bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Mechanism of Amphetamine Induced Release of Reserpine‐Resistant3H‐Noradrenaline and3H‐α‐Methylnoradrenaline
Authors: Lundborg Per , Waldeck Bertil
Published: July 2010

Mice, pretreated with reserpine and the inhibitor of monoamine oxidase, nialamide, were administered3H‐noradrenaline followed by protriptyline or amphetamine or both. The3H‐noradrenaline that accumulated in the heart was released by amphetamine but not by protriptyline. Protriptyline was able to prevent the release induced by amphetamine when given before but not after this drug. In a parallel study, nialamide was excluded and3H‐noradrenaline was replaced by3H‐α‐methylnoradrenaline. In this experiment too, protriptyline, in spite of having a releasing action of its own, was able to prevent the amine release brought about by amphetamine. A study of the subcellular distribution providing three fractions: coarse, particulate and supernatant, showed that the release of3H‐α‐methylnoradrenaline brought about by protriptyline and amphetamine was primarily from the coarse and supernatant fractions. Guanethidine, given instead of protriptyline, only partly prevented the amphetamine induced release of3H‐α‐methylnoradrenaline; however, the release from the particulate fraction was completely inhibited. It is concluded that amphetamine has to be transported into the adrenergic neuron via the amine transport mechanism of the cell membrane, the so‐called “amine pump”, in order to exert its action.
3,4‐Benzpyrene and N‐Methylaniline Metabolizing Enzymes in the Immature Human Foetus and Placenta*
Authors: Pelkonen Olavi , Arvela Pentti , Kärki Niilo T.
Published: July 2010

The metabolism of 3,4‐benzpyrene (BP) and N‐methylaniline (MA) in several tissues of the immature human foetus and in the human placenta was studiedin vitro.The highest metabolizing activity of both substrates was detected in the liver. Compared to adult rat liver the range of hepatic metabolic activity varied from 5 to 10% for BP hydroxylase and from 5 to even 50% in some foetuses for MA demethylase. Adrenal gland homogenates had measurable BP and MA metabolizing activities. In the gastro‐intestinal tract, brain, kidneys and lungs there was only negligible activity or no activity at all. In one out of five placentas studied, enzyme activity comparable to that in the liver was detected. In foetal liver 12,000 × g supernatants, the Michaelis constants were 2.6 × 10‐5M for BP hydroxylase and 1.2 × 10‐4M for MA demethylase. The cofactor requirements of these enzymes suggested that they are drug metabolizing mixed‐function oxidases. Both enzymes were inhibitedin vitroby other compounds known to be substrates of liver microsomal drug metabolizing enzymes in a concentration range from 0.1 to 20 mM. The level of glucose‐6‐phosphate dehydrogenase activity in the foetal liver was found to be the same or even higher than in the adult rat or human liver.
Inhibition of Choline Acetyltransferase by 2‐Dimethylaminoethyl Chloroacetate and Related Compounds
Authors: Ross S. B. , Florvall L. , Frödén Ö.
Published: July 2010

A number of cyclic quaternary ammonium derivatives structurally related to acetylcholine were tested for their inhibitory effect on choline acetyltransferasein vitro.They had no effect. The alcohol derivatives in this series of compounds were not acetylated by the enzyme. The tertiary amine 2‐dimethylaminoethyl chloroacetate and a few related compounds had inhibitory activityin vitro.2‐Dimethylaminoethyl chloroacetate was the most active of these compounds, being about half as potent as the quaternary derivative choline chloroacetate. It inhibited the enzyme uncompetitively with regard to choline as well as acetyl‐CoA, the Kivalues being 1.2 × 10‐4M (choline) and 4 × 10‐5M (acetyl‐CoA) under the conditions used. 2‐Dimethylaminoethyl chloroacetate and two of the other active compounds had no effect in high doses on the acetylcholine level in the mouse brainin vivo.
Studies on the Mode of Action of Acetaldehyde on the Isolated Guinea‐pig Heart
Authors: Møller Svend E.
Published: July 2010

Acetaldehyde has no positive inotropic or chronotropic effects on hearts from guinea‐pigs pretreated with reserpine. Hearts from reserpine pretreated animals do not respond to acetaldehyde after replenishing with noradrenaline (NA) and thus made sensitive to tyramine. In hearts from reserpine pretreated animals and refilled with NA, acetaldehyde inhibits the response to tyramine in a dose‐dependent manner. The positive inotropic and chronotropic effect of acetaldehyde on normal hearts is potentiated by cocaine. Acetaldehyde by repeated administration provokes tachyphylaxis in hearts of disulfiram pretreated animals but not in normal hearts.
Changes in Rat Atrial Action Potentials Induced by Promazine and Thioridazine
Authors: Landmark Knud
Published: July 2010

The action potentials of electrically stimulated left rat atria were studied in an organ‐bath continuously supplied with a Ringer solution. Action potentials derived from single myocardial cells were displayed on a Tektronix dual‐beam oscilloscope by means of fine glass capillary electrodes and photographed. Promazine 10‐5M and thioridazine 5 × 10‐5M reduced the maximum rate of rise (dv/dt) and the overshoot of the action potential, without significantly altering the resting membrane potential. The drugs also caused a slight reduction in the rate of repolarization. The decrease in the rate of the depolarization due to promazine was minimized when the external potassium concentration was reduced from 5.3 to 1.325 meq./1, a procedure which increased the resting membrane potential. An increase in the potassium concentration from 5.3 to 7.95 meq./1 reduced the resting membrane potential and augmented the effect of the drug on the rate of depolarization. It is suggested that the findings described in this study may explain the phenothiazine induced alterations in electrocardiogram of isolated rat hearts as well as the changes in excitability and refractoriness of isolated rat atria.
Toxicological and Local Anaesthetic Effects of Optically Active Isomers of Two Local Anaesthetic Compounds
Authors: Åberg G.
Published: July 2010

Mepivacaine:There was no difference in toxicity between the two optical isomers of mepivacaine after rapid intravenous injections into mice or rats. After slow intravenous injections or after subcutaneous injections the L(+)– isomer however was less toxic than the D(‐) – isomer. This might at least partly be explained by the results obtained from other experiments, which demonstrated that after slow infusions of the drugs into rabbits more L(+)–mepivacaine than D(‐)–mepivacaine was taken up by the lungs, thus reducing the concentration of the drug reaching the brain, where significantly more D(‐)– mepivacaine than L(+)–mepivacaine was found. A slow absorption of L(+)–mepivacaine in comparison with D(‐)–mepivacaine from the site of injection is demonstrated and might contribute to the differences in subcutaneous toxicity and might also be the cause of the significantly longer duration of infiltration anaesthesia by the L(+)–isomer than by the D(‐)–isomer, since the same nerve‐blocking effect of the isomers was foundin vitro. Bupivacaine:There were significant differences between the toxicity of the bupivacaine isomers when given intravenously and subcutaneously; the D(+)–isomer was more toxic. This as well as the very long duration of infiltration anaesthesia by L(‐)–bupivacaine indicate differences in absorption rates between the bupivacaine isomers similar to those demonstrated for the mepivacaine isomers.
Effect of Noradrenaline and Isoprenaline on the Circular and Longitudinal Muscle of the Oestrogen Dominated Rabbit Uterus
Authors: Nesheim Britt‐Ingjerd
Published: July 2010

Longitudinal and circular muscle strips from the oestrogen dominated rabbit uterus were stimulatedin vitrowith the α‐ and β‐adrenergic stimulating drugs, noradrenaline and isoprenaline. The isometric contractions were recorded. Noradrenaline produced an increase in force and frequency of the contractions. No differences were found between the circular and the longitudinal muscle strips, or between the different parts of the uterus. Isoprenaline produced an inhibition of the spontaneous activity of the muscle strips. There was a difference between the response of the circular and the longitudinal muscle strips. The spontaneous activity of the longitudinal strips could be totally inhibited when isoprenaline was present in the organ bath in the concentration 2 × 10‐7M. The spontaneous activity of the circular strips could only be inhibited by approximately 50%, even with isoprenaline in a concentration of 2 × 10‐6M. Higher concentrations of isoprenaline had a stimulating effect. The ED50 of the circular strips was 60 times the ED50 of the longitudinal strips. No difference was found between the different parts of the uterus. No obvious alteration with regard to the sensitivity to the drugs was observed after cold storage for 24 hours.
The Influence of Some β‐Adrenergic Stimulant Compounds on Intestinal Motilityin Vitroandin Vivoin Mice
Authors: Olsson O. A. Torsten
Published: July 2010

The four β‐adrenergic stimulant agents terbutaline (TRB), orciprenaline (OPR), KWD 2026, and isoprenaline (IPR) were compared for their inhibiting effect on mice ileumin vitroas well as for their inhibiting effect on intestinal propulsion in intact animals. The activity was related to the chemical structure of the compounds. The slightest inhibition was produced by TRB, which has the hydroxy groups in the 3–5 position in the benzene ring and t‐butyl substituted at the nitrogen. The relaxing effect was blocked by alprenolol, indicating involvement of β‐adrenergic receptors.
An Evaluation of the Toxicity of Adrenaline, Isoprenaline, and Terbutaline after Pretreatment with Isoprenaline and Terbutaline
Authors: Olsson O. A. Torsten
Published: July 2010

The toxic effects of adrenaline, isoprenaline, and terbutaline have been determined in mice after pretreatment of the animals with isoprenaline, terbutaline, and saline solution (control). Pretreatment with isoprenaline and terbutaline was without any significant effect on the mortality (LD 50) due to isoprenaline and terbutaline. The sensitivity to adrenaline, however, was considerably increased after pretreatment with isoprenaline but only slightly after terbutaline.
Oxidation and Glucuronidation of Certain Drugs in Various Subcellular Fractions of Rat Liver: Binding of Desmethylimipramine and Hexobarbital to Cytochrome P‐450 and Oxidation and Glucuronidation of Desmethylimipramine, Aminopyrine, p‐Nitrophenol and 1‐Naphthol
Authors: von Bahr Christer , Hietanen Eino , Glaumann Hans
Published: July 2010

The plasma membranes and Golgi apparatus of rat liver were isolated. Total microsomes were sub‐fractionated into rough microsomes, smooth I microsomes and smooth II microsomes. NADPH‐cytochromecreductase activity, cytochromes P‐450 and b5, the oxidation and glucuronidation of certain drugs were determined, and drug induced spectral changes were recorded.2.Oxidation was measured with aminopyrine and desmethylimipramine as substrates. Glucuronidation ofp‐nitrophenol and of 1‐napthol was measured. The “two‐step reaction”, hydroxylation of desmethylimipramine followed by glucuronidation, was also studied.3.Only low activities of drug‐oxidizing enzymes and UDP‐glucuronyl‐transferase were found in the plasma and Golgi membranes.4.Desmethylimipramine and hexobarbital induced the type I spectral change in the microsomal subfractions but not in the plasma and Golgi membranes.5.Hydroxylation of desmethylimipramine occured at higher rates in the smooth‐surfaced membranes than in the rough‐surfaced membranes, whereas demethylation of aminopyrine was considerably lower in the smooth II microsomes than in rough and smooth I microsomes.6. p‐Nitrophenol and 1‐naphthol were glucuronidated to a somewhat higher extent in rough than in smooth I microsomes, but appreciably less in the smooth II membranes. However, incubation of desmethylimipramine in the presence of cofactors required for both hydroxylation and glucuronidation resulted in glucuronide formation to about the same extent in all three microsomal subfractions. ‐ It is suggesteda.that neither plasma membranes nor Golgi membranes play an important role in drug oxidation or glucuronidation reactions;b.that both rough and smooth I microsomes have high drug oxidating and glucuronidating activities, while smooth II microsomes may be preferentially involved in the oxidation and glucuronidation of a limited number of substrates.
Para‐ Aminophenol Metabolism in an Established Cell Line with Liver‐like Functions
Authors: Dybing E. , Rugstad H. E.
Published: July 2010

The clonal MH1C1‐strain of rat hepatoma cells in culture metabolizesp‐aminophenol (PAP), measured both by substrate disappearance and by PAP‐glucuronide formation. PAP‐glucuronide was assayed by spectrophotometric determination of the diazotized product coupled with naphthyl‐ethylenediamine. In addition to glucuronidation, some of the drug is metabolized apparently by other pathway(s). Cultured cloned rat fibroblasts also exhibit PAP‐glucuronidation activity, whereas they do not conjugate bilirubin. Chang cells do not glucuronidate PAP. Flavaspidic acid has no effect on the PAP‐glucuronidation in the liver cells nor in the fibroblasts, in contrast to the inhibitory action seen on bilirubin conjugation by the same liver cells.
Studies on the Control of Glucuronide Synthesis in the Rat Small Intestine
Authors: Hietanen E. , Aitio A. , Hänninen O.
Published: July 2010

Gastrointestinal surgery was used in order to determine the role of normal food components, bile and pancreatic secretion in the control of mucosal glucuronide synthesis. Furthermore a few rats were treated either intragastrically or intraperitoneally with phenobarbitone. Both the rate ofo‐aminophenyl glucuronide synthesis in slices and the activity of UDP glucuronyltransferase in mucosal extracts were studied. In partial jejunectomies no changes were found in glucuronide synthesis when compared with the controls, but in jejunal Thiry‐Vella loops and in duodenal and jejunal blind sacs the glucuronide synthesis rate was significantly lower. In gastro‐jejunostomized rats a transient increase in the glucuronide synthesis rate was noted in the gastro‐jejunostomy area. Phenobarbitone administration did not increase the small intestinal UDP glucuronyltransferase activity when administered either intraperitoneally or intragastrically. The results indicate that the chyme factors are of importance in the control of glucuronide synthesis in the small intestine of the rat, but that phenobarbitone has no effect.
Adenyl Cyclase Activity in Kidneys of Rats with Lithium‐Induced Polyuria
Authors: Geisler Arne , Wraae Olaf , Olesen Ole Vendelin
Published: July 2010

Rats were made polyuric by the addition of lithium chloride to the food. After three weeks, when the polyuria was constant, the renal adenyl cyclase activity was determined and compared with the activity in kidneys of control rats not given lithium. Adenyl cyclase activities were determined as the amount of cyclic AMP‐14C formed from ATP‐14C; cyclic AMP was isolated by the method of Krishna & Birnbaumer (1970). Polyuric rats and control rats did not differ as regards the unstimulated and the fluoride‐stimulated adenyl cyclase activities, but the polyuric rats showed a lower vasopressin‐induced increase (39 per cent) than did the control rats (69 per cent). The lithium concentration in the incubate was below the limit of detection. Our results indicate that inhibition of the vasopressin‐stimulated adenyl cyclase in the kidney is the cause of the vasopressin‐resistant polyuria produced by lithium.
The in Vivo Effect of Tropolone on Dopamine Metabolism and the Catechol‐O‐Methyl Transferase Activity in the Striatum of the Rat
Authors: Broch Ole Jacob
Published: July 2010

The effect of tropolone (100 mg/kg intraperitoneally) on dopamine metabolism in the corpus striatum of rats was studied. The catechol‐O‐methyl transferase (COMT) and monoamine oxidase (MAO) activities were measured as were the concentrations of dopamine (DA) and its metabolites 3‐methoxytyramine (3‐MT), 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The amine synthesis was estimated by measuring the accumulation of radioactive metabolites after a constant rate infusion of14C‐tyrosine in tropolone‐treated and normal rats. In the striatum the tissue concentration of tropolone was reduced by 90% during the first 2.5 hrs period. Tropolone caused a rapid reduction in the methylated metabolites (3‐MT and HVA) while the concentrations of DA and its deaminated metabolite DOPAC were increased. The results from the studies with14C‐tyrosine suggested a reduced DA synthesis rate. All metabolite concentrations returned to normal within 24 hours. After a 20 minutes infusion with14C‐tyrosine a higher radioactivity was found in the fractions of the metabolic end products than in the amine fractions. This finding might indicate an initial turnover of DA in order of minutes and may be a reflection of a multicompartment system for amine storage.
Studies on Mechanical Actions of Mepivacaine (Carbocaine®) and its Optically Active Isomers on Isolated Smooth Muscle: Role of Ca++and Cyclic AMP
Authors: Åberg G. , Andersson R.
Published: July 2010

Abstract:The effects of the local anaesthetic mepivacaine and its optically active isomers on mechanical activity, as well as the uptake and mobilization of Ca++, on phosphorylase and phosphodiesterase activity and on the content of cyclic AMP have been studied in smooth muscle. In low concentrations L(+)‐mepivacaine had a contracting action on the rat portal vein and the guinea pig taenia coli, whereas D(‐)‐mepivacaine had a predominantly relaxing action. The contracting action was probably associated with a mobilization of tissue bound Ca++. In higher concentrations both isomers had a marked relaxing action, the D(‐)‐isomer being the most potent. The relaxation was competitively counteracted by Ca++, Ba++and Sr++, but not by K+, histamine or noradrenaline. The uptake of45Ca++was reduced; D(‐)‐mepivacaine tended to be more potent than L(+)‐mepivacaine. The content of cyclic AMP was increased by DL‐mepivacaine in taenia coli and by L(+)‐mepivacaine, but not by D(‐)‐mepivacaine in the portal vein. During isometric conditions of taenia coli the increased content of cyclic AMP was partly caused by an adrenergic β‐receptor stimulation and partly by a Ca++‐depending reduction of the phosphodiesterase activity.
Infusion of Morphine in Maternal Rats at Near‐Term: Maternal and Foetal Distribution and Effects on Analgesia, Brain DNA, RNA and Protein
Authors: Jóhannesson Torkell , Steele William J. , Becker Bernard A.
Published: July 2010

Abstract:Time‐dated pregnant (day 21–22) Sprague‐Dawley rats were infused intravenously with morphine 5 mg/kg per hr for periods up to 4 hrs. The blood, brain and placenta of maternal rats and the blood and brain of foetuses were collected and analyzed for morphine content. The morphine concentration in the blood of maternal and foetal rats was maximal after infusions for 3 hrs; at the maximum, the maternal concentration was 2800 ng/ml and the foetal concentration was 1900 ng/ml. The morphine levels of the brain were also maximal at 3 hrs. The foetal level, 2200 ng/g, was not significantly (P > 0.05) different from that of foetal blood, whereas the maternal brain level, 600 ng/g, was less than one‐fourth of the maternal blood level. The highest concentration of morphine in the placenta, 6200 ng/g, was also attained after infusion for 3 hrs. These data indicate that the placenta acts as a barrier to the passage of morphine from the maternal animal to the foetus and that a blood brain barrier to morphine exists in the adult but not in the foetal rat. Similar studies showed that an effective blood brain barrier is not present in 20 day old rats. Tolerance to the analgesic effect of morphine, 10 mg/kg subcutaneously, was demonstrated in non‐pregnant adult female rats 2 to 3 days following infusion of morphine, 5 mg/kg per hr for 4 hrs. Reaction times to a nocioceptive stimulus were thus significantly reduced at 1 hr after the test dose (from 19.6 sec. ±2.9 S.E.M. in untreated control animals to 6.8 sec. ±0.4 S.E.M. in the morphine infused animals). The saline infused rats had reaction times after the injection of morphine which did not differ significantly from the untreated control rats. Approximately 20 days after the infusion of morphine to day 21–22 pregnant rats the reaction times to a test dose of morphine were no longer significantly different from those of control rats given the test dose of morphine. The offspring of morphine infused rats were then tested for analgesic response to morphine, 0.45 mg/kg subcutaneously, at approximately 12 days of age and compared with offspring of saline infused rats. The reaction times for offspring of the morphine infused rats 1 hr after the test dose of morphine (26.2 sec. ±1.1 S.E.M.) were significantly greater than those of the offspring of saline infused rats (20.9 sec. ±1.5 S.E.M.). A rapid method for preparing isolated nuclei from adult and foetal rat brain in high yield, using detergent treatment and a onestep centrifugation on a discontinuous sucrose gradient, is described. DNA, RNA and protein content the maternal or the foetal brains, it is still possible that morphine could selectively alter RNA and protein synthesis in the brain without causing a significant change in the overall content of either RNA or protein in acute experiments.
The Effect of Phenobarbital Pretreatment on the Cerium Induced Impairment of Drug Metabolism in Rat
Authors: Arvela Pentti , Kärki Niilo T.
Published: July 2010

Abstract:The effect of phenobarbital pretreatment has been studied on cerium induced impairment of drug metabolism in rat liver. Male rats were divided into four groups: (1) controls, (2) receiving cerium intravenously 2 mg/kg, (3) pretreated with phenobarbital and (4) receiving the same amount of cerium as in group 2 after pretreatment with phenobarbital as in group 3. The pretreatment had a clear protective effect both against the cerium induced impairment of oxidative drug metabolism and the elevation of some enzyme activities. The pretreatment also normalized the decrease in blood glucose and the increase in plasma free fatty acids caused by cerium.
Potassium‐Efflux and the Contractile Response to Sympathomimetic Amines in Circular Rabbit Fundus Muscle
Authors: Haffner J. F. W. , Nesheim B.‐I. , Setekleiv J.
Published: July 2010

Abstract: The mechanical effects and the alterations in 42K‐efflux produced by carbachol, noradrenaline, adrenaline, phenylephrine and isoprenaline have been studied in circular strips from the fundus of rabbit stomachs. Carbachol, noradrenaline, adrenaline and phenylephrine caused sustained contractions of the preparations, and produced a temporary, but statistically significant increase in K‐efflux. A rough correlation was found between the magnitudes of these two effects. Isoprenaline reduced tone in strips which were contracting in response to carbachol, but had no effect on K‐efflux. It is suggested that the increase in tone and K‐efflux produced by noradrenaline, adrenaline, and phenylephrine is due to stimulation of adrenergic α‐receptors. Since the alteration in K‐efflux is only temporary it would appear that K‐efflux is associated with the excitatory processes, but not with those which maintain the contraction.
Noradrenaline Uptake Mechanisms in Human Atrium
Authors: Sachs Charlotte , Jonsson Gösta
Published: July 2010

Abstract:The3H‐amine uptake and accumulationin vitroin human and rat heart tissue was compared. The equilibration and clearance of3H‐sorbitol was the same in both species, indicating similar diffusion conditions in the extracellular space. The uptake of3H‐metaraminol (3H‐MA) in non‐nervous tissue was measured by incubation at 0° or preincubation in desipramine, both procedures known to inhibit effectively the axonal ‘membrane pump’ uptake mechanism. The extraneuronal uptake in man and rat thus measured was similarly low. A high correlation was found between neuronal3H‐MA uptake and endogenous noradrenaline (NA) concentration measured in the same human atria, thus indicating the possibility of quantitatively estimating nerve density by measuring3H‐amine uptake. The neuronal uptake process for3H‐MA in heart tissue from both man and rat was found to obey Michaelis‐Menten kinetics, whereas the affinity for the uptake sites was somewhat higher in the rat. Reserpine caused a reduced accumulation of3H‐NA in both species, which could be counteracted by the monoamine oxidase inhibitor, nialamide. The spontaneous release of3H‐NA previously taken up and accumulated was increased by reserpine in heart tissue of both man and rat. Pre‐incubation in 6‐hydroxydopamine led to a reduced uptake of3H‐MA, which was more pronounced in rat heart slices. The effect of certain drugs, known to affect monoamine uptake‐storage mechanisms, on the3H‐MA uptake in heart slices from man and rat were studied. All the drugs investigated displayed a concentration dependent inhibition of the3H‐MA uptake. The order of inhibition potency was desipramine > protriptyline > imipramine > chlorpromazine > chlorimipramine. All the drugs studied induced a more marked uptake inhibition in human than in rat heart tissue. The adrenergic nerves of human and rat heart thus showed qualitative similarities regarding uptake and storage mechanisms, but some quantitative differences were found, e. g. a higher resistance to the neurotoxic effect of 6‐hydroxydopamine and a more easily blocked ‘membrane pump’ by certain uptake blocking drugs in the human heart. It is suggested that these differences might be due to a less efficient ‘membrane pump’ in human adrenergic nerves.
Opposing Anticholinergic and Cardio‐depressive Effects of Promazine and Thioridazine in Isolated Rat Atria
Authors: Haffner J. F. W. , Landmark K.
Published: July 2010

Abstract:Acetylcholine (ACh) reduced both the rate of contraction and the contractile force in isolated rat atria, but these effects were less pronounced after the preparations had been treated with promazine or thioridazine. The anticholinergic activity of the phenothiazines was counteracted by their direct cardiodepressive effects. In electrically stimulated atria treated with promazine 5 × 10‐6M, the anticholinergic effect was dominant, the reduction in contractile force was less than that produced by ACh when acting alone. In the spontaneously beating atria promazine 5 × 10‐6M produced a depression of frequency which balanced the anticholinergic effect. The reduction in the work index produced by ACh was less in the presence of promazine 5 × 10‐6M because of the anticholinergic effect on the contractile force. The cardiodepressive effects of thioridazine 5 × 10‐6M and promazine 10‐5M and 2.5 × 10‐5M balanced or exceeded the anticholinergic effects; the reductions in cardiac performance were equal to, or greater than those produced by ACh when acting alone. It is suggested that the anticholinergic activity of phenothiazine derivatives is unspecific i.e. not due to receptor blockade, but to general membrane stabilizing effects, which counteract the changes in membrane permeability produced by ACh.
Urinary Metabolites from Rats Given L‐DOPA 1
Authors: Borud O. , Midtvedt T. , Gjessing L. R.
Published: July 2010

Abstract: Urine from germ‐free and normal rats were investigated both before and after oral L‐DOPA administration. Two neutral L‐DOPA metabolites were tentatively identified as (N‐acetyl)‐3‐methoxy‐4‐hydroxyphenylethylamine and 3‐methoxy‐4‐hydroxyphenylethanol. Conjugated dopamine and two other unknown metabolites derived from L‐DOPA were detected in addition to 3‐me‐thoxy‐4‐hydroxyphenylacetic acid, 3,4‐dihydroxyphenylacetic acid, and 3‐methoxy‐4‐hydroxyphenylethylamine. No significant difference in the excretion of urinary DOPA metabolites was observed between germ‐free and normal rats.
The Effect of Chelating Agents on Biliary Excretion of Methyl Mercuric Salts in the Rat
Authors: Norseth Tor
Published: July 2010

Abstract: DL‐penicillamine and dimercaptopropanol (BAL) increase the biliary excretion of mercury after the injection of methyl mercuric chloride. The effect is sex dependent and dependent on the time interval between mercury injection and the treatment. The time dependent effect is related to the excretion of both inorganic mercury and the intact organo‐mercurial. The results indicate that a combined use of chelating agent and the previously described resin which interrupts the enterohepatic circulation should be valuable for the treatment of exposure to organic or inorganic mercury compounds.
Studies on the Relationship between the Analgesic Activity of Salicylic Acid and the Brain Catecholamines in Mice
Authors: Paalzow Lennart
Published: July 2010

Abstract:The catecholamine content in the mouse brain has been investigated after administration of analgesic doses of salicylic acid. Doses of 300 and 450 mg/kg salicylic acid given orally did not produce any significant changes in brain noradrenaline or dopamine levels in comparison with untreated or placebo treated animals. After inhibition of the rate limiting step of the catecholamine synthesis, salicylic acid in a dose of 300 mg/kg administered orally produced significant acceleration in the decrease of brain noradrenaline induced by the synthesis inhibitor. This acceleration was significantly greater in mice showing analgesic activity and in these animals a significant acceleration was also found in brain dopamine. Furthermore, after inhibition of dopamine β‐hydroxylase with disulfiram, salicylic acid produced a significant reduction of the brain noradrenaline in animals showing analgesic activity. No corresponding changes were found in dopamine concentrations. The results obtained are similar to those obtained with morphine and it seems possible that salicylates may exert a part of their central analgesic action by interference with noradrenergic or dopamin‐ergic neurons. The investigations also showed that the analgesic test procedure used and the manner of injection did not seem to evoke any stress in the animals sufficient to produce changes in the turnover rate of brain noradrenaline or dopamine.
The Effects of Caffeine and Theophylline on Nociceptive Stimulation in the Rat
Authors: Paalzow Gudrun , Paalzow Lennart
Published: July 2010

Abstract: Nociceptive stimulation has been performed in rats with a technique which should allow us to study different pain projection levels within the central nervous system. Three different types of thresholds were studied by electrical stimulation and the stimulus responses were qualitatively and quantitatively divided into a) motor response b) vocalisation and c) vocalisation after‐discharge. Caffeine and theophylline were able to decrease the thresholds for motor response and vocalisation in a dose‐dependent manner. Both drugs were also able to reduce the thresholds for vocalisation after‐discharge. However, caffeine reduced this response to about 50‐60% of the normal, but not in a dose‐dependent manner, which is contrary to theophylline which, in a dose of 100 mg/kg, decreased the threshold to as little as 20 per cent of the normal. In general, maximum effects were obtained 30 minutes after administration and theophylline produced more long‐lasting effects than caffeine.
Differing Local Anaesthetic Potency and Toxicity of the Enantiomers of N‐n‐butyl‐3‐piperidyl 2′‐chloro‐6′‐methylcarbanilate: A New Local Anaesthetic
Authors: Åkerman B.
Published: July 2010

Abstract:The R(+)‐form of N‐n‐butyl‐3‐piperidyl 2′‐chloro‐6′‐methylcarbanilate (HS 37) was a more potent local anaesthetic than the S(‐)‐form in various types of major nerve block, in infiltration anaesthesia and after topical application (guinea‐pigs, rabbits). The potency ratio varied with the method of administration and was between 2 and 3 in most of the tests. A similar difference in blocking activity was obtained in rate and equilibrium blocks of conduction in sheathed and de‐sheathed sciatic nerve (frogs). The effect of the racemate (infiltration, frog nerve) was intermediate to that of the enantiomers. The R(+)‐form was more toxic than the S(‐)‐form, both intravenously (mice, rabbits) and sub‐cutaneously (mice). Nerve blocking and toxic potencies of the enantiomers were positively correlated with ratios of about the same order of magnitude. The findings may indicate some stereo‐selectivity of action of the enantiomers in the excitable membranes rather than differences in concentration in the biophase.
The Inhibitory Effect of Diethylaminoethyl Diphenylvalerate (SKF 525‐A) on Glucuronidation by Cultures of Rat Hepatoma Cells
Authors: Dybing E. , Rugstad H. E.
Published: July 2010

Abstract:SKF 525‐A at concentrations from 10−5M to 2 × 10−4M inhibits the glucuronidation ofp‐aminophenol (PAP),p‐nitrophenol (PNP), and bilirubin by a clonal strain of rat hepatoma cells (MH1C1) grown in culture. At higher concentrations of SKF 525‐A the glucuronidation of PAP and PNP in a homogenate system from the cell cultures and normal rat liver is also inhibited, PAP to the greatest extent. The inhibition of PAP glucuronidation in the homogenate system appears to be of the non‐competitive type.
Modification by Methyltyrosine Methylester (H 44/68) of the Amphetamine‐Induced Toxicity and Brain Catecholamine Changes in Developing Mice
Authors: Alhava Eeva
Published: July 2010

Abstract:The effect of methyltyrosine methylester (H 44/68) on the brain levels of noradrenaline (NA) and dopamine (DA) 16 hours after the administration in adult and in developing mice aged 3‐5 days and 13‐15 days was studied. In the youngest mice 250 mg/kg of H 44/68 markedly decreased the brain catechol‐amines (CA), whereas in 13‐15‐day‐old mice even 500 mg/kg of H 44/68 failed to reduce the DA level. After this dose NA was decreased to 25%. In adult brains both doses of H 44/68 caused pronounced reduction of the CA levels, DA decreasing more than NA. High doses of amphetamine (50‐120 mg/kg) given to H 44/68‐pretreated mice were less toxic than without pre‐treatment. Amphetamine generally enhanced the H 44/68‐induced depletion of brain CA, except in the youngest mice, in which amphetamine (120 mg/kg) counteracted the brain DA depletion induced by H 44/68. It is suggested that the varying changes in the CA levels in H 44/68‐treated developing mice might result from differences in the turnover rates of CA during development. Enhancement by amphetamine of H 44/68‐induced reduction in CA reflects the accelerating effect of amphetamine on CA metabolism.
The Effects of Promazine and Thioridazine on the Response to Noradrenaline in Isolated Rat Atria
Authors: Haffner J. F. W.
Published: July 2010

Abstract:The effects of promazine and thioridazine on contractile force and rate, and on the response to noradrenaline (NA) have been studied in isolated spontaneously beating and electrically stimulated rat atria. Promazine 5 × 10−6M increased the contractile force, while promazine 2.5 × 10−5M reduced it. Correspondingly 2.5 × 10−6M promazine increased the rate of contraction, while 10−5M reduced it. Only depressive effects were obtained with thioridazine 2.5 × 10−6M − 2.5 × 10−5M, and these were less marked than those produced by promazine when the highest concentrations were compared. Both drugs enhanced the effect of low concentrations (5 × 10−7M) of NA on the contractile force, and reduced the effects of higher concentrations. (The effects of promazine were statistically significant (P < 0.05), but not those of thioridazine). Promazine had the same effect on the alterations in rate produced by NA. Thioridazine on the other hand, while reducing the response to the highest concentrations of NA, had no enhancing effect on the increase in rate produced by lower concentrations. It is suggested that the enhancing effect of the phenothiazines is due to a reduced uptake of NA in sympathetic nerve endings, while the cardio‐depressive effects are due to the membrane‐stabilizing action on the myocardium.
Mental and Psychomotor Effects of Diazepam and Ethanol
Authors: Haffner J. F. W. , Mørland J. , Setekleiv J. , Strømsæther C. E. , Danielsen A. , Frivik P. T. , Dybing F.
Published: July 2010

Abstract: The performance of eight healthy young males was tested by means of 8 psychological and psychomotor tests 13/4 and 41/2 hrs after the administration of either ethanol, diazepam 10 or 20 mg, or placebo. The mean plasma concentrations of diazepam were estimated to be 230 (10 mg dose) and 495 ng/ml (20 mg) respectively after 13/4 hr and 145 (10 mg), and 310 ng/ml (20 mg) after 41/2 hrs; ethanol was estimated to be 0.091% after 13/4 hr and 0.049% after 41/2 hrs. Diazepam produced stronger subjective sensations of relaxation and reduced concentration than ethanol, whereas the test subjects experienced a similar depressing effect on motivation and effectivity after ethanol and after the largest dose of diazepam (20 mg). Both diazepam and ethanol reduced the scores in the following tests: Memorizing, Sorting (of coloured tablets), Complex Coordination and Critical Flicker Fusion Frequency. The scores in Letter‐Cancellation and Mirror Tracing tests were also reduced by both drugs, but in different ways; ethanol made the test subjects attempt more but increased their number of errors, while diazepam on the other hand slowed the subjects, so that they made fewer mistakes, but attempted less. Diazepam (20 mg) also reduced their time evaluation ability, while ethanol did not affect it significantly. Judged by clinical examination diazepam had a less marked effect on proprioception, speech and balance than ethanol. The effect of diazepam on the Flicker Fusion and Mirror Tracing tests could still be recognized 41/2 hr after administration of the drug.
Anticholinergic and Anti‐arrhythmic Effects of Phenoxybenzamine on the Isolated Rat Atrium
Authors: Landmark Knud , Refsum Helge
Published: July 2010

Abstract:The effect of phenoxybenzamine, an α‐adrenergic receptor blocking agent belonging to the β‐haloalkylamine group of drugs, has been tested on isolated rat atria. Phenoxybenzamine in concentrations ranging from 5 × 10−6M to 5 × 10−5M had positive chronotropic, but negative inotropic effects. At higher dose levels (10−4M and 5 × 10−4M), the rate decreased, whereas the depressing effect on contractile force was almost unchanged. The threshold for electrical stimulation and the effective refractory period were not affected. Phenoxybenzamine 2.5 × 10−5M protected against the changes in the rate and force of atrial contractions caused by acetylcholine 5 × 10−6M. In addition, the changes in the rat electrogram induced by acetylcholine were prevented by the drug. Atrial flutter and fibrillation produced by a standardized combination of electrical stimulation and acetylcholine were converted into sinus rhythm after the addition of phenoxybenzamine 7.5 × 10−5M.
Adenine Toxicity: A Three Week Intravenous Study in Dogs
Authors: Lindblad G. , Jonsson G. , Falk J.
Published: July 2010

Abstract:A prolonged toxicity study was performed in Beagle dogs. The adenine was dissolved by heating in the presence of an equimolar amount of lactic acid, diluted with saline to a 2.5 or 0.5% solution and given intravenously. The dose levels were 10, 20, 35, 85 and 135 mg/kg body weight. The substance was given during three weeks (five or six days a week) and the rate of infusion was either 0.6, 7.5 or 15 g adenine/hour. At dose levels above 10 mg/kg signs of renal impairment of varying degree appeared. All three dogs on 135 mg/kg, two out of three on 85 mg/kg and one out of four on 35 mg/kg died after four infusions. Another dog on 35 mg/kg died after eleven infusions. The values for serum creatinine and blood urea nitrogen were increased. The dogs also showed impairment of urine concentrating ability. In all cases autopsy re vealed evidence of uraemia. Crystals of 2,8‐dihydroxyadenine were found in the kidneys and nephrotic tubular changes were marked. The reversibility of the renal impairment was tested in one surviving dog on 85 mg/kg. The dog recovered clinically but the histological renal alterations seemed to be irreversible. The highest dose which could be considered safe in dogs was 10 mg/kg body weight.
Azaperone and the Hepatic Microsomes : Effects on Cytochrome P‐450 Concentration and on NADPH‐Cytochrome c‐Reductase Activity
Authors: Pekkanen Tho J. , Salminen Kalevi
Published: July 2010

Abstract:Twelve male mice weighing about 16 g were given 4 mg/kg azaperone subcutaneously in 0.5 ml of water. Twelve similar mice which were given 0.5 ml of water subcutaneously at the same time were kept as controls. After 7 days all the mice were sacrificed and the total protein content, the microsomal protein content, the microsomal cytochrome P‐450 concentration and the microsomal NADPH‐cytochrome c‐reductase activity of the livers was determined. In the azaperone‐treated group the mean microsomal cytochrome P‐450 concentration of the livers was significantly increased but the mean microsomal NADPH‐cytochrome c‐reductase activity of the livers was significantly decreased as compared to the controls.
Inductive Effects of Methyl Mercury on the Hepatic Microsomes of Mice
Authors: Pekkanen Timo J. , Salminen Kalevi
Published: July 2010

Abstract:36 male NMRI mice weighing about 17 g each were divided into groups of 12 animals. Groups 1 and 2 were treated once intraperitoneally with methyl mercury nitrate. Group 1 received 0.3 mg Hg/kg and group 2 10 mg Hg/kg in 0.5 ml water; the third group, which was kept as control, was treated intraperitoneally with 0.5 ml water. After 7 days all the mice were sacrificed. The mean total liver protein was found to be significantly decreased in group 2. The mean liver microsomal protein was significantly (P < 0.01) increased in groups 1 (P < 0.01) and 2 (P < 0.02) as compared to the controls. The mean cytochrome P‐450 concentration of the liver microsomes was also significantly increased in groups I (P < 0.001) and 2 (P < 0.01) as compared to the controls and in group 1 (P < 0.01) as compared to group 2. The mean liver microsomal NADPH‐cytochrome c‐reductase activity was significantly greater in group 2 (P < 0.001) and in group 1 (P < 0.01) than in the controls. The mean NADPH‐cytochrome c‐reductase activity of group 2 was also significantly greater than the mean activity in group 1 (P < 0.02).
Effect of Acetylcholine on Isolated Cat and Rabbit Heart Ventricle Preparation
Authors: Anderson P. , Person H.
Published: July 2010

Abstract:The atria and the upper part of the intra‐ventricular septum were removed from rabbit and cat heart, and the ventricular preparations were perfusedin vitrowith Krebs's solution. Preparations from twenty cats and 15 rabbits were studied for their sensitivity to acetylcholine. In the isolated rabbit ventricular preparations, acetylcholine in doses of 0.01‐0.1 pg caused a very weak negative inotropic and a chronotropic effect. Higher doses caused a dose‐dependent standstill. The cat ventricle preparations were rather insensitive to acetylcholine. When studied against noradrenaline induced increases in heart rate and force of contraction, acetylcholine in these preparations, also, caused a negative inotropic and chronotropic effect. In both the cat and rabbit preparations, the effect of acetylcholine was blocked by atropine 0.1 μg/ml in the perfusing solution. After pretreatment with atropine, acetylcholine (50‐100 μg) caused a positive inotropic and chronotropic effect that was blocked with propranolol 0.1‐0.2 μg/ml. This effect of acetylcholine was not obtained in preparations from reserpine treated animals.

It was concluded that the cat and rabbit ventricle myocardium contains receptors to acetylcholine, and that stimulation of these cause a negative inotropic and chronotropic effect. Moreover, acetylcholine may release noradrenaline from the adrenergic nerve fibres. The difference in sensitivity to acetylcholine between the two species may indicate a difference in the significance of parasympathetic nerve stimulation to the ventricular myocardium in the two species.
Protein Binding of Drugs in Plasma from Patients with Acute Renal Failure
Authors: Andreasen Frederik
Published: July 2010

Abstract:It was found byin vitroexperiments that the protein binding of acetylsalicylic acid, salicylic acid, phenylbutazone, diphenylhydantoin, sulphadiazine and thiopental was decreased in the plasma of 10 surgical patients with acute renal failure. The plasma was taken 4 to 8 days after the onset of the renal failure. At a drug concentration of 400 μg/ml the decreases ranged from 21.8 to 60.3 % as compared with a normal control group. At drug concentrations in or near the normal therapeutic level, the protein binding was even more decreased for the salicylic acids and sulphadiazine but less decreased for diphenylhydantoin and thiopental. The decreased binding could only partly be explained by the lower concentration of albumin in the patients: 3.0 g/100 ml ± 0.48 (S.D.) compared to 4.1 g/100 ml ± 0.53 (S.D.) (P < 0.01).
Cortisol Distribution in Rheumatoid Arthritis During Treatment with Gold
Authors: Kirchheiner B. , Jansen J. Aas , Hvidberg E. , Jensen E. M. , Scbou J.
Published: July 2010

Abstract: Twentyfour patients with rheumatoid arthritis (A.R.A. criteria) were examined before and after a period of gold treatment (10–33 weeks). The Rheumatoid Activity Index (according to Lansbury 1958) decreased significantly (mean ± S. D.: −33.2 ± 26, P < 0.01) as did the tissue concentration of cortisol (skin biopsies at 8 a. m.). The values decreased on an average from 51 ng/g to 20 ng/g, the mean decrease ± S. D. being 33 ng/l ±55 (P < 0.02). However, no significant correlation could be demonstrated between the fall in the Activity Index and the decrease in tissue cortisol. No consistent changes were found in the plasma cortisol (total or ultra‐filtrate). Similar to other non‐steroid anti‐inflammatory drugs, gold appears to exert a “non‐specific” influence on the distribution of endogenous cortisol.
Effects of Membrane Stabilizers on Glucuronidation and Amino Acid Transport in Cultures of Rat Hepatoma Cells
Authors: Dybing Erik
Published: July 2010

Abstract: Promazine and imipramine in concentrations between 0.005 mM and 0.20 mM, and thioridazine between 0.005 mM and 0.10 mM inhibit p‐amino‐phenol glucuronidation in rat hepatoma cell cultures. The cardiac stabilizers propranolol and quinidine have little or no effect on glucuronidation. In a homogenate system prepared from the cells promazine, thioridazine, and imipramine between 0.1 and 1.0 mM also inhibit p‐arninophenol glucuronidation. In addition, promazine, thioridazine, and imipramine inhibit alanine uptake/incorporation, α‐aminoisobutyric acid uptake and efflux in the cultures of hepatoma cells.
The Metabolism of Selenite in Cow Blood in Vitro
Authors: Sandholm Markus
Published: July 2010

Abstract: The transfer of selenite via the erythrocytes to the plasma was investigated using Se 75‐bodium selenite and cow blood. The selenite was initially fluxed into the erythrocytes by a cyanide sensitive mechanism. During the uptake period (within 1 min.) the erythrocytes consumed oxygen and it can be concluded that selenium is reduced and catalyzes the electron flow to the oxygen. The lack of electrons thus produced is balanced by the oxygenation of GSH. The release is dependent on GSH and it is possible that selenium is ejected from the erythrocytes as a glutathione complex which is fixed to the SH of plasma albumin.
Competitive Antagonism Between Phenoxybenzamine and Acetylcholine in Isolated Rat Atria
Authors: Refsum Helge , Landmark Knud
Published: July 2010

Abstract:In isolated rat atria kept at 32°, phenoxybenzamine 10−6M and 2.5 × 10−6M added 5 min. before acetylcholine (ACh), caused an almost parallel shift to the right and no fall in the maximum response in the log. dose‐response curves for ACh. In the present experiments, these results are indicative of a reversible antagonism between phenoxybenzamine and ACh.