and extracellular recording techniques. Possible effects on the excitability of CA1 pyramidal cells in slices from rat hippocampus were explored. Alaproclate increased the probability of firing to an orthodromic input, increased the membrane resistance and prolonged the action potential. Increased excitability was also observed in extracellular recording experiments. It is suggested that these effects are due to depression of potassium channels in the membrane.
Both Single‐Dose and Repeated Administration of Clomipramine Reduces the Behavioural Response to Intrathecal Capsaicin in Mice
Authors: Rosland Jan Henrik , Hunskaar Steinar , Hole Kjell
Published: March 2009

Abstract:Capsaicin injected intrathecally releases substance P from primary sensory nerve endings, and induces a pain related behaviour in mice consisting of licking, biting and scratching directed to the distal part of the body. This behavioural response was reduced by approximately 35% after intraperitoneal administration of clomipramine, 10 mg/kg, 1 hr in advance, and by 38% after repeated administration (10 mg/kg/day for 9 days). Twenty‐four hr after the last repeated clomipramine injection, the response after capsaicin was still reduced by 36%, indicating a long‐lasting effect of repeated treatment. The results indicate that clomipramine has analgesic properties against pain of central origin both after single‐dose and repeated administration.
Brain and Plasma Kinetics of the Opioid11C‐Hydromorphone in Two Macaque Species
Authors: Hartvig Per , Neil Anders , Terenius Lars , Antoni Gunnar , Rimland Annika , Ulin Johan , Långström Bengt
Published: March 2009

Abstract:The regional brain kinetics of the opioid receptor agonist, hydromorphone, labelled with11C, were studied with positron emission tomography in two Macaque species, Rhesus and Cynomolgus monkeys. The plasma kinetics of11C‐hydromorphone were simultaneously determined. Rapid plasma elimination was obvious in both monkey species. Brain radioactivity was generally low in both, but 1.4 times higher in the Rhesus than in the Cynomolgus monkey brain. This observation might explain the more rapid development of tolerance in the Rhesus monkey.
Kinetics of Methyl Mercury in Blood and Brain During Chronic Exposure in the Monkey Macaca fascicularis
Authors: Stinson Christopher H. , Shen Danny M. , Burbacher Thomas M. , Mohamed Mostafa K. , Mottet N. Karle
Published: March 2009

Abstract: The disposition parameters derived from a compartmental model kinetic analysis of blood Hg levels in nonpregnant, adult female Macaca fascicularis given daily doses of MeHg did not vary with either dosage level (50, 70 or 90 μg MeHg/kg b·wt·day) or duration of exposure (up to 507 day). In contrast, blood clearance of Hg in pregnant females was dose‐dependent; it being higher at the 90 μg MeHg/kg b·wt·day than at the lower dosage levels. Hg levels in the brain of adult fascicularis relative to blood Hg also increased at the highest level of exposure. Blood Hg half‐life in neonate fascicularis was similar to half‐life in their mothers (adults). Finally, the regional distribution of mercury in the brains of adult and neonate fascicularis exposed to low and intermediate levels of MeHg resembles the reported distribution of mercury in the brains of adult and neonate humans environmentally exposed to MeHg. Consequently, M. fascicularis may be an especially appropriate animal model for studying the neurotoxic mechanisms of chronic methyl mercury exposure.
Hormonal, Haemodynamic, and Subjective Effects of Intravenously Infused Indomethacin: No Change in the Physiological Response to Hypertonic Saline Challenge
Authors: Manner Tuula , Kanto Jussi , Ruskoaho Heikki , Karhuvaara Sakari , Viinamäki Osmo , Välimäki Mari , Scheinin Mika
Published: March 2009

Abstract:This double‐blind, placebo‐controlled human study was performed to determine the endocrine responses to intravenously administered indomethacin at two dose rates (0.36 or 0.72 mg/kg bolus followed by 0.071 or 0.143 mg/kg/hr for 150 min.). A 5% hypertonic saline infusion was used for further assess the hormonal systems regulating body fluid and electrolyte balance. Plasma renin activity (PRA) and concentrations of aldosterone and vasopressin (AVP) were unaffected by indomethacin. Hypertonic saline caused a 5% increase in plasma sodium and a 4.2% increase in serum osmolality, with a concomitant two‐fold rise in plasma AVP levels and significant declines in PRA and aldosterone. Indomethacin had no effects on these responses, and did not affect plasma catecholamine concentrations, but the hypertonic saline infusion doubled the noradrenaline levels in plasma. Atrial natriuretic peptide (ANP) ‐like immunoreactivity in plasma was not affected by indomethacin nor by hypertonic saline. The higher dose rate of indomethacin resulted in significant stimulation of growth hormore release, but plasma prolactin levels were not influenced. Thus acute intravenous administration of indomethacin proved to be devoid of significant effects on the multihormonal system regulating fluid and electrolyte balance.
In VitroEffect of Organic and Inorganic Mercury on the Serotonergic System
Authors: Oudar Pascal , Caillard Liliane , Fillion Gilles
Published: March 2009

Abstract:Interactions of organic (methyl mercury) and mineral (acetate, chloride, nitrate: Hg2+) mercury salts with the serotonergic systems were studiedin vitrousing synaptosomal fractions prepared from rat brain cortex preloaded with [3H]5‐HT. In the absence of calcium, mercury salts induced a spontaneous release of the amine corresponding to a total depletion of the synaptosomal content. EC50 for the organic and mineral forms of the ion were 66±2 μM and 107±16 μM respectively. In the presence of calcium (2.4 mM) a similar pattern of release was observed except that an additional release was induced by mineral mercury at low concentration (EC50 = 8.4±1.3 μM) which corresponded to a maximal release of 18.6±3.5% of the synaptosomal content. Therefore, the latter release appears calcium‐dependent. Parallelly, the effects of mercury salts have been examined on the binding of [3H]5‐HT to its high affinity 5‐HT1 sites; organic and mineral mercury inhibited the binding with IC50 of 27.8±3.2 μM and 10.9±0.6 μM respectively. These results show that mercury ions interact with the serotonergic system by different mechanisms depending on their concentrations and their ionic forms.
Effect of Diuretics on Adrenergic Receptors in the Rat
Authors: Brørs Odd , Sandnes Dagny
Published: March 2009

Abstract: Diuretics have been reported to alter arteriolar smooth muscle responses to adrenergic stimulation as well as lymphocyte β‐adrenoceptor density. We have investigated the effect of four days treatment with hydrochlorothiazide or furosemide (10 mg/kg and day) injected subcutaneously in the rat on α1‐,α2 ‐ and β‐adrenoceptors in different tissues, α1‐Adrenoceptor density and affinity in whole kidney and heart ventricle as determined by 3H‐prazosin binding (in the absence and presence of 10−5 M phentolamine) were unaltered by diuretic treatment, as were β‐adrenoceptor density and affinity in whole kidney, heart ventricle and skeletal muscle as determined by 125I‐iodocyanopindolol binding (in the absence and presence of 10−7 M (‐)‐propranolol). The density of α2‐adrenoceptors in particulate fraction from whole kidney homogenate as determined by 3H‐rauwolscine binding was 12.8% higher in the hydrochlorothiazide‐treated group (P<0.05) and 15.0% higher in the furosemide‐treated group (P<0.01) than in the control group. The receptor affinity was similar in the different groups. Thus diuretic‐induced alterations in adrenoceptors reported in previous studies were not observed in this study.
Fatty Acid Oxidation in Hepatic Peroxisomes and Mitochondria after Treatment of Rats with Di(2‐ethylhexyl)phthalate
Authors: Ganning Agneta E. , Olsson M. Jerker , Peterson Elisabeth , Dallner Gustav
Published: March 2009

Abstract: Rats were fed a diet containing di(2‐ethylhexyl)‐phthalate, which increases the number of peroxisomes and mitochondria in the liver. This proliferation does not change the ratio of phospholipid to protein in mitochondria or microsomes, but causes certain changes in the fatty acid composition of the phospholipids. The highest rates of peroxisomal and mitochondrial β‐oxidation are obtained with 12:0 and 16:0 fatty acids as substrates, respectively. A 3‐4 fold increase in the rate of β‐oxidation by both organelles is caused by DEHP treatment, but there are no qualitative changes in the relative rates of oxidation of individual fatty acids. Short‐ and medium‐chain carnitine acyltransferases in peroxisomes, microsomes and mitochondria, as well as the mitochondrial long‐chain carnitine acyltransferase are induced to various extents. These results indicate that the increased β‐oxidation of fatty acids caused by phthalate treatment involves the same peroxisomal and mitochondrial pathways which operate under normal conditions.
Change in Small Intestinal Brush Border Membranes of Rats Following Methotrexate Administration
Authors: Takeuchi Hajime , Kosakai Yoshinori , Tsurui Kazuyuki , Hasegawa Ken , Horie Toshiharu , Awazu Shoji
Published: March 2009

Abstract: Change in small intestinal brush border membranes of rats following methotrexate administration was monitored by the fluorescence spectra and polarization of the cationic fluorescent probe, safranin 0. Total protein content of brush border membranes of treated rats was less than that of control rats, whereas no significant difference in total sialic acid content of brush border membranes was observed between them. Thus, an apparent increase in the electronegative charge of brush border membrane vesicles per unit of membrane protein following methotrexate administration may possibly cause the change in fluorescence spectra and polarization of safranin 0.
Interaction of Human Growth Hormone and Gonadotrophins on the Function of Rat Ovaries
Authors: Jørgensen Karin Damm , Nowak Jette
Published: March 2009

Abstract: Hypophysectomized and normal female rats were used for studying the interaction of human growth hormone and gonadotrophins in stimulating the rat ovary. Groups of rats were injected with increasing doses of gonadotrophins (Pergonal® or Metrodin®) in addition to human growth hormone (Norditropin®) or placebo. In the test for follicle stimulating hormone activity the weight of the ovaries was recorded. In the hypophysectomized rats Norditropin® and Pergonal® or Metrodin® had a synergistic stimulating effect on the ovary, resulting in a greater number and a larger follicle size. Norditropin® had a slight stimulatory effect of its own. In the ovarian ascorbic acid depletion test for luteinising hormone activity Norditropin® had a significant effect of its own. In combination with Pergonal® an additive effect was seen. The effect of Norditropin® was observed in hypophysectomized rats only.
Comparison of the Effects of the Novel Antipsychotic Agent Remoxipride on Dopamine and Noradrenaline Turnover in the Rat Brain
Authors: Magnusson Olle , Fowler Christopher J.
Published: March 2009

Abstract:Theex vivoeffects of the antipsychotic dopamine receptor antagonist remoxipride on dopamine and noradrenaline turnover in the rat brain have been compared. Remoxipride (5‐125 μmol/kg intraperitoneally) produced large increases in striatal DOPAC and HVA concentrations with only marginal effects on striatal, hippocampal and hypothalamic MHPG concentrations. Both remoxipride (5.6 μmol/kg intraperitoneally) and haloperidol (0.23 μmol/kg intraperitoneally) increased the rate of striatal dopamine disappearance following inhibition of tyrosine hydroxylase by H 44/68 without corresponding effect on hypothalamic and frontal cortical noradrenaline disappearance. It is concluded that at doses of remoxipride producing compensatory increases in dopamine turnover, there is little or no effect on noradrenaline turnover, confirming thein vitrodopamine:noradrenaline selectivity of this compound.
Metabolic Activation of Carbon Tetrachloride by the Cervico‐Vaginal Epithelium in Rodents
Authors: Brittebo Eva B. , Brandt Ingvar
Published: March 2009

Abstract:The metabolism and binding of14C‐labelled carbon tetrachloride (CCl4) in the genital tract of female adult or juvenile NMRI‐mice and Sprague‐Dawley rats (mainly in the pro‐oestrous/oestrous stage) and an adult New Zealand rabbit were studied. A marked irreversible binding of radioactivity in the squamous cervico‐vaginal epithelium of mice given intravenous injections of14C‐CCl4was revealed by autoradiography of solvent‐extracted tissue. The localization of binding in the mouse genital tract incubated with14C‐CCl4under air was similar to that observedin vivo.Bound radioactivity was also present in the cylindrical epithelium of the rabbit vagina incubated with14C‐CCl4in vitro.For a comparison, no preferential binding of radiolabelled diethylstilbestrol or ethinylestradiol was observed in the mouse cervico‐vaginal epithelium. The level of irreversible binding to PMSG‐primed (pregnant mare's serum gonadotrophin) vaginal epithelial 100 × g supernatants of mice and rats incubated with14C‐CCl4under air was low. Addition of the reducing agent dithionite to the incubations increased the binding in the vaginal epithelium 20‐fold. In juvenile mice and rats injected with14C‐CCl4, the levels of metabolites in the epithelium were low, whereas PMSG‐primed juvenile rats contained a higher level of metabolites. The results show that the cervico‐vaginal epithelium can metabolically activate CCl4to reactive metabolites and suggest that the metabolism is under endocrine control.
Propentofylline and a Hydroxy Metabolite Augment A2‐Receptor Mediated Cyclic AMP Accumulation and Attenuate A1‐Receptor Mediated Inhibition of Acetylcholine Release in the Rat Hippocampus
Authors: Fredholm Bertil B. , Dunér‐Engström Marianne
Published: March 2009

Abstract: In contrast to the adenosine receptor antagonist theophylline, the xanthine derivative propentofylline (HWA 285) is reported to protect against ischaemic cell damage. We examined the effect of propentofylline on two adenosine actions in the rat hippocampus; the A2‐mediated stimulation of 3H‐cAMP accumulation and the A1‐mediated inhibition of 3H‐ACh release. Propentofylline (0.5‐1 mM) increased the adenosine (3 and 30 μM) ‐induced 3H‐cAMP accumulation. This effect was shared by its metabolite A 72 0287. The mechanism may be a decreased inactivation of adenosine, since the effect of the stable adenosine derivative NECA was not altered. In contrast, the inhibitory effect of adenosine on evoked 3H‐ACh release was inhibited by propentofylline and by its metabolite A 72 0287, but enhanced by the uptake inhibitor dipyridamole. The effect of the stable, A1‐receptor selective analogue R‐PIA (1 μM) was also blocked by propentofylline and by A 72 0287. In addition, propentofylline (0.5 mM) blocked the presynaptic inhibitory effect of carbachol (1 and 50 μM). Thus, propentofylline and one of its metabolites inhibits adenosine A1‐receptor mediated presynaptic inhibition while it enhances adenosine A2‐mediated cAMP accumulation in the rat hippocampus differently. This selectivity in action can only partly be explained by receptor subtype selectivity, and effects at sites other than the adenosine receptor are of major importance.
Enhanced Gentamicin Nephrotoxicity after Experimental Biliary Obstruction in Rats
Authors: Lucena M. I. , Gonzalez‐Correa J. A. , Andrade R. J. , Iban̄ez J. , Torres D. , de la Cuesta F. Sanchez
Published: March 2009

Abstract:To explore whether bile duct ligation increased the risk for gentamicin nephrotoxicity, male Wistar rats were subjected to bile duct ligation or sham surgery and given either gentamicin 20 mg/kg or saline twice daily intraperitoneally for 8 days. Bile duct ligated and gentamicin injected rats elicited a decline in renal function and tubular cell necrosis after 8 days of treatment whereas equal dosage regimen in sham operated rats exhibited no evidence of renal dysfunction. In addition, though serum and kidney gentamicin levels were higher in bile duct ligated rats (1.84±0.11 μg/ml versus 0.20±0.03 μg/ml, and 1453±164 μg/g versus 698±138 μg/g of cortex, respectively, P<0.05). The data indicate that complete biliary obstruction enhances renal sensitivity to gentamicin.
Guanfacine Inhibits Excitatory Amino Acid Release from Rat Cerebral Cortex Through a Non‐Adrenergic Mechanism
Authors: Uhlén Staffan , Näsström Jacques , Post Claes , Wikberg Jarl E. S.
Published: March 2009

Abstract:The effect of guanfacine on the release of excitatory amino acids from rat cerebral cortex slices was assessed after preloading the slices with3H‐D‐aspartate. It was found that guanfacine dose‐dependently inhibited the veratridine stimulated release of the excitatory amino acid analogue; the ED50 of guanfacine being 6.4±2.3 μM (mean±S.E.M.) and the veratradine stimulated efflux being completely abolished at about 48 μM of guanfacine. Guanfacine also inhibited the veratridine stimulated release of endogenous aspartate and glutamate with similar potency to the inhibition of3H‐D‐aspartate efflux. The inhibitory effect of guanfacine on the veratridine stimulated3H‐D‐aspartate efflux was neither affected by high concentrations of the α2‐adrenoceptor blocker idazoxan nor by high concentrations of the α1‐adrenoceptor blocker prazosin. It is concluded that guanfacine inhibits the neural excitatory amino acid release in the rat cortex by a novel non‐α2/α1‐adrenergic mechanism.
The Effect of Ethanol on35S‐TBPS Binding to Mouse Brain Membranes in the Presence of Chloride
Authors: Liljequist Sture , Culp Steven , Tabakoff Boris
Published: March 2009

Abstract:The effect ofin vitroandin vivoadministration of ethanol on the binding of35S‐t‐butyl‐bicyclophosphoro‐thionate (35S‐TBPS) to cortical brain membranes of C57B1 mice was investigatged using KCl (100 mM) containing assay media. Thein vitroaddition of ethanol produced a dose‐dependent inhibition of basal35S‐TBPS binding. In the presence of chloride ions, GABA and pentobarbital had a biphasic action (stimulation followed by inhibition) on35S‐TBPS binding, whereas diazepam only stimulated the binding. Ethanol reduced the stimulatory effects of GABA and pentobarbital in a dose‐dependent manner, but had no effect on the enhancement of35S‐TBPS binding produced by diazepam.35S‐TBPS binding to cortical brain membranes was inhibited by the putative Cl−channel blocking agent DIDS. This inhibitory action of DIDS was significantly, and dose‐dependently reduced by ethanol (≥100 mM ethanol). Chronic ethanol ingestionin vivo, which produced tolerance to and physical dependence on ethanol in the animals, did not alter the stimulatory and inhibitory effects of GABA and pentobarbital on35S‐TBPS binding. The enhancement of35S‐TBPS binding produced by diazepam was slightly, but significantly, enhanced in brain membranes from animals which had undergone 24 hours of ethanol withdrawal. Chronic ethanol treatment did not change the potency of picrotoxin and of the peripheral BDZ‐receptor ligand RO 5‐4864 to competitively inhibit35S‐TBPS binding. Our results suggest thatin vitroaddition of ethanol alters the activity of the GABA/benzodiazepine (BDZ) receptor complex. Although there was no change in basal35S‐TBPS binding following chronicin vivoethanol administration, our current data suggest that chronic ethanol ingestion may cause specific changes of the GABA/BDZ receptor proteins, in this study revealed as an altered modulation of35S‐TBPS binding by diazepam.
Differences in Efficacies Between Morphine and Methadone Demonstrated in the Guinea Pig Ileum: A Possible Explanation for Previous Observations on Incomplete Opioid Cross‐Tolerance
Authors: Ivarsson Mikael , Neil Anders
Published: March 2009

Abstract:We have compared the effectiveness of morphine and methadone as agonists in untreated guinea‐pig longitudinal muscle preparations and after their treatment with the specific opioid receptor alkylating agent β‐chloronaltrexamine. In untreated ilea, the naloxone pA2 was 8.5 to both morphine and methadone, and their dose‐response curves were parallel. After alkylation, the dose‐response curve for morphine was shifted to the right with a decreased maximal effect. It was found that about 70% of the receptors were inactivated by the treatment, corresponding to a morphine receptor occupancy at IC50 of about 24%. The maximal effect of methadone was not decreased by the same β‐chloronaltrexamine treatment, indicating a much higher efficacy or receptor reserve for the drug. The possibility that differences in efficacies could account for previously reported heterogeneities in actions of opioids, such as assymmetries in cross‐tolerance towards morphine and methadone in experimental animal and man, is discussed.
Effects of Hexachlorocyclohexane (HCH) on the Contractile Response Induced by Norepinephrine in the Rat Isolated Vas deferens
Authors: Gandhi D. N. , Venkatakrishna‐Bhatt H.
Published: March 2009

Abstract:Effects of hexachlorocyclohexane (Technical HCH) on the contractile responses of rat isolated Vas deferens to norepinephrine (NE) were investigated by varying the Ca++and Mg++concentrations of the incubation medium. Preparations incubated in excess Ca++(4.2 mM) or in Ca++‐free Krebs solution showed decrease in sensitivity to NE. The inhibitory action of HCH reduced the sensitivity and decreased maximum responses to NE in any Mg++concentration of the medium. In the normal Ca++and its deficient medium decrease in sensitivity to HCH and the relevant maximum response to NE were observed. In excess Ca++, the HCH effect depressed corresponding to its maximal response to NE. The presence of EDTA depressed the HCH effect irrespective of the Ca++influence on the receptors.
The SHR Exhibits Less “Anxiety” but Increased Sensitivity to the Anticonflict Effect of Clonidine Compared to Normotensive Controls
Authors: Söderpalm B.
Published: March 2009

Abstract:The behaviour of the adult (16 weeks) spontaneously hypertensive rat (SHR) was compared to that of age‐matched normotensive Wistar (WISTAR) and Wistar‐Kyoto (WKY) rats in two animal models of anxiety, Vogel's conflict test (VT) and Montgomery's conflict test (MT). With respect to “inborn anxiety”, the three strains ranked differently in the two tests, WISTAR>WKY = SHR in the VT, but WKY>WISTAR>SHR in the MT. However, the SHR was the least “anxious” strain in both tests. The SHR also appeared more active and reactive than both the other strains. In the SHR and in the WKY, but not in the WISTAR, the α2‐adrenoceptor agonist clonidine in a narrow low dose‐range produced anxiolytic‐like effects of similar magnitudes. The SHR, however, responded in a ten‐fold lower dose than did the WKY. The present findings, in conjunction with previous data, are not in all parts compatible with the locus ceruleus hypothesis of anxiety and may indicate that the anticonflict effect of clonidine is mediated through activation of postsynaptic α2‐adrenoceptors rather than of α2‐autoreceptors.
Effect of Isopropanol on Rat Brain Monoamine Levels
Authors: Gorkal A. R. , Namasivayam A.
Published: March 2009

Abstract:Changes in monoamines were studied in discrete areas of brain with varying dose of isopropanol. Acute administration of isopropanol (0.463 g/kg, 0.925 g/kg and 1.85 g/kg) decreased dopamine level in hypothalamus, pons medulla and cerebral cortex and whereas it was increased in striatum and cerebellum. Noradrenaline level was reduced in all the brain areas studied. Adrenaline level was increased in hypothalamus, striatum, midbrain and pons medulla, and decreased in hippocampus and cerebral cortex. Serotonin level was increased in hypothalamus, midbrain, pons‐medulla and cerebral cortex, and decreased in striatum and hippocampus. These changes were dose‐dependent. It is concluded that isopropanol causes changes in brain monoamine content and that this effect is not the same in all the regions of the brain.
Comparison of the Effects of Calcium and the Calcium Channel Stimulant Bay k 8644 on Neomycin‐Induced Neuromuscular Blockade
Authors: Baeyens José M. , Pozo Esperanza Del
Published: March 2009

Abstract:The effects of calcium and the calcium channel stimulant Bay k 8644 on neomycin‐induced neuromuscular blockade were evaluated using rat phrenic nerve‐hemidiaphragm preparationsin vitro.Neomycin showed maximum potency in inducing neuromuscular blockade when the calcium concentration in the bath was 1 mM. Higher calcium concentrations (1.5, 2 and 4 mM) produced a gradual decrease in neomycin potency, manifested as a progressive shift to the right of neomycin concentration‐response curves. Bay k 8644 (0.1 and 1 μM) did not significantly modify indirectly elicited diaphragm contractionsper se, nor did it antagonize neomycin‐induced neuromuscular blockade. A higher concentration of Bay k 8644 (10 μM) antagonized indirectly elicited contractions. In conclusion, our results show that Bay k 8644, at concentrations causing calcium channel stimulation at the cardiac and vascular level, did not exert stimulant effects in a nerve‐skeletal muscle preparation, suggesting that its action may be tissue‐selective to a certain degree.
Class III Antiarrhythmic Action Linked with Positive Inotropy: Acute Electrophysiological and Inotropic Effects of Amiodaronein Vitro
Authors: Tande Pål M. , Refsum Helge
Published: March 2009

Negative inotropy is an adverse feature of most antiarrhythmic drugs. Positive inotropy, however, has been demonstrated for some drugs with class III antiarrhythmic action. Although amiodarone exerts its antiarrhythmic effect by an interplay of different actions on cardiac cells, it has been regarded to be the prototype class III drug due to its prolongation of action potential duration. The present study was designed to test the hypothesis that class III antiarrhythmic action and positive inotropy may be linked. We compared the effects of amiodarone in Cordarone® and its solvent Tween 80 on automaticity, refractoriness and inotropy. Two series of experiments were done; one with spontaneously beating rat atria to study the effects on sinus node function, and one with electrically stimulated left atria to study the effects on excitability, refractoriness and inotropy. Amiodarone 1 × 10‐4M decreased spontaneous heart rate by 13% and prolonged sinus node recovery time by 105%. Without affecting the excitability amiodarone prolonged the effective refractory period by 12%. At the same time contractile force increased by 12%. Lower concentration of amiodarone (5 × 10‐6M) or Tween 80 had no significant effects. In conclusion, amiodarone exerts acute electrophysiological and inotropic effectsin vitro.The class III antiarrhythmic action of amiodarone is linked with positive inotropy.
The in Vitro and in Vivo Effects of Lead on δ‐Aminolevulinic Acid Dehydratase and Pyrimidine 5′‐Nucleotidase
Authors: Ong C. N. , Kong Y. M. , Ong H. Y. , Teramoto K.
Published: March 2009

The in vitro and in vivo effects of lead on the activity of pyrimidine‐5′‐nucleotidase (P5N, E. C. 3.1.3.5) and δ‐aminolevulinic acid dehydratase (ALA‐D, E.C. 4.2.1.24) were studied. Incubation of blood with lead at concentrations of up to 3 μmol/1 (about 60 μg/dl) did not appear to affect the activity of P5N, while the activity of ALA‐D decreased dose‐dependently with lead. Administration of lead caused a marked and rapid suppression of ALA‐D in rats. The suppression of lead on P5N appeared to be a rather slow process. The decrease of its activity only came into effect 20 days after administration with lead. These findings suggest that lead induced P5N inhibition is a slow process while the suppression of ALA‐D activity occurs much earlier.
Aminotriazole Effects on Lung and Heart H2O2Detoxifying Enzymes and TBA‐RS at Two pO2
Authors: López‐Torres M. , Pérez‐Campo R. , de Quiroga G. Barja
Published: March 2009

In order to clarify the physiological rolein vivoof H2O2‐detoxifying enzymes at low and high levels of O2tension we studied catalase (CAT), glutathione peroxidases (GP), andin vivoperoxidation (TBA‐RS) in the lung and heart ofRana perezifrogs chronically treated with hyperoxia, aminotriazole (AT) ‐a CAT inhihitor‐, or both. Hyperoxia did not change CAT, GP or TBA‐RS. Aminotriazole caused an almost complete depletion of CAT, a 30% decrease of GP and a 132% (lung) to 200% (heart) increase of TBA‐RS. Changes similar to these were found in the group treated with AT in hyperoxia. No mortality or changes in total or organ weight occurred in the experimental groups. Main conclusions are: (1) The maximal hyperoxia tolerance showed by frogs among vertebrates does not need antioxidant enzyme induction from lung or heart and is probably related to the presence of high constitutive levels of GP in relation to metabolic rate. (2) Even in normoxia the tissues present significant amounts of H2O2, and CAT is needed to avoid oxidative damage. GP does not compensate its absence. The implications of these results in relation to oxygen toxicity in man is discussed.
The Rhesus Monkey as a Model for Studies of Pregnancy Induced Changes in Metoprolol Metabolism
Authors: Högstedt Stellan , Lindberg Bo S. , Regårdh Carl‐Gunnar , Moström Ulf , Rane Anders
Published: March 2009

Five pregnant Rhesus monkeys were catheterized in the hepatic and femoral veins. They were simultaneously given 168 or 176 μg of3H‐metoprolol intravenously, and 9 mg of metoprolol per kg body weight orally. The same procedure was repeated a few months after delivery. Analyses of the unlabelled drug in blood were made by gas‐chromatography and of the3H‐labelled metoprolol, by liquid scintillation. The apparent volume of distribution as well as the terminal half‐lives of metoprolol were in the same range during pregnancy and in non‐pregnancy. The oral bioavailability of metoprolol was lower (6‐22%) during pregnancy than in non‐pregnancy (9‐49%). The apparent oral clearance and the intrinsic hepatic clearance were in a similar range although there was a greater variation in the intrinsic clearance values. The former clearance estimate was lower in the non‐pregnant state only for three of the five animals. The systemic clearance varied very little and was in the same range during pregnancy and in non‐pregnancy. The changes in apparent oral clearance and in oral bioavailability of metoprolol between the pregnant and non‐pregnant Rhesus monkey are similar to the changes observed in pregnant women, although the absolute values are different.
Tissue Distribution and Elimination of Perfluorodecanoic Acid in the Rat after Single Intraperitoneal Administration
Authors: Ylinen Markku , Auriola Seppo
Published: March 2009

Tissue distribution, metabolism, and excretion of perfluorodecanoic acid (PFDA) after a single intraperitoneal dose (20 mg/kg) were studied in female and male Wistar rats. PFDA accumulated in the serum and tissues of the rats. In the serum, more than 99% of PFDA was bound by the serum proteins. In the liver, anionic and esterified PFDA were detected. Metabolic oxidation of PFDA was not observed. PFDA was not excreted in urine either by females or males during 14 days after the administration. At the same time, about 0.5% of the administered PFDA dose was excreted daily in the faeces by both sexes. In spite of the analogical structure with perfluorooctanoic acid (PFOA), which is rapidly eliminated in urine by the female rats, PFDA accumulated similarly in females and males. The reduced elimination of PFDA partially explains its greater toxicity to rats in comparison with PFOA.
Cyclosporin Metabolism in Human Liver Microsomes and Its Inhibition by Other Drugs
Authors: Henricsson S. , Lindholm A. , Aravoglou M.
Published: March 2009

The metabolism of cyclosporin was studied in human liver microsomes. There was no metabolism in the presence of cytochrome C or carbon monoxide or in the absence of cofactors, suggesting metabolism by cytochrome P‐450 enzymes. The metabolism was inhibited by ketoconazole and erythromycin, by the steroids methylprednisolone and oestradiol, and by the calcium antagonists diltiazem, nifedipine, prenylamine and verapamil. Thesein vitrofindings correlate well with previously published clinical reports suggesting that these drugs may inhibit the metabolism of cyclosporinin vivo.Our observations suggest that metabolic interactions between cyclosporin and other drugsin vivomay be predictedin vitrounder proper experimental conditions.
A Sulfate Conjugate of Cyclosporin
Authors: Henricsson Staffan
Published: March 2009

A metabolite of cyclosporin A was isolated from human bile and plasma. The material was identified as a sulfate conjugate by plasma desorption time‐of‐flight mass spectrometry and byin vitrotechnique using human liver preparations and radiolabeled substrates. A sulfate ester at the β‐carbon on the amino acid no. 1, the methylbutenyl‐threonine amino acid, of cyclosporin was synthesized as a reference, and found to have the same plasma desorption time‐of‐flight and direct chemical ionization mass spectrum as the isolated metabolite. It also had the same chromatographic properties on both an ion‐pair reversed phase system and an ion‐exchanger. Hydrolysis with sulfuric acid on the purified and synthetic metabolite gave free cyclosporin. The amino acids in the metabolite, analyzed by gas chromatography/mass spectrometry, were the same as those in cyclosporin. Free cyclosporin was not found upon hydrolysis with commercial sulfatases.
Effect of N‐Acetyl‐cysteine, D‐Penicillamine and Buthionine Sulfoximine on Glutathione Levels and CNS Oxygen Toxicity in Rats
Authors: Lalitha T. , Kerem D. , Yannai S.
Published: March 2009

The effect of glutathione (GSH) synthesis modulators ‐ L‐buthionine sulfoximine (BSO), N‐acetyl cysteine (NAC) and D‐penicillamine (DPA) ‐ on the susceptibility of rat CNS to O2toxicity was investigated. The animals were given 5% sucrose or 40 mM solutions of BSO, NAC or DPA in 5% sucrose as drinking water for one week and sacrificed prior to or after exposure to 4.5 ATA O2. The GSH content in brain, liver, lung and blood, and the activity of glutathione peroxidase (GSH‐Px), glutathione reductase (GSSG‐R), glucose‐6‐phosphate dehydrogenase (G‐6‐PD) and superoxide dismutase (SOD) in brain and lungs were measured. The brain GSH content and the enzyme activities were not changed by any of the drugs. BSO decreased the GSH content in all the other tissues; NAC and DPA treatments increased the GSH content in lungs, blood and/or liver. The CNS toxicity threshold as measured by the time of appearance of first electrical discharge (FED) on ECoG recording was not changed by NAC or DPA, but BSO brought about a significant delay in FED time. It is suggested that increased extracerebral GSH levels do not protect against CNS oxygen toxicity, and that BSO provides some protection, probably via a glutathione‐independent mechanism.