bluuebunny/crossref_metadata_2025 huggingface dataset:
Actions of Three Local Anaesthetics: Lidocaine, Bupivacaine and Ropivacaine on Guinea Pig Papillary Muscle Sodium Channels (V̇max)
Authors: Arlock Per
Published: March 2009

Abstract:The new local anaesthetic ropivacaine (LEA 103) like lidocaine and bupivacaine used as references, blocked cardiac sodium channels in a use‐dependent fashion. At equimolar concentrations lidocaine had the lowest efficacy and bupivacaine the highest. The action potential was shortened and the plateau was depressed at high concentrations of each drug. Pacing a papillary muscle at 3.3 Hz in the presence of all three drugs resulted in a marked use‐dependent accumulation of block (P < 0.01). The accumulated block slowly dissipated after rest. At −90 mV holding (= resting) potential, and at a concentration of 10 μM, the time constant for recovery from block was 186 msec. in lidocaine (n = 4), 1.4 sec. in ropivacaine (n = 7), and 2.1 sec. in bupivacaine (n = 7). Lidocaine decreased V̇maxprogressively at high rates of stimulation, but not significantly at rates below 2 Hz. Ropivacaine progressively decreased V̇maxsignificantly at rates above 1 Hz, but to a lesser degree than bupivacaine. The use‐dependent action of the drugs was increased at more depolarized (less negative) holding potentials, whereas at more hyperpolarized potentials the block was diminished. Lidocaine and ropivacaine could be readily dissociated from the receptors at more hyperpolarized membrane potentials (−100 to −120 mV), whereas bupivacaine bound much harder. All three drugs blocked sodium channels more effectively after a long single conditioning pulse. Bupivacaine had the most prominent effect, and lidocaine was least effective. Bupivacaine and ropivacaine seem to interact with the inactivated state of the sodium channels, whereas lidocaine acted on both the open and on the inactivated state of the channels. The peak force of contraction was only moderately diminished after treatment with ropivacaine, whereas bupivacaine, even at 1 Hz, had a pronounced depressant action. Lidocaine at 10 μM had almost no effect on depolarization induced automaticity (DIA), whereas ropivacaine at 10 μM had a small depressant effect. Bupivacaine dampened the automaticity as well as peak force at 5 μM. At 10 μM no DIA could be initiated in the presence of bupivacaine.
Bepridil, Myocardial Accumulation Kinetics and Dynamic Effects in the Isolated Rabbit Heart
Authors: Nielsen‐Kudsk Folmer , Askholt Jan , Jakobsen Preben
Published: March 2009

Abstract:Both myocardial uptake and disposition of bepridil in the isolated rabbit heart showed two‐compartment characteristics which possibly reflects the existance of superficial and deep binding sites. Terminal accumulation and disposition half‐lives were 218 and 196 min., respectively. The half‐times of the initial distributory processes were about 33 min. At a drug concentration in the perfusion liquid of 0.54 μg ml−1(1.27 μM) the average concentration of bepridil in the myocardium at steady state was about 489 μg g−1(1161 μM) with 43% referable to the deepest, presumably intracellular compartment. Increasing bepridil concentrations from 3 to 2333 ng ml−1(7–5542 nM) in the perfusion liquid caused a terminal decrease in coronary flowrate to 58% of the mean control flowrate. Amplitude and velocity of myocardial contraction both decreased in a biphasic way to about 28.6 and 13.6%, respectively. Apparent dynamic steady states developed within about 20 min. Inhibitory Em‐values related to the first phase were 39.8 and 53.2%, and to the second phase 97.7 and 98.5%, respectively. Heart beating frequency also decreased biphasically to 53.9% and showed inhibitory Em‐values of 17.2 and 47.5% related to the two phases. Myocardial oxygen consumption decreased to 55.6%. The electrocardiographic PQ‐ and QRS‐ intervals increased to 147 and 133%, respectively. The frequency‐corrected QT‐interval also increased significantly from 100 to 123%. Our findings demonstrate a slow and very pronounced accumulation of bepridil in the rabbit heart. Biphasic and very marked negative inotropic and chronotropic effects and a less than proportional decrease in oxygen consumption developed much faster. Mean coronary flow‐rate decreased progressively, and only in selected hearts with a low control flow‐rate an initial increase was observed.
Convulsions and Cerebral Inositol‐1‐Phosphate Levels in Rats Treated with Diisopropyl Fluorophosphate
Authors: Savolainen Kai M. , Terry John B. , Nelson Stan R. , Samson Fred E. , Pazdernik Thomas L.
Published: March 2009

Abstract: In order to examine the relationship of organophosphate‐induced cholinergic stimulation to phosphoinositide (PI) hydrolysis in the brain, diisopropyl fluorophosphate (DFP; 1.3 or 1.5 mg/kg subcutaneously) was given to rats pretreated with saline or LiCl (5 meq/kg subcutaneously). Behaviour was monitored 60 min. after the administration of DFP, and inositol‐1‐phosphate (IP1), an intermediate in PI metabolism, was measured in the brain DFP alone caused tremors, whereas with LiCl pretreatment, DFP caused tremors and tonic‐clonic convulsions. DFP alone did not increase IP1 above control levels. LiCl alone elevated IP1 2–5 fold but did not alter rat behavior. With LiCl pretreatment, DFP caused IP1 to increase 2–4 fold above LiCl control values in convulsing rats. LiCl increased the potential of DFP to induce convulsions and greatly amplified IP1 elevations induced by DFP.
Anaesthetic Properties of Pregnanolone in Mice in an Emulsion Preparation for Intravenous Administration: A Comparison with Thiopentone
Authors: Larsson‐Backström C. , Lustig L. Lutteman , Eklund A. , Thorstensson M.
Published: March 2009

Abstract:The anaesthetic properties of pregnanolone emulsion, which is a new pharmaceutically and clinically acceptable preparation of pregnanolone, have been evaluated and compared with those of thiopentone in the mouse. “Loss of the righting reflex” for 15 sec. was used as a criterion for the anaesthetic effect. The range for the optimal infusion rate to reach the threshold anaesthetic dose was 0.25–1.0 mg/kg/min. for pregnanolone and 10–40 mg/kg/min. for thiopentone. Potency, measured at the optimal infusion rate as the mean anaesthetic dose, AD50, or as the threshold anaesthetic dose, was about six times higher for pregnanolone than for thiopentone. The induction of anaesthesia, which ensured directly after a complete dose was given, and the duration of anaesthesia were similar for pregnanolone and thiopentone in equipotent doses. The approximate therapeutic index for pregnanolone was about four times higher than that for thiopentone. The range for the time of anaesthesia was about 150 min. for pregnanolone emulsion but only about 50 min. for thiopentone. Recovery of the mice from anaesthesia occurred within minutes after pregnanolone, whereas it took hours following thiopentone. In conclusion, these results show that the advantage of pregnanolone emulsion over thiopentone include a higher therapeutic index, a wider range for the duration of anaesthesia and a shorter recovery period.
Age‐Related Changes in Rat Serotonergic and Adrenergic Systems and in Receptor Responsiveness to Subchronic Desipramine Treatment
Authors: Brunello N. , Riva M. , Rovescalli A. C. , Galimberti R. , Racagni G.
Published: March 2009

Abstract:Noradrenergic (NA) and serotonergic (5‐HT) receptor profiles were compared in the cerebral cortex of young adult (3 months old) and aged (24 months old) male Sprague Dawley rats. β and α‐1 receptors were significantly decreased in 24 month old rats, whereas α‐2 receptors remained unchanged. 5‐HT‐2 Postsynaptic receptors and 5‐HT high affinity uptake were reduced in aged animals; on the other hand the number of3H‐imipramine (3H‐IMI) recognition sites located on serotonin nerve terminals and labelled also by3H‐paroxetine (3H‐PAR), were significantly higher in the cerebral cortex of old rats. The ratio 5‐hydroxyindoleacetic acid (5‐HIAA)/5‐HT, an index of serotonin turn‐over, increased in some brain areas of senescent rats. There were no age‐related changes in the responsiveness of investigated binding sites to subchronic desipramine treatment; the density of β‐noradrenergic and 5‐HT‐2 serotonergic receptors and that of3H‐IMI binding sites was reduced both in young adult and aged rats.
The Effects of H1‐ and H2‐Receptor Blocking Agents on Postsynaptic Potentials Recorded from the Bull‐frog Sympathetic Ganglion
Authors: Tasaka Kenji , Takaoka Masanori , Kamei Chiaki
Published: March 2009

Abstract:The effects of H1‐blockers (pyrilamine, diphenhydramine and promethazine) and H2‐blockers (cimetidine, ranitidine) on the postsynaptic potentials of the bull‐frog sympathetic ganglion were studied by means of the sucrose gap method. All the H1‐blockers tested, at concentrations of 10−6‐10−4M, depressed the amplitudes of both action and slow postsynaptic potentials in positive and negative directions in a concentration‐dependent manner; these drugs had more potent inhibitory effects on postsynaptic potentials. In the case of H2‐blockers, action and postsynaptic potentials were slightly depressed as perfusion continued at 10−4M. From the present experiments, it was concluded that H1‐blockers directly inhibit postsynaptic potentials of the sympathetic ganglions, and that this inhibition may be responsible for various autonomic disturbances attributed to H1‐blockers.
Stimulatory Effect of Prostaglandin F2α on Gastric Acid Secretion in Rats
Authors: Jaatinen Tiina , Puurunen Juhani , Karppanen Heikki
Published: March 2009

Abstract: The effect of intravenously administered prostaglandin F2α on gastric acid secretion was investigated in anaesthetized rats. Doses of 0.03–0.3 mg/kg PGF2α stimulated gastric acid output in rats with intact vagi, whereas an inhibitory effect was observed in vagotomized animals. Treatment with 5 mg/kg of Na‐meclofenamate intravenously attenuated the secretory response to PGF2α, while 10 mg/kg of indomethacin intravenously and 3 mg/kg of 8‐phenyltheophylline intraperitonelly were without any effect. The results indicate that intravenously administered PGF2α stimulates gastric acid secretion in anaesthetized rats via activation of the vagus nerve. The effects of Na‐meclofenamate and indomethacin suggest that PGF2α may exert its secretagogue action via specific receptors. The lack of the effect of 8‐phenyltheophylline indicates that adenosine which reportedly had a similar effect on gastric secretion after intravenous injection seems not to be involved here.
Interaction between Bambuterol and Physostigmine: Aspects on Cholinesterase Inhibition and Neuromuscular Transmission in the Smooth and Skeletal Muscles of the Guinea‐Pig
Authors: Jeppsson A.‐B. , Waldeck B.
Published: March 2009

Abstract:Bambuterol, the bis‐dimethyl carbamate prodrug of terbutaline, and physostigmine were examined with respect to their ability to interfere with the neuromuscular transmission in an isolated vagus nerve‐trachea preparation, a phrenic nerve‐diaphragm preparation and the transmurally stimulated extensor digotorum longus (EDL) isolated from the guinea‐pig. Physostigmine increased the contractile response of the trachea to stimulation of the vagus nerve. Bambuterol had an opposite effect in this respect and inhibited the effect of physostigmine. Both compounds, in high concentrations, increased the tension of the unstimulated tracheal smooth muscle. Physostigmine, but not bambuterol, caused a threefold increase in the twitch tension of the indirectly stimulated diaphragm. Bambuterol counteracted this increase almost completely. In the EDL, physostigmine caused a concentration‐dependent and curare‐sensitive increase in the force of both twitches and subtetanic contractions. This increase was completely inhibited by bambuterol which had no effectper seon the contractions. Both enantiomers of bambuterol appeared to be equally potent in counteracting the effect of physostigmine on the EDL. It is concluded that bambuterol, in concentrations which selectively and completely block the butyrylcholinesterase, has no effect on the neuromuscular transmission. In higher concentrations, at which bambuterol might interfere with acetylcholinesterase, it counteracts the effects of the unselective inhibitor of cholinesterases, physostigmine.
Effects of 5‐Chloro‐7‐iodo‐8‐hydroxyquinoline (Clioquinol) and Nerve Growth Factor on DNA, RNA and Protein Syntheses in Neonatal Rat Superior Cervical Ganglia
Authors: Hori Shinichiro , Kayanuma Katsuhiko , Ohtani Sachiko , Sugiura Hiroko , Kotaki Hajime , Tsubaki Tadao
Published: March 2009

Abstract: To investigate molecular mechanisms involved in the neurotoxicity of clioquinol (5‐chloro‐7‐iodo‐8‐hydroxyquinoline), the inhibitory effects of this drug on DNA, RNA and protein syntheses were examined, in relation to the action of nerve growth factor (2.5S NGF). We used an organ culture of neonatal rat superior cervical ganglion (SCG). Ten μM clioquinol inhibited completely DNA and protein syntheses and abolished the stimulatory effect of NGF on RNA synthesis. With regard to the chemical structure of clioquinol, hydroxylation at the 8th carbon of quinoline is essential for the inhibition of DNA, RNA and protein syntheses, and the hydrophobicity of the 8‐HQ derivatives is a required property for potent inhibition. Compared with effects of EDTA, alizarine, sodium alizarine sulfate, o‐phenanthroline and α,α′‐dipyridyl, the loss of the NGF‐induced stimulation of RNA synthesis by clioquinol does not seem to be primarily caused by its metal‐chelating property. Clioquinol did not significantly alter the uptake rate of thymidine, uridine and leucine, thereby suggesting that the primary action of clioquinol on inhibition of DNA, RNA and protein syntheses does not relate to uptake of the precursor into SCG. Clioquinol did not significantly alter the degradation of 3H‐uridine‐labeled RNA. NGF suppressed the degradation of RNA and this suppression was overcome by clioquinol. The release of free uridine from SCG into the culture medium was enhanced by clioquinol and was partially suppressed by NGF. The inhibitory effects of clioquinol were completely prevented by bovine serum albumin (BSA), but not by NGF even at a 5‐fold concentration of clioquinol. Clioquinol also inhibited the synthesis of RNA, stimulated by pretreatment of SCG with NGF. These results suggest that the inhibitory effects of clioquinol on RNA synthesis stimulated by NGF and on the suppressed RNA‐degradation by NGF are due to actions on the intracellular processes of RNA synthesis and degradation rather than to interference at the receptor site of NGF or to the inactivation of NGF.
Screening of Pharmacological Agents Given Peripherally with Respect to TCDD‐Induced Wasting Syndrome in Long‐Evans Rats *
Authors: Pohjanvirta Raimo , Tuomisto Jouko , Vikkula Kaarina
Published: March 2009

Abstract:A salient sign of fatal 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) intoxication is dramatic body weight loss accompanied by hypophagia. Yet, the nature of this wasting syndrome is unknown. As all of the current leptogenic (weight reducing) drugs exert their action by affecting aminergic neurotransmission, this study set out to screen the reversibility of TCDD‐induced anorexia with the following agents modulating aminergic neurotransmission: amphetamine, amperozide, chlordiazepoxide, clonidine, haloperidol, morphine, PCPA, phenoxybenzamine, reserpine and sotalol. In addition, dexamethasone, indomethacin, and insulin were included in the drug battery. The agents were administered subcutaneously to adult male Long‐Evans rats over a period lasting from 3 to 14 days. Half of each drug group was concomitantly exposed to a lethal dose of TCDD (20 μg/kg). None of the regimens were able to mitigate the wasting syndrome. TCDD proved to markedly diminish the nocturnal feed intake while practically sparing daytime feed consumption. Insulin increased the daytime feeding of TCDD‐exposed rats, and the termination of treatment resulted in almost total aphagia in this group. Amphetamine, dexamethasone, PCPA, and reserpine caused weight loss in drug control rats and aggravated the action of TCDD. However, clonidine had no effect on the weight of control rats but accelerated weight decline in TCDD‐cotreated animals. TCDD seemed to have a somewhat minor influence on drinking than on feeding. Clonidine stimulated water intake in controls but not in TCDD‐exposed rats. These results suggest that aminergic neurotransmission is not specifically or crucially affected by TCDD, but further studies are needed to confirm this conclusion.
Effects of Triethyl Lead Chloride on Oestradiol Metabolism in the Female Rat Liver Microsomal Fraction
Authors: Odenbro Agneta , Rafter Joseph
Published: March 2009

Abstract:Triethyl lead chloride (TEL) was added directly to female rat liver microsomal fractions at final concentrations of 0.0, 0.005, 0.05 and 0.5 mM, respectively. The effect of oestradiol on liver microsomal metabolism was studiedin vitroby incubating the microsomes with radioactive oestradiol‐17β. The oestradiol metabolites were separated, identified and quantified. The highest treatment concentrations resulted in decreased activities of enzymes that metabolize oestradiol‐17β.
Perinatal Growth Retardation Caused by Triethyl Lead Chloride Treatment of Mice during Late Gestation
Authors: Odenbro Agneta , Kihlström Ingemar , Kihlström Jan Erik
Published: March 2009

Abstract: Female mice were injected intraperitoneally daily from day 18 of gestation and throughout lactation with triethyl lead chloride (TEL; 0.0, 0.5 and 1.0 mg/kg body wt). Off‐spring of treated mothers displayed a slight perinatal growth retardation. Male off‐spring appeared to be more sensitive to TEL, as indicated by their lower body weights. During the latter half of the lactation period the treated sucklings grew faster than controls, thereby compensating for their initially retarded growth, by the time of weaning. The hepatic cytochrome P‐450 content of 9 to 10‐day old sucklings of treated mothers was lower than in corresponding controls. We suggest that perinatal growth retardation is initiated by a disturbance in the uterus, e.g. reduced nutrient transport across the placenta.
Effects of Disulfiram, Cyanamide and 1‐Aminocyclopropanol on the Aldehyde Dehydrogenase Activity in Human Erythrocytes and Leukocytes
Authors: Helander Anders , Tottmar Olof
Published: March 2009

Abstract:The effects of the aldehyde dehydrogenase (ALDH; EC 1.2.1.3) inhibitors disulfiram, cyanamide and 1‐aminocyclopropanol (ACP) on the ALDH activities in human erythrocytes and leukocytes were studied. Assays were performed by incubating intact or sonicated blood cells in the presence of different concentrations of the inhibitors, using 3,4‐dihydroxyphenylacetaldehyde, the aldehyde derived from dopamine oxidation, as the substrate. The amount of acid metabolite formed was measured using high‐performance liquid chromatography with electrochemical detection. The erythrocyte ALDH was extremely sensitive to disulfiram, and only about 0.5 μM was needed to cause a 50% inhibition of the activity. The leukocyte activity was less sensitive, and showed a similar degree of inhibition at an 100‐fold higher concentration of disulfiram. Cyanamide and ACP were both potent inactivators of the leukocyte ALDH activity, giving a 50% inhibition at concentrations of 10 and 50 μM, respectively, whereas the erythrocyte activity was much less affected. Diethyldithiocarbamate, the reduced metabolite of disulfiram, and coprine, from which ACP is derived, were much less effective inhibitors of the erythrocyte and leukocyte ALDH activities than were disulfiram and ACP.
In Vitro Oxidation of Mercury by the Blood
Authors: Hursh J. B. , Sichak S. P. , Clarkson T. W.
Published: March 2009

Abstract: A method is described for studying the in vitro oxidation of mercury vapour by red blood cells at short times and with diminishing mercury vapour concentrations. It is found that for 40% red blood cell suspensions and 37° at concentrations greater than about 6 ng mercury vapour/ml, the oxidation rate is zero order, and that at lower concentrations the rate changes to first order. The effect of temperature and of added hydrogen peroxide are studied. Results are considered in terms of the generally aceepted belief that the catalase‐compound I system is the main path of oxidation. If the results obtained in vitro in these experiments apply in vivo to man, it follows that inhaled mercury is carried in the blood to the brain and other organs primarily as dissolved vapour rather than as inorganic mercury ions.
Antagonistic Properties of RU 24969, a Preferential 5‐HT1Receptor Agonist, at Presynaptic α2‐Adrenoceptors of Central and Peripheral Neurones
Authors: Schlicker E. , Molderings G. , Betz R. , Göthert M.
Published: March 2009

Abstract:The effect of RU 24969 (5‐methoxy‐3(1,2,3,6‐tetrahydropyridin‐4‐yl)‐1H‐indole) on the electrically evoked3H overflow was studied in superfused rat brain cortex slices preincubated with3H‐noradrenaline or3H‐serotonin and in superfused segments of the rat vena cava preincubated with3H‐noradrenaline. In cortex slices preincubated with3H‐noradrenaline, RU 24969 facilitated the electrically (3 Hz) evoked3H overflow. This effect was abolished by phentolamine but was not affected by desipramine or the 5‐HT3receptor antagonist ICS 205–930. The concentration‐response curve of noradrenaline for its inhibitory effect on the evoked overflow (determined in the presence of desipramine) was shifted to the right by RU 24969 32 and 100 μmol/1. In this respect, RU 24969 was about 500 times less potent than phentolamine. In cortex slices preincubated with3H‐serotonin, the inhibitory effect of 3.2 μmol/1 RU 24969 on the electrically evoked3H overflow was increased by phentolamine. In segments of the vena cava, RU 24969 inhibited the electrically (0.66 Hz) evoked3H overflow. The concentration‐response curve of RU 24969 was U‐shaped, since at concentrations higher than 0.1 μmol/1 the extent of inhibition decreased with increasing concentrations of RU 24969. In the presence of phentolamine, the concentration‐dependent attenuation of the RU 24969‐induced inhibition of overflow was no longer detectable. The present results suggest that RU 24969 is a weak antagonist at presynaptic α2‐adrenoceptors (by more than 2.5 log units less potent than as an agonist at presynaptic 5‐HT1Bauto‐ and heteroreceptors).
Frequency‐Dependence of3H‐Noradrenaline Release from Rabbit Pulmonary Artery: Effect of α‐Adrenoceptor Antagonists and Inhibitors of Transmitter Inactivation
Authors: Nedergaard Ove A.
Published: March 2009

Abstract:The aim of this study was to examine the modulating role of presynaptic α2‐adrenoceptors on transmitter release from vascular sympathetic neurones. This was done by examining the influence of removal of inactivation pathways on the effect of α‐adrenoceptor antagonists on the release of transmitter from noradrenergic neurones. The rabbit main pulmonary artery preloaded with3H‐noradrenaline (3H‐NA) was used. The artery was stimulated with 300 pulses at various frequencies (1, 3, 10 and 30 Hz). Pargyline (3 × 10−4M) increased the stimulation‐evoked3H‐overflow at 1 and 3 Hz and decreased it at 30 Hz. U‐0521 (3′,4′‐dihydroxy‐2‐methylpropiophenone; 3 × 10−6M) enhanced the overflow at 1 Hz and had no effect at 3–30 Hz. Corticosterone (4 × 10−5M) did not alter the stimulation‐evoked3H‐overflow at 1–30 Hz. Cocaine (3 × 10−6M) enhanced the3H‐overflow slightly at 1–30 Hz. At 3 × 10−5M, cocaine enhanced3H‐overflow at 1 Hz and reduced it at 30 Hz. Neither corticosterone (4 × 10−5M) nor propranolol (10−7M) modified this effect of cocaine. Propranolol (10−7M) alone decreased the3H‐overflow at 30 Hz and had no effect at 1–10 Hz. Phenoxybenzamine (10−6M) and chlorpromazine (3 × 10−6M) potentiated the stimulation‐evoked3H‐overflow at 1–30 Hz. Phentolamine (10−6M) decreased the3H‐overflow at 1 Hz and enhanced it at 3–30 Hz. Rauwolscine (10−6M) enhanced the stimulation‐evoked3H‐overflow maximally at 10 Hz and had no effect at 1 and 30 Hz. Cocaine (3 × 10−5M), cocaine (3 × 10−5M) + corticosterone (4 × 10−5M), pargyline (3 × 10−4M) and U‐0521 (3 × 10−6M), but not corticosterone (4 × 10−5M), increased the rauwolscine‐induced enhancement at 1 and 3 Hz, but had no influence at 10 and 30 Hz. It is concluded that at a low frequency (1 Hz) of nerve stimulation, inhibition of either neuronal uptake, extraneuronal uptake, monoamine oxidase (MAO) or catechol‐O‐methyltransferase (COMT) causes an enhancement in transmitter overflow that is due to removal of inactivation pathways. The enhancement is not mediated via facilitatory β‐adrenoceptors. At higher frequencies (3–30 Hz) inhibition of either neuronal uptake or MAO causes a sufficient amount of transmitter in the neuromuscular gap to activate the presynaptic α‐adrenoceptor mediated negative feed‐back system causing a decrease in transmitter release. α‐ Adrenoceptor antagonists enhance the stimulation‐evoked release of3H‐NA only when the junctional gap concentration of transmitter is sufficient to trigger the presynaptic α‐adrenoceptor auto‐inhibitory system.
Effects of TCDD and its Congeners 3,3′,4,4′‐Tetraehloroazoxybenzene and 3,3′,4,4′‐Tetrachlorobiphenyl on Lymphoid Development in the Thymus of Avian Embryos
Authors: Nikolaidis Efstathios , Brunström Björn , Dencker Lennart
Published: March 2009

Abstract:Thymus anlagen from 11‐day‐old chick and 14‐day‐old turkey and duck embryos were cultured in media containing 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin (TCDD) for 5 days. The maximal TCDD‐induced decrease in lymphoid cell number of chick embryo thymus (to about 60% of the control number) occured at concentrations of 10−10M and above. To produce the same effect on lymphoid cell number in the cultures of thymus anlagen from turkey and duck embryos, about a 100‐fold higher concentration of TCDD was needed. The toxicity of the TCDD congeners 3,3′4,4′‐tetrachloroazoxybenzene (TCAOB) and 3,3′,4,4′‐tetrachlorobiphenyl (TCB) to embryonic chicken thymus was testedin vitroandin ovo.In chick embryo thymus cultures, TCAOB and TCB were about two orders of magnitude less toxic than TCDD. Injection of TCAOB and TCB into chicken eggs preincubated for 11 days resulted in a dose‐dependent decrease in thymic lymphoid cell number 5 days later, declining to about 14% of the controls at 10 μg TCAOB/kg egg. The ED50value was estimated to be 3.6 and 60 μg/kg egg for TCAOB and TCB, respectively.
Glucuronidation of Morphine in Human Kidney Microsomes
Authors: Yue Qunying , Odar‐Cederlöf Ingegerd , Svensson Jan‐Olof , Säwe Juliette
Published: March 2009

Abstract:The UDP‐glucuronyltransferase (GT) activity with morphine as substrate was measured in microsomes prepared from seven human adult kidneys including one whose cortex and medulla had been separated. The formation of morphine‐3‐ and 6‐glucuronides (M3G and M6G) was determined by HPLC methods. All kidney specimen formed M3G and M6G when incubated with morphine and UDP‐glucuronic acid (UDPGA). The estimated Vmaxand Kmof morphine to form M3G and M6G were 2.2 and 0.18 nmol per mg protein and min. and 8.2 and 4.6 mM, respectively. The corresponding values for UDPGA were 1.3 and 0.13 nmol per mg protein and min. and 5.4 and 4.1 mM, respectively. The GT activity in cortex was 2.8‐fold higher than in the medulla. The human kidney thus contains glucuronyltransferase activities towards morphine, which is in contrast to previous findings in the rat.
Gastrointestinal Absorption and Urinary Excretion of Aluminium in Patients with Predialysis Chronic Renal Failure
Authors: Nordal Knut P. , Dahl Eilif , Sørhus Kirsten , Berg Knut J. , Thomassen Yngvar , Kofstad Johan , Halse Johan
Published: March 2009

Abstract: In a randomized cross‐over study, serum and urinary aluminum (Al) was measured in 8 patients with predialysis chronic renal failure. Samples were taken after ingestion of an Al‐containing phosphate binder (ACPB) with either water or 7% citric acid, and Al was analyzed by electrothermal atomic absorption spectrometry. Both serum levels and urinary excretion of Al increased markedly after ingestion of ACPB with citric acid. Only urinary Al excretion increased significantly after ACPB with water. Citric acid alone caused no change in serum concentration or urinary excretion of Al. The serum Al increase after ACPB with citric acid indicates that absorption of Al is taking place in both upper and lower intestines. Marked individual variations in gastrointestinal Al absorption, independent of kidney function, were seen after intake of ACPB with citric acid. These variations could not be predicted from changes in serum concentrations or from urinary excretion of Al after intake of ACPB with water. Intake of ACPB caused a significant decrease in serum phosphate.
Effect of Pregnancy and Sex Steroids on α1‐Adrenoceptor Mechanisms in the Guinea‐Pig Uterine Vascular Bed
Authors: Fallgren Bo , Bjellin Leif , Edvinsson Lars
Published: March 2009

Abstract:Adrenoceptor mechanisms in the extrinsic uterine arteries from late pregnant guinea‐pigs were characterized pharmacologically and compared with contractile responses of uterine arteries from non‐pregnant and oophorectomized control, progesterone and oestrogen treated animals. Pregnancy caused an increase in diameter of the arteries, more pronounced the more distal they were. There was no change in potassium‐evoked maximum contractions during pregnancy. Noradrenaline (10 nM to 1 mM), in the presence of cocaine (1 μM) and propranolol (0.1 μM), induced concentration‐dependent contractions of the arterial segments, with approximately similar pD2values. The maximum responses (Emax) were significantly increased during pregnancy and hormone supplementation. Prazosin (10 nM to 1 μM), but not rauwolscine (10 nM to 1 μM), antagonized noradrenaline‐evoked contractions of the arteries. Isoprenaline (10 nM to 1 μM), in the presence of prazosin (0.1 μM) and cocaine (1 μM), had no relaxant effect on arteries contracted submaximally by prostaglandin F2α, (5 μM). Neither cocaine nor normetanephrine modified noradrenaline‐evoked contractions of the uterine artery. The results indicate that guinea‐pig uterine vasoconstriction is mediated by α1‐adrenoceptors while relaxant β‐adrenoceptor effects, neuronal and extraneuronal uptake mechanisms are of minor importance. The observed increase in Emaxmay be due either to an increase in the number of α1‐adrenoceptors or to an enhanced pharmaco‐mechanical coupling, which conceivably is regulated by sex steroids since this response was reproduced in castrated animals by hormone supplementation.
Oral Cadmium Chloride Intoxication in Mice: Effects of Penicillamine, Dimercaptosuccinic Acid and Related Compounds
Authors: Andersen Ole , Nielsen Jesper Bo
Published: March 2009

Abstract: The antidotal efficacies of chelators during acute cadmium intoxication has previously been examined in experiments where both a soluble cadmium salt and the chelator were administered parenterally. In the present study, PA, DMSA and related compounds were studied as oral antidotes during oral CdCl2 intoxication. According to the antagonistic effects noted on mortality, peristaltic toxicity and intestinal cadmium uptake, the relative efficacies of the compounds tested were: DMSA > PAD > DMPS > MSA > PA > NAPA. None of the chelators induced major changes in the organ distribution of absorbed cadmium, in particular no increased cerebral deposition of cadmium. This study indicates that, in oral cadmium intoxication in humans, orally administered DMSA would be likely to offer protection against the local toxicity of cadmium in the gastrointestinal tract as well as to reduce the risk of systemic toxicity of absorbed cadmium.
Actions of Terodiline, its Isomers and Main Metabolite on Isolated Detrusor Muscle from Rabbit and Man
Authors: Andersson Karl‐Erik , Ekström Björn , Mattiasson Anders
Published: March 2009

Abstract: The effects of racemic terodiline on isolated detrusor preparations from rabbit and man were compared with those of its (+)‐ and (−)‐isomers, and with those of its main metabolite, parahydroxy‐terodiline. Concentration‐response (c‐r) relations for carbachol and frequency‐response relations for electrical stimulation were determined before and after addition of drugs. In preparations from both rabbit and man, all the drugs tested concentration‐dependently shifted the c‐r curve for carbachol to the right. (+)‐Terodiline was more potent than (+/‐)‐terodiline, whereas (−)‐terodiline and parahydroxy‐terodiline were less potent. All drugs in concentrations > 10−6 M had a non‐competitive effect, depressing the maximum of the carbachol contraction. All drugs had a depressant effect on electrically evoked contractions. (+)‐Terodiline was as effective (rabbit) or more effective (man) than (+/‐)‐terodiline, whereas (−)‐terodiline and parahydroxy‐terodiline were less effective. It is concluded that (+)‐terodiline contributes to a main part of the detrusor effects of the racemate, and that part of this action is anticholinergic. Parahydroxy‐terodiline had a profile of action similar to that of (+/‐) terodiline, but its potency was low. Since it is present in plasma in low concentrations, its contribution to the clinical effects of terodiline is probably small. (+)‐Terodiline may have a therapeutic potential.
Functional Restoration of Cultured Mouse Pancreatic Islets afterin VitroExposure to Alloxan
Authors: Eizirik Décio L. , Sandler Stellan
Published: March 2009

Abstract:The molecular mechanisms behind the functional responses of the β‐cells after cytotoxic damage are still largely unknown. The aim of this study was to investigate to what extent the islet β‐cells are capable of repairing cellular injuries after acute treatment with increasing doses of alloxan. Isolated mouse pancreatic islets were exposed for 30 min. at 37° to alloxan (1.0, 1.5 and 2.0 mM) or vehicle alone (controls). Immediately after alloxan exposure the islet glucose‐stimulated insulin release was severely decreased, and there were morphological evidences of partial necrosis of the islets. After further six days in culture, there was a marked decrease in islet number in the groups of islets treated with 1.5 or 2.0 mM alloxan. However, the DNA and insulin contents of the remaining islets were similar to the values observed in cultured control islets. Furthermore, the insulin secretory response to glucose and the light microscopical appearance of these islets were largerly restored on day 6. It is concluded that β‐cells surviving after an injury induced by alloxan may recover their functional capacity after an initial period of inhibited function.
Effect of Four‐Day Treatment with Carbamazepine at Different Dose Levels on Microsomal Enzyme Induction, Drug Metabolism and Drug Toxicity
Authors: Regnaud L. , Sirois G. , Chakrabarti S.
Published: March 2009

Abstract:The effect of intraperitoneal injections of 0, 30, 60 and 100 mg/kg of carbamazepine (CBZ), twice a day for 4 days, was studied in 4 groups of 6 male Sprague‐Dawley rats per group to evaluate its hepatic enzymatic induction, toxicity and metabolism. Rats were sacrificed on the fifth day and the urines of the last 24 hours were collected. While the activities of hepatic microsomal aminopyrine N‐demethylase and epoxide hydratase tended to increase with the dose of CBZ, the cytochrome P‐450 content and the activity of aniline hydroxylase however reached a maximum at 60 mg/ kg. The percentage of the administered daily dose of CBZ excreted as unchanged CBZ in the urine increased considerably with the dose, while that of metabolites such as carbamazepine‐10,11‐epoxide (CBZ‐E), trans‐10,11‐dihydrodihydroxycar‐bamazepine (TDC), and thioethers (T) did not markedly change. These data not only corroborate a maximum in enzyme induction but also suggest a saturation of the induced hepatic enzymes. Urinary T and TDC, representing more than 50% and less than 10%, respectively of the total amount recovered, tend to demonstrate that the glutathione conjugation with the intermediates of CBZ leading to the formation of higher mercapturates could be more important than the epoxide‐diol pathway for the metabolism of CBZ under conditions of repeated dosing.
Effects of Thapsigargin in Isolated Rat Thoracic Aorta
Authors: Mikkelsen E. O. , Thastrup O. , Christensen S. Bregger
Published: March 2009

Abstract:The effect of thapsigargin (Tg) was studied in rat thoracic aorta. Tg (10‐8—10‐5M) had a dual effect on rat aorta. Thus, Tg induced a concentration dependent increase in basal tone in normal physiological salt solution (PSS), while Tg in potassium (K+) precontracted aortic rings caused a concentration related relaxation and shifted the K+‐concentration response curve to the right and depressed the maximal response to K+. Removal of vascular endothelium abolished the relaxant response to Tg and increased the sensitivity of the preparations to the contractile effect of Tg. The contractile response to Tg was resistent to wash‐out in drug‐free PSS and was not affected by phentolamine, indomethacin or mepyramine but partly reduced by the calcium‐antagonist nitrendipine and eliminated by wash‐out in calcium‐free PSS. Atropine eliminated the endothelium dependent relaxant effect of carbachol, but had no effect on the Tg or on the calcium ionophore A 23187 evoked relaxation. Ultraviolet radiation decreased the relaxant effect of Tg and A 23187 without affecting the carbachol induced relaxations. The results showed that vascular endothelium depressed the contractile effect of Tg and that Tg like A 23187 had an endothelium dependent relaxant effect on rat aorta different from that of carbachol. The results indicate that Tg in vascular smooth muscle acts by stimulating the transmembranal influx of extracellular calcium.
Time Course of Resensitization of Rat Uterine β‐Adrenoceptor System
Authors: Andersson Rolf G. G. , Johansson Solveig R. M. , Salomonsson Ingrid
Published: March 2009

Abstract:The time course of resensitization of the down‐regulated β‐adrenoceptor system of rat myometrium was studied. The isoprenaline‐induced decrease of myometrial cAMP reversed rather rapidly and after 4 and 8 days no significant change of the cAMP level was demonstrated, however, the cAMP level was higher than in the control myometrium after 12 days. The elevated phosphodiesterase activity dereased to 80% of control activity after 4 days, but returned to control activity after 8 days. The decreased number of β‐adrenoceptors increased gradually after discontinueing the treatment and reached the number of the controls after 12 days. Our results suggest that the resensitization of the β‐adrenoceptor‐cAMP‐system is rather complex, the normalization of the cAMP content and the phosphodiesterase activity is more rapid than the normalization of the β‐adrenoceptor number which is a rather slow process in myometrial tissue.
Tolerance to the Anticonvulsant Effect of Clorazepate and Clonazepam in Mice
Authors: Scherkl R. , Kurudi Doxa , Frey H.‐H.
Published: March 2009

Abstract: The rate of development of tolerance to the benzodiazepines clorazepate and clonazepam against pentetrazole‐induced seizures in mice was compared. Treatment with clorazepate (0.1% solution as drinking water) for 21 days led to tolerance beginning at day 7. When mice were treated with clonazepam (0.5 mg/kg twice daily intraperitoneally), tolerance was evident already at the fourth day of treatment. Twenty‐four hours after cessation of treatment the seizure threshold was significantly decreased after treatment with both drugs. Clorazepate, a prodrug of the main metabolite of diazepam, desmethyldiazepam, regards further interest for anticonvulsant therapy because of a relatively slow onset of tolerance.
Long‐Term Effects on Biotransformation of Labelled Choline in Different Parts of the Rat Brain Induced by Single Choline Injections
Authors: Nordberg Agneta , Wablström Göran
Published: March 2009

Abstract:The long‐term effects of single choline (Ch) injections on the uptake and metabolism of a tracer dose of3H‐Ch were studied in male rats. Choline was administered as a threshold infusion to obtain convulsions 10 and 4 weeks before sacrifice (group 1). At a single threshold infusion of choline 4 weeks before sacrifice no convulsions were induced in 50% of the animals in a second group (group 2 ‐) whereas convulsions were induced in the remainder of the animals in this group (group 2+). Group 3 contained control animals. One min. after administration of a tracer dose of3H‐Ch the animals were sacrificed and examined for3H‐total activity,3H‐Ch,3H‐acetylcholine (3H‐ACh) and3H‐phosphorylcholi‐ne (3H‐PhCh). These activities were determined in three parts of the brain (cortex, striatum, midbrain + medulla oblongata). In thecortexa significant negative correlation between brain weight and3H‐ACh synthesis was seen in group 1. A comparison between group 2+ and group 2‐indicated that induced convulsions were not critical for this effect. In thestriatumthere was a significant reduction in the total uptake of radioactivity in group 1 and group 2‐when values were compared to the control group. Furthermore a significant positive correlation was detected between the concentration of radiolabel and3H‐ACh synthesis and a negative relationship with the level of3H‐Ch. In themidbrain preparationthe synthesis of3H‐ACh was reduced in group 1 where a significant negative correlation was found between the average threshold dose of choline and both3H‐ACh and3H‐PhCh synthesis. Thus the Ch threshold doses given several weeks before testing seem to have long term effects on the uptake and utilization of a tracer dose of3H‐Ch in the cortex and striatum. The relation between the sensitivity to the choline threshold and the changes found later in the utilization of the tracer dose of Ch in the midbrain indicates that the midbrain could be involved in the initiation of the convulsions.
Seasonal Variations in Serum Aluminum Concentrations
Authors: Nordal Knut P. , Dahl Eilif , Thomassen Yngvar , Brodwall Erling K. , Halse Johan
Published: March 2009

Abstract: During 1984 and 1985 we performed frequent measurements of serum aluminum (Al) in patients with moderate chronic renal failure, and healthy controls, all living in the Oslo region. The results demonstrated seasonal variations with high levels in the autumn. During the peak periods serum A1 increased by a factor greater than four. Outside the peaks patients using Al‐containing phosphate binders had higher serum Al levels than non‐users, a difference not seen during the peaks. Serum Al levels were unrelated to parathyroid hormone (PTH) concentrations and to calcitriol intake. Urinary excretion and the glomerular filtration rate was stable during the period with high serum A1 in the autumn 1984. Increased gastrointestinal absorption of Al, possibly caused by a waterborne factor with chelating properties, may explain the seasonal variations.
Congestive Heart Failure in Rabbits after a Single Intrapleural Administration of a Low Dose of Doxorubicin or Epirubicin
Authors: Elisson Lars Ove , Björkmnn Sven
Published: March 2009

Abstract:Seventeen healthy rabbits were given doxorubicin, 0.1‐1.6 mg kg‐1, or epirubicin, 0.41.6 mg kg‐1, through a catheter into the right pleural space. Sacrifice and autopsy one week later showed a local inflammatory reaction with, in some animals, sparse adhesion forming between parietal and visceral pleura. There was a clearly dose‐dependent production of thin, straw‐coloured exudate. Nineteen healthy rabbits were given intrapleural doxorubicin or epirubicin, 0.2, 0.4 or 0.8 mg kg‐1. Autopsy on spontaneously dead (n = 3) or sacrificed animals after six weeks gave clear indications of congestive heart failure after the two higher doses. There were also fibrous adhesions and/or tissue necrosis engaging the pleura, diaphragm and lung. It was concluded that doxorubicin and epirubicin are 40 to 100‐fold more cardiotoxic in rabbits when given by the intrapleural route than when given by the intravenous route. The implications are two‐fold: 1. doxorubicin or epirubicin should not be given intrapleurally to patients, 2. a new model for drug‐induced congestive heart failure has been created, which has the advantage of requiring very small quantities of drug.
Tissue Distribution of 125I‐Labelled Bovine Superoxide Dismutase (SOD) in the Rat
Authors: Odlind B. , Appelgren L.‐E. , Bayati A. , Wolgast M.
Published: March 2009

Abstract: Bovine copper/zink superoxide dismutase (SOD) was labelled with 125I using the chloramine‐T method. The tissue distribution of 125I‐SOD (dose of SOD 5 mg/kg) was studied with whole‐body and microautoradiography at various times after an intravenous injection. The distribution of 125I‐SOD showed a remarkable organ specificity in that the localization of the enzyme to the kidneys and the urinary tract completely dominated the autoradiograms. The time pattern of localization of 125I‐SOD also gives a clear picture of the renal handling of the enzyme in that, as a consequence of the renal elimination, the enzyme rapidly disappears from the circulation with an elimination half time of about 6 min. Up to 20 min. after the injection, there were high concentrations of 125I‐SOD in the renal pelvis, ureter and urinary bladder showing that in addition to renal uptake there was an initial substantial urinary excretion of the enzyme. From the microautoradiography it is clear that the grains were exclusively localized over proximal tubular cells and tended to be concentrated at the luminal rather than the peritubular side of tubule. This would be compatible with renal uptake secondary to glomerular filtration of 125I‐SOD, which is what one would expect from the renal handling of a protein with a molecular weight around 31,000 and an isoelectric point around pH 5.4. Pretreatment with a large dose of SOD (88 mg/kg) tended to competitively decrease the renal uptake of labelled SOD after 5 min. and apparently further increase its renal excretion. However, a noticable renal uptake of 125I‐SOD was still apparent. The radioactivity in the kidneys subsided gradually, from 4 hours up to 48 hours with a parallel increase in the radioactivity in the thyroid, indicating metabolic degradation of 125I‐SOD by tubular cells and suggesting “retention” by the kidney of at least some of the enzyme and/or its end products.
ChroNc Treatment with Lithium Chloride: Reduced Number of GABA Receptors in Frontal Cortex of Rat Brain
Authors: Hetmar Ole , Nielsen Mogens
Published: March 2009

Abstract: Chronic consumption of lithium leads to a significant decrease in GABA receptor binding in frontal cortex of rat brain with no change in the binding characteristics in the remaining part of the cortex and in the hippocampus. In conclusion, the effect of lithium on the muscimol receptor is brain region‐specific and due to a change in the number of receptors rather than in the affinity constant.