bluuebunny/crossref_metadata_2025 huggingface dataset:
Assay of Adenylate Cyclase in Rat Brain Homogenates and Lysed Turkey Erythrocytes: Two Different Methods give Different Results with Brain but not with Erythrocytes
Authors: Grynne Birthe H.
Published: July 2010

Abstract:Experiments showed that the cyclic AMP (cAMP) fraction isolated by alumina or Dowex 50/ alumina chromatography from brain adenylate cyclase reaction mixtures contained “P radioactivity 10–12 times in excess of that which could be accounted for by determination of cAMP using binding assays. No such discrepancy was found when lysed turkey erythrocytes were assayed. This indicated that special precautions must be taken for the purification of32PcAMP from brain adenylate cyclase assays due to the formation of32P‐labelled contaminants.
Disposition Kinetics and Urinary Excretion of Sulphadimidine in Normal and Alloxan Diabetic Dogs
Authors: Nawaz Muhammad , Akhtar Semin , Hashmi A. S.
Published: July 2010

Abstract:Disposition kinetics and urinary excretion of sulphadimidine were investigated in 16 dogs following a single intravenous injection (100 mg/kg body weight). Biochemical parameters including blood pH, blood glucose, plasma triglycerides and total plasma proteins of these animals were determined. The animals were injected alloxan (125 mg/kg) intravenously and when blood glucose level exceeded 300 mg%, the biochemical parameters, disposition kinetics and urinary excretion of sulphadimidine were determined again. After alloxan treatment of the dogs, there was a highly significant (P < 0.01) decrease in blood pH, increase in blood glucose and plasma triglycerides levels when compared with the pretreatment values. The alloxan diabetic dogs showed a highly significant (P < 0.01) reduction in elimination half‐life (t1/2β) and apparent volume of distribution (Vd(area)and increase in overall elimination rate constant (kel), total body clearance (ClB) and percentage of sulphadimidine dose excreted in urine. In normal dogs, one‐half of the intravenous dose and after alloxan treatment two‐third of the dose was eliminated through urinary excretion during 48 hours after injection. This study shows that the metabolic alterations of alloxan induced diabetes in dogs, influence the drug disposition and urinary excretion which indicate the need for the adjustment of dosage regimen in such metabolic disorders.
Hepatic Elimination of Femoxetine in Pig
Authors: Bechgaard E. , Keiding S. , Lund J. , Christiansen L. A.
Published: July 2010

Abstract:Hepatic elimination of femoxetine was studied in seven anaesthetized 40 kg pigs by means of constant rate infusions of 3–41 mg/min. (8.6–118 μmol/min.) into the portal vein. The elimination followed saturation kinetics (Michaëlis‐Menten constants: Vmax12 mg min.−1kg−1liver; Km1.3 mg‐1−1blood)and was characterised by high hepatic extraction, due to metabolism. The hepatic output of the active metabolite, nor‐femoxetine, was very low, indicating that other metabolic pathways than demethylation were more important in the pig. The high hepatic elimination in the pig corresponds to the high first pass effect, earlier found in man, and it depends upon the infusion rate as well as the total dose.
Hexachlorocyclohexane‐Induced Testicular Dysfunction in Rats
Authors: Shivanandappa T. , Krishnakumari M. K.
Published: July 2010

Abstract:Weanling male albino rats were fed 100, 750 and 1500 p.p.m. of technical HCH for 90 days. There was marked testicular atrophy with reduced tubule size and spermatogenetic arrest at 1500 p.p.m. Histochemically, there was accumulation of cholesterol‐positive lipids in the Sertoli cells and the Leydig cells of the atrophied testis and biochemical estimation revealed significant increase of total lipid and cholesterol contents. Activities of Δ53 β hydroxysteroid dehydrogenase (Δ53 β HSDH), 17 β hydroxysteroid dehydrogenase (17 β HSDH)and glucose‐6‐phosphate dehydrogenase (G‐6‐PDH) in the interstitial cells were markedly decreased suggesting steroidogenic inhibition in the Leydig cells of the atrophied testis due to HCH feeding.
Characterization and Stability of Rat Liver Microsomes Isolated by a Rapid Gel Filtration Method
Authors: Pyykkö Kaija
Published: July 2010

Abstract:A simple and rapid method for the isolation of the microsomal fractions from rat livers by small Sepharose CL‐2B gel columns is presented. The procedure is well suited for routine preparation of numerous samples. No expensive apparatus is needed. The purity of microsomes and the values for microsomal enzyme activities are as well or better than the values for microsomes isolated by repeated ultracentrifugation, though the preparation time is only one fifth. Gel‐filtrated microsome suspensions stored at −70° were stable at least one year.
Effects of B‐HT 920 and B‐HT 933 on Dopamine and Noradrenaline Autoreceptors in the Rat Brain
Authors: Andén Nils‐Erik , Nilsson Helene , Ros Eva , Thornström Ulla
Published: July 2010

Abstract:B‐HT 920 at low doses inhibited the accumulation of DOPA following treatment with reserpine and a DOPA decarboxylase inhibitor in the dopamine‐, but not in the noradrenaline‐predominant regions of the rat brain. B‐HT 933 selectively inhibited this DOPA accumulation in the noradrenaline‐predominant regions. These effects of B‐HT 920 and B‐HT 933 were completely antagonized by haloperidol and yohimbine, respectively. The rat motor activity was reduced by B‐HT 920 and it was restored following apomorphine. B‐HT 933 decreased the motor activity by a yohimbine‐sensitive mechanism. The results indicate that B‐HT 920 can selectively and potently stimulate the dopamine autoreceptors whereas B‐HT 933 can selectively stimulate the noradrenaline autoreceptors.
The Influence of Orphenadrine or Imipramine on the Hypertensive Response of Physostigmine in the Rat
Authors: Zandberg P. , Sangster B.
Published: July 2010

Abstract:An intravenous infusion of orphenadrine or imipramine to artificially ventilated, urethane anaesthetized rats, completely blocked the physostigmine induced increase in blood pressure and the blood pressure increase induced by electrical stimulation of the posterior hypothalamus; effects mediated via the sympathetic nerve. The noradrenaline induced blood pressure increase was not changed during an infusion with orphenadrine but was markedly depressed during an infusion with imipramine. During an infusion with both orphenadrine or imipramine the pressor response induced by stimulation of the spinal cord were completely blocked in pithed rats. The pattern of the blockade was comparable with the blockade of the pressor response after hypothalamic stimulation. These results show that at least in rats both orphenadrine and imipramine prevents the central stimulatory sympathetic effects on the cardiovascular system by interfering with the sympathetic nervous system. The site of action is discussed. In conclusion: the present results show that although physostigmine may be helpful in the treatment of central anticholinergic effects caused by overdoses of orphenadrine and imipramine it is of no use for combating the direct toxic effects of both drugs on the cardiovascular system.
Effects of 3,4‐Diaminopyridine on Mechanical and Electrical Responses of Frog Single Muscle Fibres
Authors: Khan Rauf A. , Lemeignan Madeleine
Published: July 2010

Abstract:The effects of 3,4‐diaminopyridine (3,4‐DAP) were studied on isolated muscle fibres of the frog in concentrations ranging between 0.025 and 5.0 mM. Isometric twitch and tetanus responses were recorded at temperatures between 2.5 and 3.9°. 3,4‐DAP caused a concentration‐dependent increase in twitch amplitude, maximum effects being obtained at a concentration of 3 mM with a mean increase in tension of 70± 12% of control (n = 7). 3,4‐DAP in 3 mM concentration had only a slight increase in initial rate of rise of twitch tension (mean increase 8 ±4%) but increased the time to half peak tension by 59 ±9% and the time from peak tension to half relaxation by 78 ± 10%). No significant effect of 3,4‐DAP was observed on the initial rate of rise and total amplitude of the isometric tetanus. The twitch potentiating effect of 3,4‐DAP developed gradually with the number of times the fibre was stimulated and reached a maximum level after 40–50 stimulations. A gradual increase in the duration of the action potential was also observed. It is suggested that 3,4‐DAP, like 4‐aminopyridine, potentiates the twitch by means of prolonging the duration of the action potential.
Demonstration of α‐Adrenoceptors in the Rabbit Bladder Base and Urethra with3H‐Dihydroergocryptine Ligand Binding
Authors: Larsson Bengt
Published: July 2010

Abstract:The purpose of this work was to demonstrate the presence of α‐adrenoceptors in a crude membrane preparation made from rabbit bladder base and urethra. This was achieved by radioligand binding studies, using3H‐dihydro‐α‐ergocryptine (3H‐DHE) as the radioligand. The specific binding, i.e. the binding that could be inhibited by 10≃5M phentolamine, was saturable with 73 fmol3H‐DHE bound per mg membrane protein. Binding was at steady state after 60 min., and reversible. Rate constants for association and dissociation were 3 × 107M−1min.−1, and 2× 10−2min.−1, respectively. A number of compounds were tested for their abilities to compete with3H‐DHE for the binding sites. The relative affinity of some adrenoceptor agonists was: (‐)‐adrenaline>(‐)‐noradrenaline(±)‐isoprenaline. Stereoselectivity was shown, since (‐)‐noradrenaline had 42 times higher affinity than (+)‐noradrenaline. Adrenoceptor antagonists inhibited3H‐DHE binding in the following order of potency: DHE>phentolamine(±)‐propranolol. The dissociation constant, KD, for DHE to the binding sites was estimated in three different ways. The constants were derived from saturation, competition, and kinetic studies, and gave KDvalues of 1.1,1.4 and 0.7 nM, respectively. The results suggest that α‐adrenoceptors were labelled by3H‐DHE in the tissue homogenates.
Metabolism of Safrole in the Rat
Authors: Klungsøyr Jarle , Scheline Ronald R.
Published: July 2010

Abstract:The urinary metabolites ofsafrole(4‐allyl‐l,2‐methylenedioxybenzene)in the rat were identified using gas chromatographic — mass spectrometric methods. The amounts of the individual metabolites excreted were determined gas chromatographically. Metabolite excretion was 93% in 72 hrs and most of this material (86%) consisted of metabolites formed via demethylenation of the methylenedioxy moiety. The other metabolic routes observed were allylic hydroxylation and the epoxide‐diol pathway.
Relationship between Catalase Activity and Uptake of Elemental Mercury by Rat Brain
Authors: Eide Ingvar , Syversen Tore L. M.
Published: July 2010

Abstract:Uptake of mercury by brain after intravenous injection of elemental mercury was investigated in the rat. Catalase activity was inhibited by aminotriazole either by intraperitoneal injections affecting catalase in most tissues of the animal or by intraventricular injections affecting catalase in the brain selectively. Uptake of elemental mercury by rat brain was not influenced by intraperitoneal administration of aminotriazole resulting in 50% inhibition of brain catalase. However, when the inhibitor was injected intraventricularly in concentrations to give a 50% inhibition of brain catalase, it was shown that the mercury uptake by the brain was significantly decreased. In the latter case when only brain catalase was inhibited and the supply of elemental mercury to brain was maintained, mercury uptake by brain was proportional to the activity of catalase in brain tissue and to the injected amount of elemental mercury. Contrary to the intraventricular injection of aminotriazole, in animals receiving aminotriazole intraperitoneally prior to elemental mercury injection, we suggest that the lower activity of brain catalase is compensated by an increased supply of elemental mercury caused by the generally lower oxidation rate in the animal. This view is supported by the finding that mercury uptake by liver increased due to aminotriazole intraperitoneally athough activity of catalase was depressed.
Brain Catecholamine Metabolism Changes and Hypothermia in Intoxication by Anticholinesterase Agents
Authors: Coudray‐Lucas C. , Prioux‐Guyonneau M. , Sentenac H. , Cohen Y. , Wepierre J.
Published: July 2010

Abstract:Sublethal doses of physostigmine, paraoxon and soman induce a short‐lasting fall in rat core temperature potentiated by α‐methyl‐para‐tyrosine (α‐MT) (early effects). When the own hypothermic effect of the anticholinesterase agent has disappeared (late effects), α‐MT induces a new decrease in temperature. Parallel biochemical studies of catecholamine levels and turnover were performed in several brain areas. The norepinephrine (NE) turnover is generally increased particularly in the hypothalamus, suggesting that NE hypothalamic changes might be linked to a latent perturbation of thermoregulatory mechanisms. Furthermore, it was shown that soman acts differently from the other drugs by inducing quite important changes in both NE and dopamine levels.
Cyclic AMP in Urine, Kidney and Liver Following Long‐term Administration of Fluoride to Rats
Authors: Hongslo Cecilie F. , Hongslo Jan K. , Ekstrand Jan , Holland Roy I.
Published: July 2010

Abstract: Rats were exposed to fluoride (F) for up to 8 weeks through the drinking water containing 100 p.p.m. F. Urine samples were regularly collected, together with tissue samples of liver and kidney at termination. All samples were assayed for cyclic AMP. No F‐effect was found on liver or kidney levels of cyclic AMP. In the urine from the F‐exposed rats there was an overall increase in the cyclic AMP concentration, but a decreased or unaffected 24 hrs urinary excretion of cyclic AMP. However, the F‐exposed rats exhibited a considerably lower diuresis than the control animals. Because a significant negative correlation was found between diuresis and urinary concentration of cyclic AMP, the material was corrected to similarity in the mean diuresis between the two groups. Then no effect of F‐exposure could be detected either in the urinary concentration or the daily excretion of cyclic AMP.
Placental Transfer of Hexachlorophene (HCP) in the Marmoset Monkey (Callithrix jacchus)
Authors: Brandt I. , Dencker L. , Larsson K. S. , Siddall R. A.
Published: July 2010

Abstract: Autoradiography was used to study the distribution of 2,2′‐14C‐methylene‐bis‐(3,4,6‐trichlorophenol) (HCP) in pregnant marmoset monkeys in early (day 30–50) and late (around day 120) gestation and in a newborn (11 days old) pup. Radioactivity was present in the conceptus at all stages of gestation, although the foetal concentration was lower than the maternal. In the embryo an accumulation was observed in the neural tube and in the embryonic membranes. In the late foetus and newborn monkey the highest concentration of radioactivity was found in the liver and the intestinal contents. The brain of the adult and newborn animals showed low concentration. A partial blood‐brain barrier was present in the late foetus but, in relation to other tissues, the foetal brain concentration was higher than that of the mother.
Pharmacodynamic Effects of Nicotine and Acetylcholine Biosynthesis in Mouse Brain
Authors: Nordberg Agneta , Sundwall Anders
Published: July 2010

Abstract:Nicotine (4; 8 mg/kg) given intraperitoneally to mice had a marked hypothermic effect with a duration of more than 2 hours. Mecamylamine (0.5; 2.5 mg/kg) prevented the hypothermic effect of 2 mg/kg nicotine but had no effect on 4 mg/kg nicotine. Atropine (5 mg/kg) did not affect the hypothermia produced by nicotine. Other symptoms induced by nicotine (0.5–4 mg/kg) were convulsions, rigidity, tremor and decrease in motor activity. Pretreatment with mecamylamine (0.5 mg/kg) prevented convulsions but had only a slight effect on the decreased motor activity. Atropine pretreatment was ineffective. It thus seems as if the effects of nicotine at least to some part are mediated by nicotine‐like receptors. When a tracer dose of labelled choline (3H‐Ch) was given to mice treated with nicotine (4 mg/kg) a marked increase (+ 100%) in the biosynthesis of labelled acetylcholine (ACh) in the striatum was found when the animals were killed by decapitation. If the mice were killed by a more rapid technique, microwave irradiation of the head, no change in3H‐ACh formation was observed in comparison to controls. The findings indicate that nicotine can preserve a very labile pool of newly synthesized ACh in the striatum.
Separation of Plasma Kallikrein and a Kallikrein‐like Plasminogen Activator Generated by Acetone in Rat Plasma
Authors: Johansen Harald Thidemann , Briseid Kjell
Published: July 2010

Abstract: Plasminogen activator (PGA), kininogenase (Kase) and benzoyl arginine ethyl ester (BAEe) activities generated in plasminogen‐free rat plasma by incubation with acetone (23% v/v) at 22° were purified. The activities passed unadsorbed through columns of DEAE‐Sephadex A‐50 (pH 7.8) and arginine methylester‐Sepharose 4B (pH 8.5). Part of the activities (rat plasma kallikrein) was adsorbed onto a soybean trypsin inhibitor (SBTI)‐ Sepharose 4B column at pH 8.5. At pH 7.0 a fraction with higher ratios PGA/BAEe esterase and Kase/BAEe esterase was also adsorbed. Both fractions could be eluted with 5 mM sodium hydroxide. The fraction not adsorbed at pH 8.5, but adsorbed at pH 7.0 was designated low molecular weight plasminogen activator (LMr‐PGA), a plasminogen activator fraction with higher molecular weight, but without esterase activity being also present (Berstad & Briseid 1982). LMr‐PGA was strongly inhibited by tranexamic acid (AMCA) 0.10 mM, whereas the fraction designated rat plasma kallikrein was not. By polyacrylamide gel electrophoresis Mr‐values in the range 120,000 to 130,000 were established for native samples of both rat plasma kallikrein and LMr‐PGA, whereas Mr‐values of 78,000 to 80,000 were established after treatment with SDS.
Increase in Dopamine Uptake in Rat Striatal Synaptosomes after an Acutein VivoAdministration of Organic and Inorganic Lead
Authors: Komulainen Hannu , Pietarinen Raili , Tuomisto Jouko
Published: July 2010

Abstract:Adult male Wistar rats were administered acute toxic doses of lead (Pb), triethyl lead (TriEL) or tetraethyl lead (TEL) by gavage. The ability of striatal, hypothalamic and cortical synaptosomes to take up tritiated monoamines was assayed 24 hours later. Pb, TriEL as well as TEL increased dopamine (DA) uptake into striatal synaptosomes at least at some dose level. Pb increased, but TEL decreased 5‐hydroxytryptamine(5‐HT) uptake into hypothalamic synaptosomes, while TEL increased noradrenaline (NA) uptake into cortical synaptosomes. After a 3 week administration to initially 4 week old rats of even toxic doses of Pb in drinking water, monoamine uptake was not significantly affected. On the contrary, the neurotoxicity of TEL was cumulative in that a much lower dose decreased 5‐HT uptake when divided over a 3 week period than acutely.In vitroTriEL inhibited DA uptake (IC50; 0.8 μM) into striatal and 5‐HT uptake (5.0 μM) into hypothalamic synaptosomes but TEL and delta‐aminolevulinic acid did not. The results suggest that dopaminergic and serotonergic neurones differ in their response to alkyl leadin vivo. The differences could be due to basic differences in the neurochemical behaviour of these two types of nerve endings.
Ca‐Dependence of Accumulation of Monoamines into Synaptosomes and its Inhibition by Copper
Authors: Tuomisto Jouko , Komulainen Hannu
Published: July 2010

Abstract:Effects of various concentrations of extracellular Ca on the high affinity uptake of dopamine (DA), noradrenaline (NA) and serotonin (5‐HT) as well as the effects of Ca on Cu‐induced uptake inhibition were studied by using striatal, cortical and hypothalamic synaptosomes, respectively. The spontaneous release of all three amines from preloaded synaptosomes by Cu increased slightly with increasing external Ca up to 2.5 mM. The sensitivity to Ca of the accumulation of the amines into synaptosomes decreased in the order of DA>NA>5‐HT. Below 0.3 mM Ca, DA uptake increased due to concurrent decreased release of DA from synaptosomes. The pattern was similar but less evident for NA while 5‐HT uptake and its spontaneous release did not change upon buffer Ca at all. The uptake inhibition of none of the amines dependend on extracellular Ca. Zn reversed the Cu‐induced inhibition of 5‐HT uptake but increased additively the inhibition of DA uptake and that of NA uptakein vitro.The potency of Cu to inhibit uptake decreased when the protein concentration in the incubation medium was increased. Cysteine, added concurrently with Cu, did not protect uptake from the toxic influence of Cu. The results so far suggest that the primary mechanism in the Cu‐induced inhibition of uptake is blocking the membrane uptake carrier. The release of an accumulated amine from synaptosomes may rather be secondary and result from the inhibition of the reuptake.
Inhibition by Methylprednisolone Treatment of the Aortic Mineral Accumulation in Rabbits with Chronic Renal Failure
Authors: Tvedegaard Erling , Szpirt Wladimir , Nielsen Maja
Published: July 2010

Abstract: The effect of methylprednisolone treatment on the mineral accumulation in the rabbit aorta during chronic renal failure (CRF) was investigated. Groups of rabbits with surgically induced CRF and sham operated controls were treated for 14 weeks with 0.40 mg of methylprednisolone per day and compared to corresponding groups receiving placebo. After sacrifice the thoracic aorta was excised and divided into an inner intima‐media and an outer media layer before determination of the content of cholesterol and minerals. The surface area and wet weight of both layers were significantly increased in the CRF groups but methylprednisolone treatment had no effect on these parameters. Neither CRF nor methylprednisolone caused significant changes of the cholesterol content of the intima‐media. Methylprednisolone treated CRF rabbits had a significantly decreased mineral content of the intima‐media layer compared to CRF rabbits receiving placebo although the treatment caused no significant changes in the serum concentrations of calcium and phosphate. In rabbits with normal renal function a similar effect could not be demonstrated.
Characterization of Mechanical Effects and β‐Adrenoceptor Binding of Prenalterol in Rat Myocardium
Authors: Aass Halfdan , Hedberg Anders , Skomedal Tor , Carlsson Enar , Osnes Jan‐Bjørn
Published: July 2010

Abstract:The partial β‐agonist prenalterol has been found to differ from the full agonist isoprenaline in some aspects of its cardiac action. We therefore studied in rat myocardium whether prenalterol elicited the same qualitative changes of the contraction‐relaxation cycle as was previously found for isoprenaline. We also measured binding of prenalterol to β‐adrenoceptors. Prenalterol augmented relaxation more than contraction and thus evoked the same qualitative changes of the contraction‐relaxation cycle as did isoprenaline. However, the response developed slowlier than that to isoprenaline, and the effect on relaxation followed a more protracted time course than the effect on contraction. Prenalterol bound non‐selectively to β1‐ and β2‐adrenoceptors in both heart and lung broken cell preparations. pKdfor binding to β‐adrenoceptors and pD2values for functional effects in heart were similar, i.e. prenalterol had to occupy half the amount of β‐adrenoceptors in order to evoke half‐maximal functional effects. The non‐selective α‐blocker phentolamine potentiated the effects of prenalterol on contraction, but did not change the equilibrium binding of prenalterol to cardiac β‐adrenoceptors. Phentolamine did not change the potency and efficacy of isoprenaline. Thus, although prenalterol qualitatively evoked the same response as isoprenaline, it also exhibited some properties which differed.
Monoamine Uptake in Brain Synaptosomes after Administration of Copper to Rats
Authors: Komulainen Hannu
Published: July 2010

Abstract: In our previous studies, divalent copper (Cu) has proved to be a potent inhibitor of monoamine uptake in rat brain synaptosomes in vitro. To study whether Cu affects monoamine uptake in the brain in vivo, rats were given Cu (as CuCl2) acutely as a single dose of 30, 100, 200 or 300 mg/kg by gavage, intravenously 9 mg/kg or subacutely in drinking water, 200, 400, or 600 mg/l Cu for 3 weeks. Control animals were given deionized water. Cu was an order of magnitude more toxic intravenously than orally as judged by the Cu dose. The high affinity uptake of dopamine, 5‐hydroxytryptamine and noradrenaline did not change in striatal, hypothalamic and cortical synaptosomes, respectively, after these Cu administrations. A single dose of 300 mg/kg Cu orally was lethal and increased hypothalamic Cu by 13% and cortical Cu by 26%. Lower doses increased neither blood nor brain Cu significantly 24 hrs after administration of Cu. After the 3 week administration of 600 mg/l Cu in drinking water blood Cu had increased by 22% and cerebral Cu by 19%. The results indicate that Cu is not liable to affect monoamine uptake in nerve endings in vivo. This may be explained by effective endogenous protective mechanisms against Cu.
Characterization of and Drug Influence on a Calmodulinsensitive Phosphodiesterase Purified from Bovine Brain
Authors: Andersen P. H. , Geisler A.
Published: July 2010

Abstract:A calmodulin‐sensitive phosphodiesterase was purified from bovine brain. The purification procedure involved ammonium sulphate fractionation, two chromatographic steps on DEAE‐cellulose, gel‐filtration on Sephadex G‐200, and finally one DEAE‐cellulose run, and gave a 2300‐fold purification. The purified phosphodiesterase had a Vmaxfor cyclic AMP of 126 μmol/mg protein X min. and was activated 8‐fold by addition of calmodulin and calcium. According to SDS‐electrophoresis the purified enzyme contained one major peptide of 59,000 daltons, but the preparation was not homogeneous. The enzyme was characterized kinetically and with regard to the effect of cations, pH, temperature, and nucleotides. Furthermore, the influencein vitroon enzyme activity of several classes of drugs, e.g. antidepressants, neuroleptics, antiallergics, platelet inhibitors, and some “reference phosphodiesterase inhibitors” was investigated.
Metabolism ofp‐tert.‐Butyltoluene in the Rat and Guinea Pig
Authors: Walde Anna , Scheline Ronald R.
Published: July 2010

Abstract:The metabolism ofp‐tert.‐butyltoluene (TBT) was studied in the rat and guinea pig. Both the methyl and thetert.‐butyl group were oxidized to alcohol and carboxylic acid derivatives in these species. The major urinary metabolites in rats werep‐tert.‐butylbenzoic acid and its alcohol derivative 2‐(p‐carboxyphenyl)‐2‐methylpropan‐1‐ol whereasp‐tert.‐butylbenzoylglycine was the most prominent metabolite in guinea pig urine. No significant differences in metabolism were found when TBT was given intragastrically or by inhalation. The intragastric administration of14C‐TBT to rats showed that the bulk of the excretion of radioactivity occurred within three days. A recovery of 83% was achieved and the ratio of urinary/faecal radioactivity was roughly 3.5:1.
Comparative Metabolism of Fenitrothion and Methylparathion in Male Rats
Authors: Yamamoto T. , Egashira T. , Yoshida T. , Kuroiwa Y.
Published: July 2010

Abstract:The mechanisms for the lower toxicity of fenitrothion as compared with methylparathion were investigated in male rats. The difference in the acute toxicity of the insecticides could be the more rapid decomposition of fenitrothion and fenitrooxon in rat liver than that of methylparathion and methylparaoxon. In particular, the decomposition of fenitrothion by hepatic microsomes was accelerated by increasing the insecticide concentration as the substrate. The oxygen analogues of both insecticides, fenitrooxon and methylparaoxon, were not detected in the brain after the administration of their parent compounds. From these results, it is concluded that the lower toxicity of fenitrothion as compared with methylparathion could be due to the greater rate of the decomposition of fenitrothion to its less toxic metabolites, rather than to the relative rate of penetration of the oxygen analogues into brain.
Influence of Dithiocarb, (+)‐Catechin and Silybine on Halothane Hepatotoxicity in the Hypoxic Rat Model
Authors: Siegers Claus‐Peter , Frühling Andreas , Younes Maged
Published: July 2010

Abstract: In phenobarbital (phenemalum NFN)‐pretreated male rats exposed to 1% halothane for 2 hrs under hypoxic conditions (10% 02), significant increases in serum enzyme activities of alanine aminotransferase and sorbitol dehydrogenase were observed 24 and 48 hrs later indicating liver damage. In this known model of halothane hepatotoxicity, pretreatment with (+)‐catechin (200 mg/kg orally) or silybine (150 mg/kg orally) protected against halothane‐induced liver injury, whereas diethyldithiocarbamate (200 mg/kg orally) failed to be effective. Halothane decreased the concentration of reduced glutathione in liver only under hypoxic conditions indicating that glutathione might be involved in the non‐oxidative metabolic pathways of halothane. Free fluoride in plasma was used as a measure of non‐oxidative defluorination of halothane. Higher plasma fluoride levels were observed under conditions which led to hepatotoxicity but did not correlate with the protective effects of the antidotes. This further supports the assumption that 2‐chloro‐1,1,1‐trifluoroethane might be the radical intermediate responsible for halothane hepatotoxicity.
Methods using tissue preparations and isolated biomolecules.
Authors: Heilbronn E.
Published: July 2010

AbstractThe possibility to use organs, organelle preparations and biologically active chemicals in toxicity tests and in toxicology will be reviewed. Examples are perfused liver preparations, tissue slices and homogenates, isolated nerve preparations, nerve‐muscle preparations, membrane preparations, microsomes, mitochondria, synaptosomes, antibodies and isolated chemical compounds (receptors, enzymes).
Shortcomings of alternative techniques for the assessment of acute toxicity.
Authors: Rowan A.
Published: July 2010

Abstract Relatively little work has been done on the development of cell culture and other models to assess the acute toxicity of chemicals. Many of the present shortcomings have already been addressed in earlier presentations but will be summarized by the author. The parameters necessary for an appropriate model of acute toxicity will be discussed and the difference between testing for specific and general effects will be highlighted. Some possible future research directions and research needs will be discussed.
Central Effects of Lithium in Rats: Lithium Levels, Body Weight and Water Intake
Authors: Smith Donald F. , Amdisen Amdi
Published: July 2010

Abstract: Male rats received LiCl for one week either by continuous intracerebroventricular injection from osmotic minipumps or by oral administration in the diet. Control groups received corresponding treatment with NaCl. The intracerebroventricular lithium treatment produced relatively high lithium levels in brain regions (0.6–2.3 mmol/kg) and negligible lithium levels in plasma (less than 0.1 mmol/l) while the oral treatment produced moderate lithium levels in brain regions as well as in blood (0.5–0.9 mmol/kg and 0.5–0.75 mmol/l, respectively). Body weight loss and enhanced water intake occurred in groups given oral lithium treatment as well as in those given lithium via minipumps. The results suggest that administration of lithium by minipumps may be of use to study central actions of lithium.
Chemosterilization and its Reversal in the Snail Lymnaea acuminata
Authors: Singh Ravindra , Agarwal R. A.
Published: July 2010

Abstract: Treatment of the snail Lymnaea acuminata, the vector for the liver flukes Fasciola hepatica and Fasciola gigantica, with two alkylating agents (cyclophosphamide and busulfan) and one thiocarbamide (thiourea) caused reduction in the number of eggs and production of non‐viable embryos. All the three drugs caused reduction in the levels of DNA, RNA and protein and the activity of alkaline phosphatase in the gonadal tissues of this snail. There was enhancement in free amino acid levels and activity of acid phosphatase by these drugs. Discontinuation of treatment could not reverse the cytotoxic effects of these drugs. Treatment of sterilized snails with prostaglandin E1 (PGE1), prostaglandin F2α(PGF2α) or hydrogen peroxide not only restored the number of eggs but also caused full embryonic development. Also, there was near total recovery of RNA, DNA and protein levels and small changes in free amino acid levels as well as the activity of alkaline and acid phosphatase. It has been suggested that the prostaglandins play a modulatory role in protein synthesis. The possible therapeutic use of PGE1, PGF2α and H2O2 has been pointed out.
The Feline Carotid Rete: Vasomotor Reactivity of Isolated Arteries
Authors: Edvinsson L. , Uddman R.
Published: July 2010

Abstract:Vasomotor responses of arteries from the feline carotid rete were examined using a sensitivein vitrosystem. The vessel segments constricted in response to several vasoactive agents and putative neurotransmitters. Sympathomimetic agents (noradrenaline, adrenaline, oxymetazoline, phenylephrine), 5‐hydroxytryptamine, histamine, angiotensin II, and prostaglandin F2αall induced concentration‐dependent contractile responses. The contractions induced by noradrenaline, 5‐hydroxytryptamine, and histamine could be antagonized by phentolamine, methysergide, and mepyramine, respectively. Cholinomimetics (acetylcholine, carbacholine), vasoactive intestinal peptide and papaverine induced potent dilatory responses. The effect of carbacholine was shifted towards higher agonist concentrations by atropine. Dilatations, though small in magnitude, were found by application of adenosine, isoproterenol, and histamine. These results correlate well with the recent demonstration of autonomic nerves and indicate the occurrence of corresponding receptor sites in the walls of the carotid rete arteries.
In vitroMetabolism of Propoxyphene in Rat Liver: Reaction of a Carbinol Metabolite with Acetaldehyde
Authors: Hermansson Inger , Hermansson Jörgen , Stjernström Nils E.
Published: July 2010

Abstract:The metabolism of the analgesic drug propoxyphene (α‐d‐propoxyphene) has been investigated in the rat liver 9,000Xg supernatant fraction. The incubations were analyzed by HPLC. The major metabolite was norpropoxyphene carbinol, obtained through demethylation and ester hydrolysis. The demethylated metabolite of propoxyphene, norpropoxyphene, was also detected. Addition of acetaldehyde to the incubation mixture decreased the metabolism of propoxyphene. Reactions between norpropoxyphene carbinol and acetaldehyde resulted in a fast disappearence of the carbinol and the formation of a reaction product, the significance of which is discussed.
Rapid and Simple Determination of Homovanillic Acid in Plasma Using High Performance Liquid Chromatography with Electrochemical Detection
Authors: Chang Wen‐Ho , Scheinin Mika , Burns R. Stanley , Linnoila Markku
Published: July 2010

Abstract: A rapid, yet highly reliable, procedure for determination of homovanillic acid (HVA) in plasma is described. After precipitation of proteins with perchloric acid, separation of sample components is directly achieved with high performance liquid chromatography on a reversed‐phase column (C8), followed by quantitation based on electrochemical detection. The sensitivity of this method is 0.5 pmol/injection. Detector response is linear from the limit of detection to at least 0.5 nmol/injection. The intra‐assay coefficient of variation is 2.2% in the concentration range of 50–150 pmol/ml plasma. The inter‐assay coefficient of variation is 6.3%, based on determinations on 30 working days. A comparison of the present method and a specific gas chromatographic‐mass spectrometric assay showed good agreement between the two procedures. One chromatographic run requires less than 16 min. for plasma and 10 min. for a standard.
Pharmacodynamics and Toxicology of Fenflumizole, a New Non‐steroidal Anti‐inflammatory Imidazole Derivative
Authors: Corell Tim , Hasselmann Gert
Published: July 2010

Abstract:Fenflumizole, (2‐(2,4‐difluorophenyl)‐4,5‐bis(4‐methoxyphenyl) imidazole), a new non‐steroidal anti‐inflammatory agent, was investigated for anti‐inflammatory, analgesic and anti‐pyretic activity in experimental animals. Comparison was made to other non‐steroidal anti‐phlogistics. Furthermore, general pharmacodynamics and toxicity of fenflumizole was studied. Fenflumizole was comparable to or weaker than indomethacin in models of acute inflammation (carrageenin paw oedema and pleurisy, rats, ultraviolet erythema, guinea‐pigs) and stronger than indomethacin as an analgesic (writhing, mice). As an antipyretic agent (arachidonic acid pyresis, rats) fenflumizole was 3 times weaker than indomethacin. The acute gastro‐ulcerogenicity and toxicity of fenflumizole was low as compared to reference drugs. No untoward activity of fenflumizole on respiratory and circulatory systems was observed in rabbits and dogs. Fenflumizole is a potential new therapeutic agent with anti‐inflammatory, analgesic and anti‐pyretic activities comparable to other anti‐phlogistics but with reduced side effects.
Increased Cytochrome P‐450 Independent Drug Metabolism and Mutagen Activation in Rat Liver by Octachlorostyrene
Authors: Holme Jørn A. , Dybing Erik
Published: July 2010

Abstract:Single intraperitoneal injections of 200 mg/kg octachlorostyrene (OCS) increased the activites of flavin‐containing monooxygenase, epoxide hydrolase and glutathione S‐transferase in the livers of male Wistar rats. UDP‐glucuronyl transferase activities measured with aglycones increased by methylcholanthrene or phenobarbital treatment, were both slightly increased by OCS treatment. A liver 9,000Xg supernatant fraction from OCS pretreated rats increased the bacterial mutagenicity of 2‐acetylaminofluorene and 2‐aminofluorene compared to controls, while insignificant or only minor effects were seen on N‐hydroxy 2‐acetylaminofluorene and benzo(a)pyrene mutagenicity. The effect of OCS on mutagen activation was similar to that seen after phenobarbital treatment. The use of monolayers of hepatocytes instead of 9,000Xg subfractions did not reveal any qualitative differences in mutagen activation.
Acute Effects of Halothane and Enflurane on Drug Metabolism and Protein Synthesis in Isolated Rat Hepatocytes
Authors: Aune Håkon , Bessesen Atle , Olsen Harald , Mørland Jørg
Published: July 2010

Abstract: The metabolism of sulphanilamide, antipyrine and paracetamol was studied in the absence and presence of the anaesthetics halothane and enflurane at three different concentrations (0.5, 1.0 and 2.0 mM) in isolated hepatocytes from the rat. Cell viability and protein synthesis were monitored to evaluate toxic effects. A strong concentration related inhibition of antipyrine oxidation (40–70%) and paracetamol conjugation (20–40%) was caused by both halothane and enflurane. Acetylation of sulphanilamide was not inhibited, however, as a slight augmentation was noticed. A significant dose related decrease of cell viability (3–13%) was caused by both anaesthetics. Dose dependent inhibition of the synthesis of stationary cell proteins (15–60%) and the synthesis/secretion of medium proteins (35–85%) was caused by halothane. Similar but slightly less pronounced effects were caused by enflurane. The present findings show that volatile anaesthetics may have general effects as well as different degrees of specific effects on both membrane bound enzyme and soluble enzyme activities.
Effects of Continuous Trichloroethylene Inhalation on Different Strains of Mice
Authors: Kjellstrand P. , Holmquist B. , Mandahl N. , Bjerkemo M.
Published: July 2010

Abstract: Seven different strains of mice (wild, C57BL, DBA, B6CBA, A/sn, NZB and NMRI) were continuously exposed to 150 ppm trichloroethylene (TCE) during 30 days. After exposure all strains showed large increases in liver weight, while changes in kidney and spleen weights were small. Plasma butyrylcholinesterase (BuChE) activity increased in males of all strains and in females of strains A/sn and NZB. The increase in the females was less than that of the corresponding males. We concluded that there are moderate, but in some cases, significant differences in TCE sensitivity between different mouse strains. The differences observed between sexes emphasizes the importance of specifying sex as well as strain when reporting on toxic effects.
Age‐ and Sex‐related Differences in Rat Liver Microsomal Enzymes and their Inducibility by Toluene
Authors: Pyykkö Kaija
Published: July 2010

Abstract:In the liver microsomes of toluene‐treated and control Sprague‐Dawley rats (n=148, males and females aged 13–93 days), the contents of cytochrome P‐450 and b5and the activities of NADPH – cytochrome c reductase and four monooxygenases were studied. In male control rats, cytochrome contents and NADPH – cytochrome c reductase, aminopyrine N‐demethylase and aniline hydroxylase activities increased to the age of one month, and after a slight decrease in cytochrome concentrations, the average adult level was reached by the age of two months. Aniline hydroxylase and 7‐ethoxycoumarine O‐deethylase activities decreased to about half at the same age period. In control female rats, the activities of aminopyrine N‐demethylase and aniline hydroxylase decreased after the age of one month, and they remained at a considerably lower level in adult females than in males. The sex‐dependence of other enzymes was negligible. Toluene induction was already well developed in the youngest age group of both sexes; in most cases the induced enzyme levels in young rats were as high or higher than in adults. In adult female rats, toluene induction of all enzymes was weaker than in males. In male rats, the toluene‐induced level of aniline hydroxylase and 7‐ethoxycoumarine O‐deethylase showed deep minima at the age of 43–53 days, at the puberty of rats.
Estimation of the Rate of Energy Production of Rat Mast Cells in Vitro
Authors: Johansen Torben
Published: July 2010

Abstract: Rat mast cells were treated with glycolytic and respiratory inhibitors. The rate of adenosine triphosphate depletion of cells incubated with both types of inhibitors and the rate of lactate produced in presence of antimycin A and glucose were used to estimate the rate of oxidative and glycolytic ATP synthesis.
Acute Ethanol Intoxication Decreases Subsequent Food Intake and Changes Hepatic Microsomal Enzyme Activities Similarly to Fasting
Authors: Gadeholt Gaut , Stowell Allan , Mørland Jørg
Published: July 2010

Abstract:The effect of intragastric ethanol, 7.8 g/kg, on the microsomal enzyme activities NADPH cytochromecreductase, aminopyrine N‐demethylase and aniline hydroxylase, were investigated in two sizes (150 g and 260 g) of mature male rats having free access to food and water for the 23 hours following ethanol administration. Controls received intragastric water and were given free access to food and water (fed controls) or only water (fasted controls). The ethanol group had a significantly lower food intake than the fed control group, and food intake in the large rats was more decreased by ethanol than that of the small rats, corresponding to slower recovery from intoxication. Ethanol and fasting increased aniline hydroxylation and decreased acetone enhancement of aniline hydroxylation to the same degree, whereas only fasting caused a significant decrease in aminopyrine N‐demethylation. Some of the effects of acute ethanol intoxication on hepatic microsomal enzyme activities appear to be mediated via decreased food intake.
Correlations of Alkylating Activity and Mutagenicity in Bacteria of Cytostatic Drugs
Authors: Hemminki Kari , Kallama Seija , Falck Kai
Published: July 2010

Abstract: Alkylating activity of cytostatic drugs was studied in relation to their mutagenicity and toxicity in E. coli WP2 uvrA. Four classes of directly acting cytostatic drugs were studied: nitrogen mustards (nitrogen mustard, melphalan, chlorambucil and phosphoramide mustard, a metabolite of cyclophosphamide), ethyleneimine derivatives (Thio‐TEPA, TEPA and triethylenemelamine), busulfan, and halogenated nitrosoureas. The reference compounds included methyl methanesulfonate, ethyleneimine and methylnitrosourea. Guanosine alkylation was determined by fluorometry. The rate of guanosine and nitrobenzylpyridine alkylation agreed well. Nitrogen mustard derivatives and triethylenemelamine were the most potent alkylating agents among the cytostatic drugs; nitrogen mustard was 5 to 10 times more active than methyl methanesulfonate. Ethyleneimine derivatives, busulfan and the nitrosoureas were relatively weak alkylating agents. Nitrogen mustard and triethylenemelamine were the most potent mutagens to bacteria; they were also among the most toxic drugs studied.
Influence of Anoxia and Dinitrophenol on Ca2+Efflux and PhosphorylaseaActivity in Rabbit Colon Smooth Muscle
Authors: Pettersson Göran
Published: July 2010

Abstract:It was observed in earlier studies that when the phosphorylaseaactivity of rabbit colon smooth muscle was increased by anoxia or 2,4‐dinitrophenol (DNP), the calcium content of the mitochondrial fraction decreased. Despite this, under basal conditions there was no significant increase in the Ca2+content in the fraction consisting of microsomes and cytoplasm. In the present study it was therefore investigated whether mitochondrial Ca2+released by anoxia and DNP is translocated from the smooth muscle cells into the extracellular fluid. The Ca2+efflux from rabbit colon into a Ca2+‐free Krebs‐Ringer bicarbonate buffer was measured by using a Ca2+‐selective electrode. Both anoxia and DNP (6.6 × 10‐5M) increased the Ca2+efflux from the smooth muscle cells. The local anaesthetic D‐mepivacaine, at a concentration of 1×103M, reduced the increase in Ca2+efflux and simultaneously enhanced the anoxic or DNP‐induced rise in phosphorylaseaactivity. The replacement of external Na+by choline was found to reduce the basal Ca2+efflux and to moderately increase the phosphorylaseaactivity. On addition of DNP to the Na+‐free and Ca2+‐free buffer there was no significant change in the Ca2+efflux, but the increase in phosphorylaseaactivity was greater than in the physiological buffer containing 137 mM Na+. These observations support the suggestion that anoxia and DNP, by releasing Ca2+from the mitochondria, increase the phosphorylaseaactivity of smooth muscle.
Metabolism ofI4C‐Codeine in the Isolated, Perfused Rat Liver
Authors: Christensen Chr. Broen , Jansen J. Aas , Ravn‐Jonsen A. , Reiff L.
Published: July 2010

Abstract:The metabolism of14C‐codeine in the isolated rat liver was studied in single‐pass and recirculation perfusion experiments. The perfusate, a semi‐synthetic medium with bovine erythrocytes, was delivered at a constant rate (12 ml/min.) and contained codeine in the range of 3–57 nmol/ml. Samples of perfusate were collected and analyzed for codeine and its metabolites after extraction and thin‐layer chromatographic separation. In single‐pass perfusion, steady state was reached within 20 min. The codeine concentration in the effluent perfusate varied from 17 to 48% of that in the affluent corresponding to extraction ratios of 0.83 to 0.52. There was a significant negative correlation between codeine dose and extraction ratio (r = 0.86, P<0.05, N = 6). The steady state concentration of free and conjugated morphine made a total of 21 to 49% of the molar concentration of codeine at the inflow side. The recovery of radioactivity at the end of the perfusions was on an average 89%. In recirculation perfusion experiments the codeine extraction ratios varied from 0.65 to 0.35. The amount of free morphine in the reservoir increased to a maximum within 25–45 min. Our results suggest a relatively high hepatic first‐pass metabolism of codeine in the rat which is apparently dose‐dependent. The quantitatively most significant metabolites of codeine are morphine and conjugated morphine. The rate and extent of morphine formation is compatible with the hypothesis that metabolically produced morphine may be responsible for the analgesic effect of codeine.