bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Diphenylhydantoin on Lysosomal Enzyme Release during Bone Resorptionin Vitro
Authors: Lerner Ulf , Hänström Lennart
Published: July 2010

Abstract:The effect of diphenylhydantoin (DPH) on the release of lysosomal enzymes during resorption of cultured mouse calvarial bone was studied. The enzyme activities of β‐glucuronidase and β‐galactosidase in the culture medium was taken as indicators for lysosomal enzyme release. In concentrations 50 μg/ml or higher, DPH inhibited the release of β‐glucuronidase and β‐galactosidase in parallel with bone resorption as indicated by reduced release of45Ca, Ca2+, Piand hydroxyproline. The release of the cytosolic enzyme lactate dehydrogenase was not influenced by concentrations of DPH up to 50 μg/ml but higher concentrations caused an increased release indicating cell injury. When bone resorption was stimulated by prostaglandin E2, DPH (50 μg/ml) also reduced the mobilization of bone mineral and the release of β‐ glucuronidase without influencing the release of lactate dehydrogenase. It is suggested that DPH by interfering with cellular release processes reduces the resorption of bone.
The Uptake of14C‐Chloroquine by Mouse Pancreatic Isletsin Vitro
Authors: Tjälve Hans , Olsson Sten , Andersson Arne
Published: July 2010

Abstract:The uptake of14C‐chloroquine by isolated mouse pancreatic isletsin vitrowas investigated. The islets were found to have a very high capacity to accumulate the substance. The uptake of14C‐chloroquine in the islets was a saturable process. Metabolic inhibitors, oubain, anaerobic conditions and absence of glucose did not inhibit the uptake of14C‐chloroquine in the slets, suggesting that the substance is accumulated by some means other than energy‐dependent active transport or pinocytosis. The uptake ofl4C‐chloroquine was inhibited by low temperature and low pH and in the presence of mepacrine, chlorpromazine, imipramine and desmethylimipramine. Only a small part of the14C‐chloroquine which had been taken up in the islets left the cells during 45 min. incubation in non‐radioactive media. Two possible mechanisms for the uptake of14C‐chloroquine in the islets are considered: (1) The accumulation may be due to a binding of the substance to cellular constituents. (2) Chloroquine may be trapped by protonation within lysosomes or other membrane‐surrounded organelles with low pH.
Toxicity of Soman after Repetitive Injection of Sublethal Doses in Rat
Authors: Sterri Sigrun H. , Lyngaas Synnøve , Fonnum Frode
Published: July 2010

AbstractInjection of sublethal doses of soman in rat intraperitoneally or subcutaneously every 4, 8, 12 or 24 hours led to chronic LD50 doses which were markedly higher than the acute one. When rats were exposed every 24 hrs to half LD50 doses of soman, several of the animals did not show symptoms of soman poisoning and survived a total exposure of 4–7 times the acute LD50 dose. Brain and diaphragm acetylcholinesterase activities declined steadily during the chronic soman exposure. The so‐called external acetylcholinesterase activity of the diaphragm was inhibited to a slightly less degree than the total acetylcholinesterase of the same tissue. The ability of the liver to hydrolyze soman was similar in rats which survived several 24 hr doses and untreated rats.
Absence of an Effect of Naloxone on Ethanol Intoxication and Withdrawal Reactions
Authors: Hemmingsen Ralf , Sørensen Søren C.
Published: July 2010

AbstractExperimental and clinical results suggest a relationship between the action of ethanol and opiates. Therefore, we have tested whether the specific morphine antagonist naloxone (2 mg/kg intraperitoneally every six hours) affects signs of severe ethanol intoxication or modifies the withdrawal syndrome following chronic ethanol intoxication in rats. Using a double blind technique, we did not find any difference between saline treated and naloxone treated animals with respect to level of intoxication and severity of withdrawal symptoms. We must therefore conclude that naloxone does not modify signs of severe ethanol intoxication or change the ethanol withdrawal syndrome in the rat. These findings do not rule out that there might be a biochemical link between actions of ethanol and opiates, but this link is probably not localized at the level of specific drug receptor interaction.
Fluoride Sensitivity of Cells from Different Organs
Authors: Hongslo Cecilie F. , Hongslo Jan K. , Holland Roy I.
Published: July 2010

AbstractThe fluoride sensitivity of cells released from rat livers and kidneys by collagenase perfusion was investigated by measuring effect on protein synthesis ratein vitro. Both cell types were sensitive to fluoride with clear concentration/effect relationships. Significant difference in sensitivity for fluoride between the cell types was found, with the kidney cells being the most sensitive type.
Chronic Ethanol Administration Decreases 5‐HT and Increases 5‐HIAA Concentration in Rat Brain
Authors: Gothóni Patrick , Ahtee Liisa
Published: July 2010

AbstractThe effect of acute and chronic ethanol administration on cerebral 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations of male Sprague‐Dawley and Wistar rats was studied. Acute ethanol administration caused a slight fall (by 13%) in 5‐HT concentration and a slight increase (by 10%) in 5‐HIAA concentration one hour after administration. In chronically treated rats the whole brain 5‐HT concentration was decreased by 9% during ethanol intoxication. This fall was significant in the part of brain containing diencephalon, mesencephalon and telencephalon except cortex (by 23%; P<0.01) and in that containing pons and medulla oblongata (by 37%; P<0.001) but not in cerebral cortex. The cerebral 5‐HIAA concentrations of chronically treated Wistar and Sprague‐Dawley rats were increased during intoxication (4–6 hrs after last ethanol administration) and even more during withdrawal (16–18 hrs after last ethanol administration, by 24–58%; P<0.05–0.01). The increase was observed in all three parts into which the brain of Wistar rats were dissected. Because ethanol did not further increase the probenecid induced elevation of cerebral 5‐HIAA concentration, our results suggest that ethanol increases the cerebral 5‐HIAA concentration by attenuating its removal from the brain.
Studies on thein VitroUptake of Polyamines by Girardi Heart Cells
Authors: Alfheim I. , Hongslo J. K.
Published: July 2010

AbstractThe uptake of spermine and spermidine in human heart cells in culture has been studied. Spermidine was accumulated to a higher degree than spermine whereas more spermine was absorbed to the cell surface. The results indicate that the uptake of spermidine and spermine is mediated by a common carrier. In addition, spermine enters the cells by several other transport mechanisms. The accumulated polyamines were not removed by washing with spermine or spermidine solutions, but they were released by treatment of the cells with butanol.
Myocardial Pharmacokinetics of Amitriptyline and Clomipramine in the Isolated, Perfused Rabbit Heart
Authors: Nielsen‐Kudsk F. , Quist Søren
Published: July 2010

AbstractThe myocardial pharmacokinetics of amitriptyline and clomipramine were investigated in isolated rabbit hearts, which were perfused with a modified Krebs‐Henseleit solution containing the equimolar concentrations 0.25 or 0.28 μg ml‐1of the compounds, respectively. The rate of myocardial uptake of the drugs as a function of time was indirectly followed by determinations of the concentrations of the compounds in fractional samples of the coronary output of perfusate. The time course of disposition of amitriptyline from the myocardium was similarly followed after changing from amitriptyline perfusion to perfusion with drug‐free liquid. The amitriptyline accumulation and disposition processes were found to fit bi‐exponential functions indicating myocardial two‐compartment characteristics of the compound. Clomipramine did only exhibit one‐compartment myocardial characteristics. The biological half‐life of amitriptyline in the myocardium was about 37.7 min. and a pronounced cardiac accumulation of about 340 μg of the compound at steady state was evidenced. The myocardial half‐life of clomipramine was about 106 min. and the accumulated amount at steady state was calculated to be 1055 μg. After amitriptyline perfusion an increase in the pharmacokinetic rate constants k10and k12and a decrease in the apparent central volume of distribution was observed.
Plasma and Tissue Concentrations of Methylergometrine (Methylergonovine) in the Rabbit
Authors: Mäntylä R. , Kanto J. , Kleimola T. , Seppälä M.
Published: July 2010

Abstract The concentrations of methylergometrine (M) (methylergonovine) in the plasma, uterus, liver, and kidneys of the rabbit were determined by a radioimmunoassay after a single 0.2 mg/kg intravenous injection and the drug responce was studied in the uterus in situ. M disappeared quickly from the plasma with a mean distribution phase half‐life of 0.91 min. According to the fast uterine tissue uptake of M the drug response in this effector organ began quickly. The simulated concentrations in the peripheral compartment of the two‐compartment open model can be useful in the understanding of the rapid drug effect, but they do not describe the real situation in any particular tissue.
Effects of Amitriptyline and Clomipramine in the Isolated, Perfused Rabbit Heart
Authors: Nielsen‐Kudsk F. , Quist Søren
Published: July 2010

AbstractThe cardiac effects of supratherapeutic concentrations of two tricyclic antidepressants were studied in isolated rabbit hearts, which were perfused with a modified Krebs‐Henseleit solution containing 0.25 or 0.50 μg ml‐1of amitriptyline or 0.28μg ml‐1of clomipramine. The followingparameters were continuously recorded: heart rate, amplitude and rate of contraction, coronary flow rate, myocardial oxygen consumption and ECG. The lowest concentration of amitriptyline caused a time correlated decrease (20%) in the frequency of spontaneous beating and a pronounced decrease in the amplitude (62%) and rate of cardiac contraction (58%). Maximum increases of the PQ‐interval of about 46% and of the QRS‐complex of about 100% were observed. At the higher amitriptyline concentration these effects further increased. Clomipramine 0.28 μg ml‐1also had a very pronounced and time correlated negative inotropic effect, but the effects upon the conduction velocities were substantially lesser than those produced by the equimolar concentration of amitriptyline. The compounds caused only insignificant changes in coronary flow. The oxygen consumption did not decrease in proportion to the decrease in contractility, as an expression of decreased myocardial efficiency. The effects of the drugs are discussed in relation to their myocardial accumulation pharmacokinetics and influence upon the membraneous sodium and calcium flux and intracellular metabolism.
On the Effects of Nutrition on the Metabolism of Foreign Compounds in the Liver of Reindeer (Rangifer tarandus tarandusL)
Authors: Laitinen Matti , Nieminen Mauri , Hietanen Eino , Hänninen Osmo
Published: July 2010

AbstractThe effects of seasonal feeding on the structure and function of the hepatic microsomes of the reindeer were studied. In native microsomes the protein content did not vary depending on seasonal feeding, but there was a slight modification of the lipid moiety. The sensitivity of microsomes to membrane treatments changed from season to season. Seasonal feeding did not affect the hepatic cytochromecreductase activity. However, the poor winter food depressed UDPglucuronosyltransferase activity to one third of that after summer feeding. The UDPglucuronosyltransferase activity was lower in both native and treated microsomes. No differences were found in serum activities of aspartate or alanine aminotransferase although there were changes in the structure and function of hepatocytes. The poor winter feeding of the reindeer decreases their capacity to glucuronate foreign compounds and this is mediated by structural modification on the hepatic endoplasmic reticulum.
Relative Contribution of Parenchymal and Non‐parenchymal Cells to the Hepatic Distribution and Metabolism of Iron‐poly(sorbitol‐gluconic acid) Complex in the Rat
Authors: Lake‐Bakaar Desmond M.
Published: July 2010

AbstractThe hepatic cellular distribution in rats of radioiron and radiocarbon after [14C‐gluconic acid] — and59Fe‐labelled iron‐poly(sorbitol‐gluconic acid) complex, glusoferron (Ferastral®), has been investigated. Following administration of the59Fe‐iron complex at a dose level corresponding to 10 mg of iron per kg bodyweight, the ratio of radioactivity per 108cells in parenchymal (P) and non‐parenchymal (NP) cell fractions, the P/NP ratio, was 3.0 after 24 hours and rose to 10.4 at day 14. After 100 mg/kg the ratio was 0.9, 10.5 and 5.7 at day 1,4 and 14, respectively. Radiocarbon content in the different cell compartments fell steadily throughout. Radioiron from59Fe‐iron‐poly(sorbitol‐gluconic acid) complex was shown to be incorporated into whole liver59Fe‐ferritin.In vitrouptake studies with the different liver cells were also performed. Parenchymal cells were found to be more active than non‐parenchymal cells with regard to cellular uptake of radiolabel from both iron complex and polymeric ligand without iron.
Correlation between Changes in Enzymatic Activities and Induction of Different Forms of Rat Liver Microsomal Cytochrome P‐450 after Phenobarbital‐, 3‐Methylcholanthrene‐ and 16α‐Cyanopregnenolone Treatment
Authors: Toftgård R. , Nilsen O. G. , Ingelman‐Sundberg M. , Gustafsson J.‐A.
Published: July 2010

AbstractMultiple forms of liver microsomal cytochrome P‐450 in rats were identified on SDS‐polyacrylamide gels stained for protein and peroxidase activity after induction with phenobarbital, 3‐methylcholanthrene, and 16α‐cyanopregnenolone. The induced forms were correlated to thein vitrometabolism of biphenyl, benzo(a)pyrene and the steroids 4‐androstene‐3,17‐dione and 5α‐androstane‐3α,17β‐diol. Induction of two forms with apparent molecular weights of 54,000 (RLvMc P‐45054) and 50,000 (RLvMc P‐45 050) was obtained with phenobarbital, induction of RLvMc P‐45055and RLvMc P‐45058with 3‐methylcholanthrene and induction of RLvMc P‐45054with 16α‐cyanopregnenolone. The RLvMc P‐45050was mainly associated with the formation of benzo(a)pyrene‐4,5‐dihydrodiol, and 7α‐hydroxy‐4‐androstene‐3,17‐dione. The RLvMc P‐45055and/or the RLvMc P‐45058was mainly associated with the formation of 2‐ and 3‐hydroxybiphenyl and benzo(a)pyrene‐7,8‐dihydrodiol and RLvMc P‐45054was to some extent associated with the formation of benzo(a)pyrene‐4,5‐dihydrodiol and several metabolites of 5α‐androstane‐3α, 17β‐diol. It is suggested that SDS‐polyacrylamide gel electrophoresis may be a valuable complement to enzyme assays in evaluating effects of drugs and environmental chemicals on the liver microsomal hydroxylase system.
Weight Gain and Body Composition in Lithium Treated Rats
Authors: Vendsborg Per B.
Published: July 2010

Abstract Long‐term lithium treated growing animals given 0.8–2.0 mmol/kg/day had a slightly but significantly faster weight gain than control animals. Greater doses did not give rise to significantly increased weight gain. Body composition, i.e., the percentage of water, fat, ash and “protein” was not affected in the faster growing lithium treated animals. The wet weight and the weight after drying of the stomach (with content) was increased shortly (hours) after the acute administration of lithium. The duration of the effect depended on the dose given. The weight of the large intestine was also increased after a dose of lithium, but only after some days of lithium pretreatment and mainly the wet weight. The effect was small but similar on the small intestine. In long‐term lithium treated rats did the faecal weight and volume increase mainly due to increased water content, but only after some days of lithium treatment.
A double‐blind, cross‐over study of the effects of terodiline in women with unstable bladder
Authors: Ekman G. , Andersson K.‐E. , Rud T. , Ulmsten U.
Published: July 2010

AbstractIn a double‐blind, cross‐over study, the effects of terodiline were evaluated in 12 women with motor urge incontinence. The patients were investigated by simultaneous urethro‐cystometry before and after treatment for 2‐week periods with placebo and terodiline 12.5 mg twice daily. The effects on subjective symptoms were also assessed. In all patients but one, terodiline increased the bladder capacity and also the bladder volume at which urgency was experienced. No effects on the urethral pressure profile or residual urine were found. Subjective improvement was reported by all but one of the patients. Placebo treatment had no effect on the measured parameters or on the subjective symptoms. No side effects were reported during any of the treatment periods. — It is concluded that terodiline can be used for treatment of female motor urge incontinence, and that it is a promising alternative to drugs presently used for this disorder.
Enhancement of Urinary Prostaglandin Excretion by Chlorazanil in Rats. Effects of Indomethacin
Authors: Olsen Uffe Bang , Eilertsen Eva , Arrigoni‐Martelli Edoardo
Published: July 2010

Abstract:In conscious unloaded Sprague‐Dawley female rats chlorazanil (10 mg/kg orally) markedly increased urinary prostaglandin E2‐excretion from 51±9 to 813±112 ng/kg/6 hrs. Urinary flow rate increased from 12.8 ±0.6 to 42.0± 1.4 ml/kg/6 hrs and urinary sodium excretion from 0.96±0.12 to 3.86±0.33 mmol/kg/6 hrs Urinary potassium excretion was unchanged. Indomethacin pretreatment (5 mg/kg orally) greatly reduced the effect of chlorazanil on urinary prostaglandin E2‐excretion. In addition indomethacin modified the excretory effects of chlorazanil, thus the enhancement of urinary flow rate was attenuated, the potassium excretion decreased, while sodium excretion tended to be potentiated. In non‐pretreated condition chlorazanil variably affected urinary kallikrein excretion (TAMe‐esterase activity) from 108±6 to 92±33 mEU/kg/6 hrs. After indomethacin pretreatment chlorazanil invariably reduced urine enzyme excretion from 111±6 to 32±4 mEU/kg/6 hrs.
HPLC‐Determination of some Antiinflammatory, Weak Analgesic and Uricosuric Drugs in Human Blood Plasma and its Application to Pharmacokinetics
Authors: Nielsen‐Kudsk F.
Published: July 2010

Abstract: HPLC‐determination of naproxen, indomethacin, ketoprofen, fenoprpfen, ibuprofen, diclofenac sodium, tolfenamic acid, phenylbutazone, mofebutazone, salicylic acid, acetylsalicylic acid, phenacetin, paracetamol, sulfinpyrazone and probenecid by means of an adjustable, rapid, accurate and specific method is described. Plasma samples of 0.2 ml were deproteinised and the drugs extracted simultaneously with pure acetonitrile. Aliquots of 25 μl of this primary extract were directly injected on the column. As elution solvent for drug screening was basically used 55% methanol in 50 mM phosphate buffer at pH 4.0. Optimal separation of some drugs or reasonable elution times for others were obtained by varying the methanol concentration of the elution solvent or possibly its pH. The method used for individual drug determinations is very applicable for therapeutic monitoring purposes as well as for use in pharmacokinetic investigations. As an example, the practical detection limit for naproxen in plasma was about 0.2 μgml‐1. By concentrating the extract this could be lowered to about 0.04 μg ml‐1. The method was applied in a study of the pharmacokinetics of naproxen in a person, who ingested a single oral dose of 2.5 mg kg‐1. Pronounced two‐compartment kinetics were found. Vc was 0.038 1 kg‐1 Vdas 0.138 1 kg‐1, t½ (β) 21.3 hrs, t½ (α) 0.99 hr and t½ (ka) 0.67 hr.
Plasma and Brain Levels of Δ6‐THC and Seven Monooxygenated Metabolites Correlated to the Cataleptic Effect in the Mouse
Authors: Ohlsson A. , Widrnan M. , Carlsson S. , Ryman T. , Strid C.
Published: July 2010

Abstract:The brain and plasma levels of unchanged Δ6‐tetrahydrocannabinol (Δ6‐THC), 7‐hydroxy‐Δ6‐THC, the five side‐chain hydroxylated Δ6‐THC derivatives and 1α, 2α‐epoxyhexahydrocannabinol (EHHC) were correlated to the cataleptic effect in the mouse up to 60 min. after intravenous administration of radiolabelled compounds in the range 1.3 to 12.4mg/kg. All cannabinoids except Δ6‐THC and l″‐hydroxy‐Δ6‐THC showed a very good correlation between brain/plasma concentrations and cataleptic effect. 4″‐Hydroxy‐ and l″‐hydroxy‐Δ6‐THC reached the highest concentration in the brain but the most potent cannabinoids were: Δ6‐THC, 7‐hydroxy‐, 3″‐hydroxy‐Δ6‐THC, and EHHC followed by 5″‐hydroxy‐, 4″‐hydroxy‐, 2″‐hydroxy‐, and 1″‐hydroxy‐Δ6‐THC in decreasing order. It was concluded that structural rather than pharmacokinetic features are most important in determining the psychoactivity of the various cannabinoid metabolites of THC.
β2‐Microglobulin Levels in Serum and Urine of Cadmium Exposed Rabbits
Authors: Piscator Magnus , Björck Lars , Nordberg Monica
Published: July 2010

Abstract: Male rabbits were exposed to cadmium during 16 weeks by subcutaneous injections of either 0.25 mg or 0.5 mg Cd as cadmium chloride per kg body weight 3 times per week. β2‐microglobulin (β2‐m) and creatinine in serum, cadmium in blood, as well as total protein, creatinine, β2‐m and cadmium in urine were determined before exposure and after 3 and 7 weeks of exposure. Measurements were also made at 19 weeks, 3 weeks after the last exposure. During exposure, there was a slight increase in the serum β2‐m/creatinine ratio among rabbits with the highest exposure, while no effect of the cadmium burden could be observed once exposure had ceased. Urinary excretion of β2‐m was related to urinary pH, which appeared to be the case also for excretion of total protein. In the high exposure group, a significant increase in urinary β2‐m excretion, indicative of renal tubular dysfunction was seen after 7 weeks of exposure. This was, however, not related to serum β2‐m levels. It was concluded that before renal damage has occurred even heavy cadmium exposure has very little influence on serum β2‐m levels.
Failing Effect of Digoxin on Myocardial Uptake of Violamycin B1
Authors: Hoffmann H. , Härtl A. , Lisalo E. , Pekkarinen A.
Published: July 2010

Abstract:The effect of digoxin on both the negative inotropic action and the myocardial uptake of a new anthracycline antibiotic violamycin B1 has been studied in isolated guinea pig atria. In concentrations upto 2.0×10−7M/l digoxin did not prevent the negative inotropic effect of violamycin B1 caused by the concentrations of 0.7 and 5.0×10−4M/l. Corresponding to these findings, the uptake of violamycin B1 into the atrial tissue was not influenced by digoxin. However, violamycin B1 in the cardiotoxic concentration of 5.0×10−4M/l decreased the atrial uptake of digoxin. It is suggested that no competition seems to exist in myocardial uptake of anthracycline antibiotics and cardiac glycosides.
Preliminary Studies on the Absorption, Distribution, Metabolism, and Excretion of THIP in Animal and Man using 14C‐labelled Compound
Authors: Schultz Birgit , Aaes‐Jørgensen Tove , Bøgesø Klaus Peter , Jørgensen Aksel
Published: July 2010

Abstract: Distribution of radioactivity in rats, serum levels in human volunteers and rats and elimination of radioactivity in volunteers, rats, and mice following oral administration of 14C‐labelled THIP have been investigated. Peak values of radioactivity in the organs and in serum were seen half an hour after administration, indicating a rapid absorption. Highest concentrations of radioactivity were found in the kidneys, but radioactivity was seen in all investigated tissues including the brain. The radioactivity was mainly excreted with urine (84–93%). Thin‐layer chromatography of urine from volunteers, rats, and mice showed that most of the excreted radioactivity corresponds to unchanged THIP. Three metabolites were found in urine from rats each in amounts of 2–7% of the total dose given. Two of these metabolites were also found in urine from the volunteers in amounts of 30–35% and <2%, respectively, and in urine from mice in amounts of 21% and 6% of the total dose, respectively. No radioactivity corresponding to unchanged THIP was found in faeces indicating complete absorption of THIP following oral administration. One of the metabolites, the main one in man and mouse, seemed to be a glucuronic acid conjugate of THIP, but the chemical structure of the metabolites has not yet been established.
Inhibition of RNA and Protein Synthesis by Ethanol in Regenerating Rat Liver: Evidence for Transcriptional Inhibition of Protein Synthesis
Authors: Pösö H. , Pösö A. R.
Published: July 2010

Abstract:The effect of ethanol on RNA and protein synthesis was studied in regenerating rat liver. Partial hepatectomy stimulated the activity of ornithine decarboxylase (ODC) and that of tyrosine aminotransferase (TAT) as well as the synthesis of RNA. The intubation of ethanol (3 g/kg) 1 hr before the operation inhibited the stimulation of ODC and TAT when measured 4 hrs after the operation. Ethanol administration also inhibited RNA synthesis. By using inhibitors of alcohol dehydrogenase and aldehyde dehydrogenase it was shown that the inhibition of RNA synthesis (and also that of protein synthesis) was most probably a direct effect of ethanol itself. When RNA synthesis was measuredin vitroin purified nuclei, ethanol inhibited the incorporation of nucleotides to RNA. It is suggested that ethanol inhibits protein synthesis in regenerating rat liver at the transcriptional level by interfering in nuclei with the synthesis of RNA.
Combined Effects of Ethanol and pH‐Change on Protein Synthesis in Isolated Rat Hepatocytes
Authors: Wallin Bengt , Mørland Jørg , Fikke Anne‐Marie
Published: July 2010

Abstract: Rat liver parenchymal cells were isolated and incubated for 80 min. in buffered salt solutions. 14C‐valine incorporation in the presence of a high concentration of unlabelled valine (4.2 mM) was taken as a measure of protein synthesis. The pH dependence of the synthesis of cell and medium proteins was studied at pH values varying from 6.6 to 7.9. The results showed that maximum protein synthesis occurred close to the physiological pH value. Protein synthesis was reduced at both lower and higher pH‐values. Protein synthesis was inhibited by the addition of ethanol (30 mM). The relative inhibition caused by ethanol got more pronounced as the pH of the hepatocyte suspensions was lowered. The metabolism of ethanol resulted in lowering of the pH in cell suspensions. It is suggested that the depression of protein synthesis by ethanol could be mediated by the fall in pH due to ethanol metabolism.
Excretion of Zinc in Rat Bile – A Role of Glutathione
Authors: Alexander Jan , Aaseth Jan , Refsvik Tor
Published: July 2010

Abstract: Fractionation of the bile from rats injected with 65ZnCl2 (5 μmol/kg) showed that zinc was mainly bound to low molecular weight compounds eluted corresponding to the zinc‐glutathione complexes. Diethylmaleate (3.9 mmol/kg), cyclohexene oxide (4.9 mmol/kg) and acrylamide (3.5 mmol/kg) administered intraperitoneally to rats caused a rapid decrease in the endogenous excretion of both zinc and reduced glutathione into bile. This depression probably reflects the conjugation of the aforementioned substances to glutathione in the liver cells. These results indicate that zinc is transferred from liver to bile by glutathione dependent process and most likely as zinc‐glutathione complexes.
Effect of Pentobarbital on the Formation of Diastereomeric Oxazepam Glucuronides in Man: Analysis by High Performance Liquid Chromatography
Authors: Seideman P. , Ericsson Ö. , Gröningsson K. , von Bahr C.
Published: July 2010

Abstract:Barbiturate treatment can enhance drug oxidation in man, but its effects on glucuronidation of clinically used drugs are unknown. We have studied the effect of 10 days treatment with pentobarbital on oxazepam glucuronidation in six volunteers. The diastereomeric (+ and minus;) glucuronides in urine were analyzed separately by high performance liquid chromatography and oxazepam in plasma by gas liquid chromatography. The area under the plasma concentration time curve for oxazepam (15 mg sod) decreased after pentobarbital treatment in all subjects, mean 10.4 before and 6.9 hXμmol/l after treatment (P<0.05) and oxazepam's plasma clearance increased by about 50 per cent. The glucuronides appeared more rapidly in the initial urinary fractions. The ratio between the glucuronides (+/minus;) appearing in urine decreased on pentobarbital treatment. Our data indicate that pentobarbital treatment increases the clearance of oxazepam by increased glucuronide conjugation, probably reflecting barbiturate induced changes of UDP glucuronyltransferase.
Reduced Urine Kallikrein Excretion and Antikaliuresis by Chlorazanil in Rats
Authors: Olsen Uffe Bang , Eilertsen Eva
Published: July 2010

Abstract:In normal conscious female Sprague‐Dawley rats chlorazanil (3 mg/kg intraperitoneally) reduced urine kallikrein excretion by approximately 80%. Thus, urine kininogenase activity decreased from 54±5 U/kg/3 hrs to 10±2 U/kg/3 hrs and urine TAMe‐esterase activity decreased from 34±1.5 mEU/kg/3 hrs to 7.4±1.0 mEU/kg/3 hrs. In addition kidney kallikrein content decreased by approximately 50% from 0.76±0.03 U/kidney to 0.40±0.07 U/kidney at three hours post treatment. Chlorazanil (3 mg/kg intraperitoneally) increased urine sodium excretion from 0.48±0.04 mmol/kg/3 hrs to 2.48±0.98 mmol/kg/3 hrs and decreased the potassium excretion from 1.06±0.45 mmol/kg/3 hrs to 0.29±0.09 mmol/kg/3 hrs. Comparable antikaliuretic doses of amiloride (5 mg/kg intraperitoneally) or triamterene (10 mg/kg orally) did not change urine kallikrein excretion. It is suggested that chlorazanil inhibits kidney kallikrein synthesis perhaps by an innate antimineralocorticoid‐like effect.
The Use of HPLC to Elucidate the Metabolism and Urinary Excretion of Furosemide and its Metabolic Products
Authors: Andreasen F. , Christensen C. Kjeldahl , Jakobsen F. Kjær , Mogensen C. E.
Published: July 2010

Abstract: Three principles for the use of HPLC with spectrophotometric detection to determine the concentration of furosemide and of 4‐chloro‐5‐sulfamoyl anthranilic acid (CSA) were studied. A reversed phase microbondapack C18 column was used for the separation of either unchanged furosemide (I), CSA (II) or the diazo product of CSA (III). The sensitivity of the methods for the determination of furosemide added to serum in vitro were for I 0.05, for II 0.020 and for III 0.01 μg/ml. The methods I and II were used to study the excretion pattern in the urine of furosemide and CSA after intravenous injection of 80 mg to 10 normal subjects. An average of 48.1±9.8% (S.D.) of the furosemide was excreted during the first hour as unchanged furosemide. Simultaneously 1.9±0.8% of the dose was excreted as CSA. Only very low concentrations of CSA were found in serum and that metabolite apparently was excreted with a higher renal clearance than furosemide during the period 30–60 min. after the administration (303±145 ml/min. for CSA and 88±23 ml/min. for furosemide). During the 24 hour period following the administration 52.6±8.1 mg was excreted as unchanged furosemide and 11.4±5.2 mg as a glucuronidated product.
Correlation between Vascular Smooth Muscle Relaxation and Increase in Cyclic GMP Induced by some Organic Nitro Esters
Authors: Axelsson Krister L. , Andersson Rolf G. G. , Wikberg Jarl E. S.
Published: July 2010

Abstract:Three different nitro compounds glyceryl mononitrate (GMN), glyceryl dinitrate (GDN) and ethylene glycol dinitrate (EGDN) were tested on histamine contracted bovine mesenteric artery. GDN and EGDN caused a dose‐dependent relaxation which was accompanied by an increase in the endogenous cGMP level. The ED50‐value for GDN and EGDN with regard to the relaxant action was 1.06×10−6M and 4.20×10−8, respectively. GMN was almost completely ineffective as a relaxing agent and did not cause any significant change in cGMP. Regression analysis revealed a significant correlation between relaxation and increase in cGMP for both GDN and EGDN. The regression model for EGDN could be significantly improved by including the squared cGMP change, indicating a non‐linear relationship. With regard to GDN a hyperbolic relationship between relaxation and cGMP increase was found. A slight improvement of the regression model was found for EGDN when the change in cAMP was included. For GMN and GDN no improvement of the regression model could be revealed by including the change of cAMP. It is suggested that the present data give further evidence for cGMP as a mediator of vascular smooth muscle relaxation induced by nitro compounds.
Antitumour Activity, Toxicity and Disposition of LS 1727, a Nitroso‐Chloroethyl Carbamate of 19‐Nortestosterone, in Rats and Mice
Authors: Gunnarsson Per Olov , Ellman Marianne , Fabiansson Eva , Gunnarsson Kjell , Jensen Gunborg , Müntzing Jonas
Published: July 2010

Abstract: LS 1727, a nitroso‐chloroethyl carbamate of 19‐nortestosterone, given intraperitoneally had a high cytostatic activity against some experimental tumours. In vitro studies showed that the tested tumours differed in their ability to hydrolyze LS 1727. The hydrolytic capacity was related to the sensitivity to treatment with LS 1727. Distribution studies with double‐labelled LS 1727 demonstrated that the chloroethyl‐part of the molecule was retained in dimethylbenz(a)anthracene‐induced mammary tumours in the rat. Our findings suggest that the antitumour activity of LS 1727 is exerted by alkylating metabolites released at hydrolysis of the compound. LS 1727 had no oral antitumour activity probably due to pre‐systemic hydrolysis. When given intravenously, hydrolysis of LS 1727 in lungs caused severe pulmonary toxicity already at low doses.
Inhibition of Adrenergic Neuroeffector Transmission in Rabbit Pulmonary Artery and Aorta by Adenosine and Adenine Nucleotides
Authors: Husted Steen , Nedergaard Ove A.
Published: July 2010

Abstract:The effect of adenosine and adenine nucleotides on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta was studied. Adenosine (10−5— 3 × 10−4M) decreased the contractile response of pulmonary artery and aorta evoked by electrical‐field stimulation. The decrease was reversible. No tachyphylaxis developed. Inhibition of either adenosine deaminase by deoxycoformycin (3.6 × 10−6M) or of adenosine transport by dilazep (3 × 10−6M) did not alter the inhibitory effect of adenosine on the neurogenic contractions in the pulmonary artery. However, deoxycoformycin plus dilazep markedly enhanced the inhibitory effect of adenosine. The calcium antagonists nifedipine (1.5 × 10−8M) and nimodipine (1.3 × 10−8M) had no effect on the adenosine‐induced inhibition. This was also the case with theophylline (5 × 10−5M), atropine (10−7M), and the prostaglandin synthetase inhibitors indomethacin (5 × 10−5M) and suprofen (3 × 10−5M). The contractile response of the pulmonary artery elicited by exogenous (—)‐noradrenaline (NA; 10−9— 3 × 10−4M) was essentially not altered by adenosine (10−5— 3 × 10−4M). Adenosine (10−4M) did not alter the spontaneous3H‐outflow from rabbit aorta preloaded with3H‐(—)‐noradrenaline (3H‐NA). Adenosine (10−5— 3 × 10−4M), ADP (10−4M), ATP (10−5M), and inosine (10−4M) diminished the overflow of tritium from pulmonary artery and aorta preloaded with3H‐NA. The spontaneous outflow of tritium from aorta preloaded with3H‐NA consisted of3H‐NA (17%),3H‐dihydroxyphenylglycol (3H‐DOPEG; 30%),3H‐dihydroxy‐mandelic acid (3H‐DOMA, 4%),3H‐O‐methylated and deaminated metabolites (3H‐OMDA; 42%), and3H‐normethanephrine (3H‐NMN; 2%). Adenosine (10−5and 10−4M) enhanced3H‐DOPEG and3H‐NMN, decreased3H‐NA, and did not alter3H‐DOMA and3H‐OMDA. The stimulation‐evoked overflow of tritium for aorta preloaded with3H‐NA consisted of3H‐NA (31%),3H‐DOPEG (18%),3H‐DOMA (2%),3H‐OMDA (46%), and3H‐NMN (3%). Adenosine (10−5and 10−4M) enhanced3H‐NA and3H‐DOPEG, decreased3H‐OMDA and did not alter3H‐DOMA and3H‐NMN. Adenosine (10−6— 10−4M) did not alter the accumulation of3H‐NA (10−8M) by aorta. It is concluded that adenosine inhibits vascular sympathetic neuroeffector transmission by diminishing the release of transmitter from the nerve terminals.
Dual Effect of the Muscarinic Agonist McN‐A‐343 on Vascular Neuroeffector Transmission
Authors: Nedergaard Ove A.
Published: July 2010

Abstract:The site and mechanism of action of McN‐A‐343 (4‐m‐chlorophenylcarbamoyloxy)‐2‐butynyltrime‐thylammonium chloride) on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery was studied. Low concentrations (10−6— 3 × 10−5M) of McN‐A‐343 and cocaine enhanced (up to 210 and 236%, respectively) the contractions evoked by electrical‐field stimulation, while higher concentrations (10−4— 3 × 10−4M) inhibited them. McN‐A‐343 (10−4M) caused an initial transitory potentiation (222% of control) of the stimulation‐evoked contractions followed by an inhibition. In the presence of cocaine (3 × 10−5M), the potentiation caused by McN‐A‐343 was prolonged and the secondary inhibitory phase was thus abolished. Physostigmine (10−5— 10−4M), hexamethonium (10−5M), atropine (3 × 10−7M), suprofen (10−5M), and 4‐aminopyridine did not alter the effect of McN‐A‐343 (10−4M). Cocaine (3 × 10−5M)and(+)‐amphetamine (10−5M) reversed the McN‐A‐343‐evoked block, while they did not alter the inhibition caused by tetracaine (3.2 × 10−5M). Atropine (3 × 10−7M) had no effect on the McN‐A‐343‐induced block, while 4‐aminopyridine (10−4M) caused a partial and transitory reversal. On the aorta McN‐A‐343 (10−4M) did not alter the contractile concentration‐response curve of (—)‐noradrenaline (10−9— 3 × 10−4M), while that of serotonin (10−8— 3 × 10−5M) was moved to the right in a competitive manner. McN‐A‐343 (10−4M) did not alter the contractions evoked by noradrenaline (10−7M) during the period corresponding to the stimulation‐evoked enhancement and subsequent inhibition. McN‐A‐343 (10−4M) slightly antagonized the contractions caused by tyramine (10−6— 10−3M) and carbachol (10−6— 10−3M). It is concluded that McN‐A‐343 enhances stimulation‐evoked transmitter release by a presynaptic facilitatory action mediated via receptors localized on the outer surface of adrenergic neurones and to a lesser extent by inhibition of noradrenaline re‐uptake. The enhancement does not involve presynaptic nicotine or muscarine receptors. Furthermore, McN‐A‐343 inhibits transmitter release by acting as an adrenergic neurone blocking agent at an intraneuronal site. The inhibition does not involve presynaptic muscarine inhibitory receptors and is prostaglandin‐independent.
Effect of Different Doses of D‐Penicillamine and Combined Administration of D‐Penicillamine and Methylprednisolone on Collagen, Glycosaminoglycans, DNA and RNA of Granulation Tissue, Skin, Bone and Aorta in Rats
Authors: Junker Peter , Helin Grethe , Lorenzen Ib
Published: July 2010

Abstract:D‐penicillamine (D‐pen) in doses of 20, 100 and 500 mg/kg/day or D‐pen 100 mg/kg/day plus methylprednisolone (MP) 2.0 mg/kg/day was administered daily for 42 days to rats implanted with viscose‐cellulose sponges. Operated, pairfed rats served as controls. D‐pen increased the DNA content of granulation tissue, but had no effect on the amount of tissue produced. In contrast, high dose D‐pen reduced the content of DNA and collagen in skin. A dose related inhibition of collagen crosslink formation occurred in all tissues, particularly in skin, as indicated by increased proportions of extractable collagen with increased α/β chain ratio and aldehyde content. Moreover, low doses of D‐pen increased the hydroxyproline/proline ratio of acid soluble skin collagen, presumably due to solubilization of type III collagen as demonstrated by SDS‐polyacrylamide gel electrophoresis in the presence of 3.6 M urea. These changes were associated with increased skin fragility and edema plus excess elastin deposition in the aorta after high dose D‐pen treatment. Low dose D‐pen stimulated the35S‐sulphate uptake into the sulphated glycosaminoglycans (GAGs) of granulation tissue without altering their relative amounts, whereas high dose D‐pen reduced the concentration of chondroitin‐4/6‐sulphate in skin. MP antagonized the solubilizing effect of D‐pen on collagen, probably by inhibition of the collagen synthesis. In addition, MP inhibited the cell proliferation and GAG metabolism. Food restriction reduced the DNA content of granulation tissue. The inhibitory effect of D‐pen on the formation of granuloma collagen crosslinks in the presence of unaltered rate of collagen biosynthesis may diminish the amount of fibrotic tissue due to increased degradability of crosslink deficient collagen. Simultaneous administration of MP may facilitate this effect by inhibiting the biosynthesis of collagen. However, long‐term D‐pen treatment seems to increase the susceptibility of normal tissues to mechanical injury.
A Gas Chromatographic Method for the Determination of Antidepressant Drugs in Human Serum
Authors: Kristinsson Jakob
Published: July 2010

Abstract: A universal gas chromatographic method for the determination of the most commonly used antidepressant drugs in I ml of serum is described. Prior to extraction the samples were washed with hexane at acid pH. After the hexane wash the drugs were extracted into hexane at pH approximately 10, and subsequently reextracted from the hexane into a 1% solution of formic acid in methanol. The methanolic phase was evaporated, the residue dissolved in isopropanol and analysed by gas chromatography with nitrogen detection on a 3% OV‐225 column. Recoveries for amitriptyline, nortriptyline, clomipramine, desmethylclomipramine, doxepin, desmethyldoxepin, imipramine, desipramine, maprotiline, protriptyline, trimipramine and desmethyl‐trimipramine were found to be 80% or higher. Limits of detection were found to be 5–10 ng/ml for tertiary amines and 10–20 ng/ml for secondary amines. Interferences from some common basic drugs were investigated as well as interferences between different antidepressant drugs. Gas chromatographic data are given for 28 drugs and metabolites.
Effects of Hydroflumethiazide in Congestive Heart Failure: Renal Electrolyte Excretion Related to Urinary Thiazide Excretion and Aldosterone
Authors: Brørs O. , Enger E. , Jacobsen S. , Aakvaag A. , Foss O. P.
Published: July 2010

Abstract: The effect of hydroflumethiazide (HFT) on renal excretion of sodium, chloride, and potassium was studied in congestive heart failure and related to urinary excretion of thiazide and aldosterone. HFT 75 or 150 mg was administered orally once daily for 4 days to 8 male patients with roentgenological evidence of enlarged heart and slight or no peripheral oedema receiving digitalis and controlled diet. Urinary excretion of HFT did not change after repeated doses, whereas urinary excretion of a metabolite increased significantly. Initially, HFT induced a significant increase in the urinary excretion of sodium and potassium. After repeated doses, the natriuretic effect declined gradually in 6 of the patients. There was consistently a small natriuretic effect and a large kaliuretic effect at high serum aldosterone concentrations and high urine aldosterone excretion rates, whereas at low aldosterone levels, there was a wide range in magnitude of these effects. Relationships of the log urinary excretion rate of HFT to the increase in urinary excretion rate of sodium, chloride, and potassium showed positive and significant correlations. It was concluded that reduced natriuretic effect of HFT in congestive heart failure is not due to reduced delivery of thiazide to renal tubular cells but to compensatory adjustments of the kidney in part induced by aldosterone.
Effects of Intraperitoneally Injected Acrylonitrile on Liver, Kidney and Brain
Authors: Zitting A. , Tenhunen R. , Savolainen H.
Published: July 2010

Abstract: Intraperitoneal injection of Chinese hamsters with acrylonitrile (30 mg/kg) decreased the glutathione content of liver and brain 4 hrs later. Twentyfour hrs after the injection, liver and kidney weights were increased; cerebral and renal glutathione concentrations were also increased. Cerebral succinate dehydrogenase and cytochrome oxidase activities were decreased as were liver and kidney ethoxycoumarin deethylase activity and liver microsomal cytochrome P‐450 content. These biochemical effects may have been caused by acrylonitrile metabolites, i.e. glycidonitrile and cyanide ion; the hypoxic consequences associated with the latter being largely abolished after 72 hrs.
Dissociation of the Effect of Captopril on Blood Pressure and Angiotensin Converting Enzyme in Serum and Lungs of Spontaneously Hypertensive Rats
Authors: Forslund Terje , Tikkanen Ilkka , Grönhagen‐Riska Carola , Fyhrquist Frej
Published: July 2010

Abstract:Spontaneously hypertensive rats (SHR) of the Okamoto‐Aoki strain (n=40) were treated with captopril (SQ 14.225; D‐3‐mercapto‐2‐methylpropanoyl‐L‐proline) orally, dose0.2 mg/mlin drinking water. The treatment was initiated early and later during the course of developing hypertension. Continuously treated ratsdid not develop hypertension.Rats receiving captopril for 12 weeks remained normotensive, whereas withdrawal of the drug resulted in hypertension. Captopril treatment was effective in the rats with established hypertension and decreased the blood pressures to nearly normal values. Serum angiotensin converting enzyme (ACE) activity rose3‐foldin captopril treated rats. ACE in lung plasma membranes increased during captopril treatment, indicating that captopril induced biosynthesis of pulmonary ACE. No qualitative differences were found in the ACE from treated and not treated animals. The dissociation of the antihypertensive effect of captopril and of increased ACE activity in serum and lungs reduce the value of relating blood pressure effects of the drug to measured enzyme activity in the SHR.
Effects of Methyl Mercury on Protein Synthesis in Vitro
Authors: Syversen Tore L. M.
Published: July 2010

Abstract: Methyl mercury has been shown to interact with protein synthesis in vivo and in vitro. In the present paper a brain postmitochondrial supernatant was used for studies in vitro. Inorganic mercury (Hg2+) was shown to be a more potent inhibitor of protein synthesis than methyl mercury, puromycin or cycloheximide. The inhibitory effect of methyl mercury was potentiated by puromycin. It is thus possible that methyl mercury causes disintegration of polysomes in brain cells.
Effect of a New Vasodilator, Pinacidil (P 1134), on Potassium, Noradrenaline and Serotonin Induced Contractions in Rabbit Vascular Tissues
Authors: Nielsen Chr. Kærgaard , Arrigoni‐Martelli E.
Published: July 2010

Abstract:Ring preparations of rabbit aorta were contracted by potassium (127 mM). Pinacidil (P 1134), a new vasodilator (2.3×10−5M), the calcium antagonists verapamil (3.4×10−7M), nifedipine (3.4×10−9M) and hydralazine (1.9×104M) relaxed the preparation by 50%. 50% relaxation of noradrenaline‐contracted tissues was obtained with pinacidil, 6.8×10−5M, verapamil, 2.4×10−4M and hydralazine, 1.9×10−3M. At 2×10−7M concentration nifedipine was almost inactive. In ring preparations of rabbit aorta exposed to calcium‐free medium and then depolarized with potassium (127 mM), pinacidil, 5×10−5M and nifedipine, 10−8M significantly inhibited the contractions by cumulative addition of calcium. Hydralazine, 10−3M had no effect. Noradrenaline‐induced contractions in calcium‐free medium or in presence of increasing amounts of calcium were significantly inhibited by nifedipine, 10−8M and hydralazine, 10−3M. Pinacidil, 10−4M had no effect. Pinacidil, 1.3×10−5M and verapamil, 2.0×10−5M inhibited by 50% the serotonin‐induced increase of perfusion pressure of isolated rabbit ear artery. The noradrenaline effect in this preparation were 50% inhibited by pinacidil, 2.4×10−4M and by verapamil, 8.8×10−5M. Hydralazine, 10−3M exerted minor inhibitory effect. It is suggested that interference with calcium influx contributes to the vasodilator activity of pinacidil.