bluuebunny/crossref_metadata_2025 huggingface dataset:
Function of the Auditory and Visual Systems, and of Peripheral Nerve, in Rats after Long‐Term Combined Exposure to n‐Hexane and Methylated Benzene Derivatives. II. Xylene
Authors: Nylén Per , Hagman Maud
Published: March 2009

Rats were exposed to xylene, to n‐hexane. or to xylene together with n‐hexane, each solvent 1000 p.p.m. (1000+1000 p.p.m. in mixed exposure), 18 hr/day, 7 days/week during 61 days. Neurophysiological recordings were made 2 days, 4 months, and 10 months after the end of exposure. Exposure to n‐hexane alone, or xylene alone, caused a slight loss of auditory sensitivity as recorded by auditory brainstem response 2 days after the exposure. Exposure to n‐hexane together with xylene caused persistent loss of auditory sensitivity (7‐17 dB; P<0.05) which was non‐additively enhanced (P<0.01). The latencies of the flash evoked potentials in the group exposed to n‐hexane alone were prolonged (re C group) 2 days after exposure, while smaller prolongations were found in the group exposed to xylene together with n‐hexane. Exposure to n‐hexane alone caused a marked decrease in nerve conduction velocity, while simultaneous exposure to xylene inhibited n‐hexane‐induced velocity reduction in peripheral nerve (P<0.01).
Characterization of the CGRP Receptor and Mechanisms of Action in Rat Mesenteric Small Arteries
Authors: Lei Shi , Mulvany Michael J. , Nyborg Niels C. Berg
Published: March 2009

Rat α‐calcitonin gene‐related peptide‐induced concentration‐dependent (100 pM ‐ 10 nM) relaxations in rat mesenteric small arteries (i.d.≈220 urn) contracted with noradrenaline, proslaglandin F2αor K+, however, the maximal relaxation depended on the precontractile stimulus, being highest (95%) in arteries contracted with PGF2αand lowest (51%) in arteries contracted with 125 mM K+. The relaxation was inhibited between 10 pM and 1 nM by removal of the endothelium, but was not antagonized by glibenclamide (1 μM), tetraethylammonium (30 mM), apamine (0.3 μM) and 4‐aminopyridine (3 mM). The concentration‐response curve to rat α‐CGRP and human P‐CGRP was shifted to the right in the presence of I μM human α‐CGRP(8‐37) indicating a receptor affinity, ‐ log (KB[M]), equal to 7.2 and 7.0, respectively. It is concluded than the relaxation induced by CGRP depends minimally on the endothelium and K+–channel opening is not a principal process in the relaxing effect of CGRP, thus a third mechanism must mediate the relaxation in these vessels. The main CGRP receptor type mediating relaxation in rat mesenteric small arteries belongs to the CGRP1subtype.
Alternative Pathways of Sulfite Oxidation in Human Polymorphonuclear Leukocytes
Authors: Constantin D. , Mehrotra K. , Jernström B. , Tomasi A. , Moldéus P.
Published: March 2009

Sodium sulfite is metabolized by human polymorphonuclear leukocytes by two alternative pathways, one enzymatic route dependent on sulfite oxidase and one non‐enzymatic which involves intermediate formation of sulfur trioxide anion radicals. Initiation of the oxidative burst by phorbol myristate acetate significantly stimulates sulfate formation through the second pathway. The activity of sulfite oxidase in polymorphonuclear leukocytes varies greatly among individuals, a variation consistent with the suggested polymorphic distribution of sulfite oxidase in the human population.
Low Dose Acetylsalicylic Acid in the Antithrombotic Treatment of Patients with Stable Angina Pectoris and Acute Coronary Syndromes (Unstable Angina Pectoris and Acute Myocardial Infarction)
Authors: Winther Kaj , Husted Steen E. , Vissinger Henrik
Published: March 2009

Acetylsalicylic acid has an antithrombotic effect by inhibition of thromboxane A2synthesis in platelets. Thromboxane A2is a potent stimulator of platelet aggregation and vasoconstriction and synthesis may be completely inhibited by a single oral dose of 150 mg acetylsalicylic acid or an intravenous dose of 100 mg. A daily maintenance dose of 75 mg acetylsalicylic acid is sufficient to effectively inhibit thromboxane A, synthesis in long‐term treatment. Acetylsalicylic acid therapy reduces acute myocardial infarction and sudden death in patients with stable angina pectoris and the drug is equally effective in patients with symptomatic and ‘silent’ angina pectoris. Early intervention with acetylsalicylic acid in patients with unstable angina pectoris reduces the risk of acute myocardial infarction and death. In patients with acute myocardial infarction, acute therapy with acetylsalicylic acid significantly reduces mortality both in monotherapy and in combination with thrombolytics. In the secondary prophylaxis following acute myocardial infarction, acetylsalicylic acid reduces the incidence of reinfarction and coronary death. Treatment of 100 patients with acute coronary syndrome (unstable angina pectoris or acute myocardial infarction) for 2 years may hinder the development of 3‐4 fatal and 4 non‐fatal vascular events. The risk of gastrointestinal side‐effects and bleeding during acetylsalicylic acid therapy is dose‐dependent and the incidence is low with a daily dose of 75‐150 mg.
Blockade of Sensitization to the Toxic Effects of Cocaine in Mice by Nitric Oxide Synthase Inhibitors
Authors: Itzhak Yossef
Published: March 2009

Repeated administration of cocaine to animals results in sensitization to several reactions to the drug, including seizures and mortality. These consequences are thought to be related to the pathology that develops in humans abusing cocaine. Previous studies implied the involvement of the N‐methyl‐D‐aspartate (NMDA) type of glutamate receptors in cocaine‐induced toxicity, and recent studies documented a role for nitric oxide in NMDA‐receptor mediated neurotoxicity. The present study was undertaken to determine whether nitric oxide synthase inhibitors block the development of sensitization to the toxic effects of cocaine in mice. Repeated administration of cocaine (45 mg/kg/day; intraperitoneally) to Swiss Webster mice, for 7 days, resulted in a progressive increase in the duration of the convulsive response to cocaine, an increase in the number of animals that had seizures, and augmentation in lethality rate. Pretreatment with NG–nitro‐L‐arginine methyl ester (L‐NAME; 100 mg/kg/day; intraperitoneally) or NG–nitro‐L‐arginine (NO‐Arg; 25 mg/kg/day; intraperitoneally) completely abolished the sensitization to the convulsive and lethal responses to cocaine. Receptor binding assays indicated first, that pretreatment with L‐NAME apparently diminished cocaine‐induced upregulation of cortical NMDA receptors, and second, that the effects of the nitric oxide synthase inhibitors tested arenotmediated via a direct interaction of the drugs with the phencyclidine/NMDA receptor complex. Taken together, the present study suggests an important role for nitric oxide in the development of sensitization to the toxic effects of cocaine, and further supports the relationship between NMDA‐receptor mediated neurotoxicity and nitric oxide.
Arterial Smooth Muscle Responses in Adult and Moderately Aged Spontaneously Hypertensive Rats
Authors: Wuorela Heikki , Arvola Pertti , Kähönen Mika , Vapaatalo Heikki , Pörsti Ilkka
Published: March 2009

In order to further clarify differences between spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) rats as well as the effects of ageing, vascular smooth muscle responses of mesenteric arterial rings and intracellular free calcium concentration ([Ca2+]i) in platelets and lymphocytes were studied in 20‐week‐old and 32‐week‐old animals. Arterial contractile responses induced by noradrenaline and potassium chloride were comparable in 20‐week‐old SHR and WKY rats, whereas at 32 weeks of age maximal contractile force generation to both of these agents was clearly lower in SHR. In both age groups the calcium entry blocker nifedipine was more effective in inhibiting potassium chloride‐evoked responses in SHR than in WKY rats, and arterial relaxation responses by endothelium‐dependent (acetylcholine) and endothelium‐independent (nitroprusside, isoprenaline) mechanisms were more pronounced in WKY rats when compared with SHR. The ability of vascular smooth muscle cells to sequester calcium was evaluated by first depleting cellular calcium stores with maximal contractions to noradrenaline in calcium‐free buffer, whereafter calcium was returned to the organ bath. After a 10 min. calcium loading period the arterial rings were rechallenged with noradrenaline. Both in 20‐week‐old and 32‐week‐old rats these reponses were less marked in SHR than in WKY rats, suggesting reduced ability of smooth muscle cells to sequester calcium. In addition, platelets and lymphocytes were used as cell models to examine [Ca2+]iin the experimental groups by the fluorescent indicator quin‐2. In these two cell types [Ca2+]iwas higher in SHR than in WKY rats in both of the age groups studied. In summary, differences between SHR and WKY rats in cellular calcium handling are expressed as impaired relaxation and reduced sequestration in SHR vascular smooth muscle and as higher [Ca2+]iin blood cells. Ageing seems to have clear effect only on contractile force generation which is reduced in SHR mesenteric artery both in agonist‐mediated and in depolarization‐induced responses.
Effect of 8‐Hydroxy‐, 8‐Mercapto‐ and 5‐Chloro‐7‐iodo‐8‐hydroxy‐quinoline on the Uptake and Distribution of Nickel in Mice
Authors: Borg‐Neczak Kathleen , Tjälve Hans
Published: March 2009

Oral administration of Nr2+ together with 8‐hydroxyquinoline (8‐OH‐quinoline), 8‐mercaptoquinoline (8‐SH‐quinoline) or 5‐chloro‐7‐iodo‐8‐hydroxyquinoline (clioquinol) resulted in increased tissue levels of the metal in several tissues of mice in comparison with animals given the Ni2+ alone. Ni2+ forms lipophilic complexes with these compounds and it can be assumed that this will facilitate the uptake of the Ni2+ over the walls of the gastrointestinal tract. Our results showed that 8‐SH‐quinoline, in contrast to 8‐OH‐quinoline and clioquinol, induces a markedly changed distribution pattern of the Ni2+ in the body, with uptake of the metal in tissues such as the central nervous system, pigmented tissues, the pancreatic islets and the thyroid. It is probable that the Ni2+ ‐complex with 8‐SH‐quinoline is stable enough to persist for a time period in the tissues and that the obtained pattern partly reflects the distribution of the complexed metal. In contrast, following the absorption from the gastrointestinal tract there may be a dissociation of the complexes between Ni2+ and 8‐OH‐quinoline or clioquinol, resulting in increased metal levels in various tissues, but with similar distribution as when the Ni2+ is given alone.
Drug Analysis for Control Purposes in Forensic Toxicology, Workplace Testing, Sports Medicine and Related Areas
Authors: Christophersen Asbjørg Solberg , Mørland Jørg
Published: March 2009

This MiniReview describes the present guidelines for drug testing in forensic toxicology, workplace testing and doping control of athletes. Such guidelines are established to secure the chain of custody, from sample collection through analysis with screening, confirmation methods and interpretation, to the final report of results. Specifications for good laboratory practice, facility maintenance and quality assurance programs are described. The advantages and limitation of immunological drug assays and the necessity of specific chromatographic confirmation methods are discussed. The importance of correct interpretation of positive test results is illustrated. The effect of drug testing on the prevalence of drug abuse, accident rales and effectivity at the workplace is discussed.
Cleft Palate and Open Eyelids Inducing Activity of Lorazepam and the Effect of Flumazenil, the Benzodiazepine Antagonist
Authors: Jurand A. , Martin L. V. H.
Published: March 2009

Lorazepam (Ativan®, Wyeth) at dosages of 20‐36 mg/kg was used to test for developmental toxicity in the mouse embryo/foetus model. Two separate regions were considered: (1) the central nervous system and (2) the roof of the mouth and the eyelids. In the first case a single administration oflorazepam was applied at the very beginning of the 9th gestation day. In the second, it was administered in preliminary tests on two consecutive gestation days between the 11th and 14th days and in later experiments once only on the 13th or 14th gestation day. In the first part of investigations regarding the development of the central nervous system, lorazepam unlike many other neurotropic drugs, was found not to induce any aberrations in the process of the neural tube closure. In the second part, in which palate closure and the temporary closure of eyelids were monitored, it was found that lorazepam does interfere with these processes. In order to test whether lorazepam's neurocristopathic activity can be prevented, suggesting the presence of benzodiazepine receptors in the neural crest cells, we used the benzodiazepine antagonist, flumazenil (Anexate®, Roche). The results of these experiments indicated the flumazenil was able to prevent cleft palate and open eyelids cases almost completely if it was administered 3 hr after administration of lorazepam. If the treatments were administered in the reverse order, the frequency of neurocristopathy cases was unaffected, i.e. flumazenil did not influence the teratogenic activity of lorazepam.
The Modulating Activity of Interferon on Benzo(a)pyrene Bioactivation and Clastogenesis in Mice
Authors: Hrelia Patrizia , Morotti Marta , Vigagni Fernanda , Maffei Francesca , Paolini Moreno , Mesirca Renata , Cantelli‐Forti Giorgio
Published: March 2009

Acute intraperitoneal administration of benzo(a)pyrene (80 mg/kg b.wt.) resulted in time‐dependent increases in chromosome aberrations, expecially of break‐type in the bone marrow of treated mice. Pretreatment with murine interferon‐α/β (5×104IU daily for two days) caused a significative decrease in the cytogenetic responsein vivoof benzo(a)pyrene (up to 51%) and a stabilization of aberrant cells up to 48 hr. The administration of murine interferon‐α/β gave rise to a marked depression of microsomal monooxygenase system after 24 hr, as exemplified by the significant reduction of cytochrome P450 content as well as deethylation of ethoxyresorufin. Interferon treatment delayed the obtainment of basal levels of oxidative metabolism to approximately 30 hr. After interferon plus benzo(a)pyrene treatment, ethoxyresorufin O‐deethylase activity showed a reduction up to 60%; levels comparable to benzo(a)pyrene treated group were restored by 48 hr. Immunoblotting analysis confirmed reduced CYPIA1 level. Results suggest that the inhibition of benzo(a)pyrene hepatic metabolsim by interferon was reflected by changes in its clastogenic activity. Persistance of low level of chromosome aberration at 48 hr may be reconducible to other interferon sensitive processes than effects on hepatic mixed‐function oxidase system, such as DNA repair activity and cell proliferation.
Modulating Effects of the Synthetic Thymic Dipeptide Pidotimod on the Immune System in the Aging Rat
Authors: Chiarenza A. , Iurato M. P. , Barbera N. , Lempereur L. , Cantarella G. , Scapagnini U. , Bernardini R.
Published: March 2009

We have investigated the in vivo and in vitro effect of pidotimod, a synthetic thymic‐derived drug, on the immune response in young (2 month‐old), and aging (24 month‐old) Sprague‐Dawley rats. We studied the effect of different doses of pidotimod on the responsiveness of both cultured peripheral blood lymphocytes and splenocytes to mitogenic stimuli, as well as on interleukin‐2 production by peripheral blood lymphocytes after stimulation with interleukin‐1 and phytohemagglutinin. Treatment with pidotimod in vivo as well as in vitro resulted in an increase of tritiated thymidine incorporation in both mitogen‐stimulated lymphocytes and splenocytes from 24 month‐old rats. Production of IL‐2 from lymphocytes of 24 month‐old rats was significantly increased in groups of animals treated with pidotimod. On the other hand, treatment with pidotimod did not influence the responsiveness of 2 month‐old rat lymphocytes to mitogens, nor affected IL‐2 production. Our results suggest a possible specific modulatory activity of pidotimod on the aging immune system.
Effect of Iron on the Absorption and Distribution of Clodronate after Oral Administration in Rats
Authors: Österman Thua , Juhakoski Auni , Laurén Leena , Sellman Raija
Published: March 2009

The effect of iron on the absorption and distribution of disodium clodronate in rats after oral administration was studied. Disodium clodronate (300 mg/25 μCi/kg) was given both alone and with an equivalent amount of ferrous sulphate. The radioactivity in plasma and various tissue was measured. Concentration of clodronate in plasma was also determined with the GC‐mass‐selective detection method and the values compared with those measured with the isotope method. After administration, clodronate was rapidly cleared from plasma. Most of the dose was taken up by bone and only small amounts were found in non‐calcified tissues. Concurrent ingestion of iron caused a marked decrease in the absorption of clodronate.
Effects of 3,3′,4,4′‐Tetrachlorobiphenyl on Foetal Germ Cells in Two Mouse Strains after Repeated Treatment of the Dams During and After Pregnancy
Authors: Rönnbäck C. , de Rooij D. G.
Published: March 2009

Female mice from the C57/B1‐ and CBA/S‐strain, respectively, were administered 3,3′4,4′‐tetrachlorobiphenyl once a week for two weeks prior to mating, during mating, gestation and lactation, altogether at seven weekly occasions. The orally administered amounts were 9 or 15 mg/kg b.wt. per occasion. Male and female offspring (F1), exposed in utero were collected for histological analysis of the testes and ovaries. Other C57/Bl‐females (F1) were tested for their reproductive capacity. In the C57/Bl‐males tetrachlorobiphenyl only had a temporary effect on germ cell numbers, and spermatogenesis was normal again at 56 days after birth. In the ovaries 28 days after birth, an increased number of oocytes and follicles were observed, the effect being more pronounced in the C57/Bl‐strain. The reproductive capacity expressed as mean litter size seemed not to be affected by the histologically observed changes. Concerning the number of litters per female there were indications of an enhanced productivity in tetrachlorobiphenyl‐exposed F1‐females. Malformations of any kind were not observed.
Multiple Effects of 2,3‐Butanedione Monoxime
Authors: Sellin L. C. , McArdle J. J.
Published: March 2009

2,3‐Butanedione monoxime. also known as diacetyl monoxime, is a nucleophilic agent which dephosphorylates acetylcholinesterase poisoned with organophosphates. This “chemical phosphatase” activity stimulated studies of the effect of 2,3‐butanedione monoxime on phosphorylation‐dependent cellular processes. As a result of these studies, we know that the drug affects a number of mechanisms including muscle contraction, ionic current flow and synaptic transmission. Furthermore, it may be used as a component of cardioplegic solutions since it protects cardiac tissue exposed to certain ischaemic conditions. While this MiniRewiev reveals the diversity of its cellular actions, there continues to be unresolved questions regarding its molecular mechanism.
Studies on the Interaction of Roxindole with Brain Monoamine Oxidases and Dopaminergic Neuronesin Vitroandin Vivo
Authors: Seyfried Christoph A. , Adam Georg
Published: March 2009

Roxindole, a structurally novel psychotropic indolylbutyl‐4‐phenyltetrahydropyridine, was studied with respect to the formation of potentially neurotoxic pyridinium metabolites in comparison to MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine). In contrast to MPTP, roxindole failed to serve as a substrate for monoamine oxidases (MAO) from mouse, monkey and human brainin vitro. Accordingly, neither the putative MAO‐oxidation product of roxindole (ROX+) nor MPP+(1‐methyl‐4‐phenylpyridinium ion) was detected in mouse striatum after high subcutaneous doses of roxindole in spite of the presence of ~ 6 μg of roxindole per g of striatum in these animals. After multiple subcutaneous treatments with 95.2 mg/kg roxindole, no long‐term striatal dopamine depletions were observed in contrast to MPTP. Furthermore, unlike MPP+, ROX+did not induce release of previously accumulated3H‐dopamine in mouse striatal slices indicating that ROX+cannot utilize the dopamine uptake carrier to enter neurones. ROX+at doses up to 100 mg/kg subcutaneously failed to alter striatal biogenic amine levels and gross behaviour of mice. Thus, no MPTP‐like neurotoxic metabolites are formed from roxindolein vivoand neurotoxic effects of ROX+, even if formed in minute amounts by some MAO‐independent pathway, are highly unlikely.
Effects of Oxodipine and Nitrendipine on the Size of Experimental Myocardial Infarct in the Rat
Authors: Pérez‐Cao Ana , Gil‐Loyzaga Pablo , Merchàn‐Pérez Angel , Tamargo Juan
Published: March 2009

The protective effect of either oxodipine or nitrendipine (4 mg/kg/twice daily, orally), two dihydropyridines exhibiting calcium channel‐blocking properties, against induced infarct‐like lesions was examined. Experimental myocardial infarct‐like lesions were induced in rats by subcutaneous injection of isoproterenol (0.5 mg/kg). The lesions were mainly located in subendocardial areas of the free wall of the left ventricle, and were intramural at the apex and ventricular septum. Pretreatment with oxodipine significantly reduced the infarct size in the apical and basal myocardium (P <0.05). Possible explantations for the lack of effect of nitrendipine pretreatment are discussed.
The Effects of GABAergic Drugs on Grooming Behaviour in the Open Field
Authors: Barros H. M. T. , Tannhauser S. L. , Tannhauser M. A. L. , Tannhauser M.
Published: March 2009

In a previous study it was demonstrated that sodium valproate, a drug that increases GABA cerebral concentrations, decreases grooming in the open field. This effect was not modified by morphine or naloxone. To provide evidence for the participation of the GABA system in the expression of grooming, other GABAergic drugs were acutely administered to rats before the test in the open field. The drugs, in the doses tested, did not modify locomotion, rearing, freezing or defaecation. Aminooxiacetic acid 10 mg/kg, barbital 60 mg/kg, baclofen 1.5 mg/kg, clonazepam 0.1 mg/kg, sodium valproate 150 mg/kg and 4,5,6,7‐tetrahydroxi‐azolo‐5,4c‐pyridine‐3‐ol (THIP) 0.75 mg/kg were the lowest doses to decrease the frequencies of grooming. The estimated ED50to suppress grooming behaviour in the open field were 1.75 mg/kg baclofen, 52 mg/kg barbital, 0.86 mg/kg clonazepam and 1.0 mg/kg THIP. The decrease in grooming produced by the lowest effective doses of aminooxiacetic acid, clonazepam, sodium valproate and THIP was antagonized by concomitant administration of picrotoxin 1 mg/kg or bicuculline 1 mg/kg. The effects of baclofen and barbital on grooming were not modified by the antagonists. It is concluded that the GABA system, through GABA A and GABA B receptors may play a role in the expression of novelty‐induced grooming behaviour.
Influence of Tolfenamic Acid on Airway Contractility in Guinea Pigs
Authors: Rydberg Iréne G. M. , Andersson Rolf G. G.
Published: March 2009

Abstract The effect of the NSAIDs tolfenamic acid and indomethacin was tested on acetylcholine‐induced and antigen‐induced contractions in guinea pig airways. Indomethacin potentiated antigen‐induced contractions while tolfenamic acid showed dilatory properties. The effect of the drugs on acetylcholine‐induced contractions showed no significant differences; indomethacin had a slightly increasing tendency while tolfenamic acid reduced the contractile response. These results indicate that tolfenamic acid does not have bronchoconstrictive properties, which is a common side effect of other NSAIDs in asthmatics.
Transcriptional Activation of a Model Reporter System by Retinoids and Retinoic Acid Receptor Isoforms
Authors: Huggenvik Jodi I. , Sharma Ragbubir P.
Published: March 2009

Abstract: Retinoic acid (RA) and its congeners mediate their biologic effects after binding to nuclear transcription factors called retinoic acid receptors. Biological effects and binding affinities to various receptors vary widely. Activation of transcription ability for selected retinoids was investigated using a standardized model system. CV‐1 cells were cotransfected with a retinoic acid responsive reporter plasmid and expression vectors for retinoic acid receptors (RARs, α, β or γ) and/or retinoic X receptor (RXRα), and were treated with a retinoid (all‐tran‐RA, 13‐cis‐RA, Ro 12‐4894, SRI 5898‐21, or Ro 13‐7410). Gene transcription for all retinoids tested was activated in a dose‐dependent manner. All‐trans‐RA was the most potent activator of RARα while SRI 5898‐21 was the least active. RARa and RARβ showed similar levels of activation with all the retinoids tested, Ro 12‐4894 and Ro 13‐7410 induced little transcription in the presence of RARγ. Cotransfection of RXRα with the RARs changed the ability of the retinoids to activate transcription. Transcriptional activation in cells cotransfected with RXR and RARβ or RARγ was lower than in cells cotransfected with RARβ alone or RARγ alone. Such models with specific responsive elements may be useful for evaluating the relative activity of various retinoids in vitro, however, complex interactions are likely depending on the choice of the reporter construct and other transcription factors available in the cell.
Effects of Zinc on Production of Active Oxygen Species by Rat Neutrophils
Authors: Takeyama Yuko , Ogino Keiki , Segawa Hiroyuki , Kobayashi Haruo , Uda Taizo , Houbara Tatsuya
Published: March 2009

Abstract: The effects of zinc on the production of active oxygen species were investigated in rat neutrophils by chemilumi‐nescence and spectrophotometric assays. The luminol‐dependent chemiluminescence in unstimulated neutrophils showed a single peak. Zinc at concentrations lower than 0.1 mM augmented the intensity of chemiluminescence and showed a bimodal pattern, the first peak of which was inhibited by superoxide dismutase and catalase, while the second peak disappeared in the presence of catalase, but was unaffected by superoxide dismutase. At the same concentrations of zinc, O2− and H2O2 production increased, but secretion and activity of myeloperoxidase were not affected. Zinc at 0.1 mM enhanced the second peak of luminol‐dependent chemiluminescence, and concomitantly O2− and H2O2 production of neutrophils stimulated with formyl‐methionyl‐leucyl‐phenylalanine. Homogenized neutrophils showed a bimodal pattern on induction by zinc, the second peak of which was inhibited slightly by catalase and completely by sodium azide, but was not inhibited by superoxide dismutase. Zinc‐induced O2− production was inhibited by pertussis toxin, but was not significantly inhibited by a protein kinase C inhibitor, 1‐(5‐isoquinolinesulfonyl)‐2‐methylpiperazine dihydrochloride (H‐7), or a calmodulin antagonist, N‐(6‐aminohexyl)‐5‐chloro‐1‐naphthalenesulfonamide (W‐7). These results suggest that zinc can augment luminol‐dependent chemiluminescence by increasing O2− production through the classical signal transduction pathway, and by increasing H2O2 not via O2−.
Improved Isolation of Cardiomyocytes by Trypsination in Addition to Collagenase Treatment
Authors: Viko Håvard , Osnes Jan‐Bjørn , Sjetnan Anne Elisabeth , Skomedal Tor
Published: March 2009

Abstract: The present study was undertaken to develop an improved and stabilized method for isolating cardiomyocytes from perfused rat heart. Different lots of the commercial collagenases used for isolating cardiomyocytes give variable results both with respect to the total cell yield and the percentage of elongated cells obtained. When trypsin was present both before and during collagenase treatment of the tissue, the performance of the collagenases was improved and stabilized, and a high and stable cell yield (7.5X106 cells per heart), and a high percentage of elongated cells (about 70%) was regularly obtained. The cells posessed aradrenergic binding sites with binding properties (Bmax=43.5 fmol/mg protein and Kd=125.5 pmol/1) in agreement with values previously reported. The cells were able to respond functionally, as the cellular uptake of 86Rb+ increased by 18% after α1‐adrenoceptor stimulation with phenylephrine. These criteria indicate that the cells were well preserved during the isolation procedure.
Metabolism of Mercury in Hamster Pups Administered a Single Dose of 203Hg‐Labeled Methyl Mercury
Authors: Dock Lennart , Rissanen Riitta‐Liisa , Vahter Marie
Published: March 2009

Abstract: Golden Syrian hamster pups were administered a single subcutaneous dose of 203Hg‐labeled methyl mercury (MeHg), 0.4 nmol/g body weight, seven days after birth, and were sacrified 2, 7, 14, 21 or 28 days later. The excretion of 203Hg followed a biphasic elimination pattern with an average half‐time of 8.7 days for the rapid component. The slow component had a much longer half‐time and probably reflects binding of 203Hg to growing hair. The concentration of 203Hg in the liver, kidneys and brain two days after administration was 0.44, 0.38 and 0.19 nmol/g, respectively. The retention of 203Hg was higher in the kidney than in the liver and the brain. The content of inorganic 203Hg in the liver and kidneys increased the first weeks after administration, demonstrating that hamsters are able to demethylate MeHg before two weeks of age.
Effects of Remoxipride and Raclopride on Prolactin Release from Clonal Pituitary Tumour Cells
Authors: Nilsson Christer L. , Eriksson Elias
Published: March 2009

Abstract:The dopamine D2receptor antagonist remoxipride (30 μM) stimulated prolactin release from the prolactin‐producing rat pituitary tumour cell strains GH3and GH4C1as well as from transfected GH4C1cells expressing the short isoform of the rat D2receptor (GH4ZR7). The effect of remoxipride on prolactin release is probably not due to an interaction with D2receptors since GH4C1cells, in contrast to GH3and GH4ZR7cells, are completely devoid of D2receptors; in contrast, we have previously shown that the D2antagonist haloperidol causes prolactin release from D2receptor‐expressing cells, only. Exposure of GH3cells to the inhibitor of intracellular Ca2+mobilization, 8‐(diethylamino)‐octyl 3, 4, 5‐trimethoxybenzoate hydrochloride (TMB‐8) prevented the prolactin‐releasing effect of remoxipride whereas pretreatment with the membrane Ca2+channel antagonist nimodipine did not influence the response. The D2receptor antagonist raclopride counteracted the reduction of VIP‐stimulated prolactin release induced by the D2agonist quinpirole but caused no prolactin releaseper se.
Effects of Gabexate, a Protease Inhibitor, on Smooth Muscle of Guinea‐Pig Stomach Fundus
Authors: Hirano Ken , Nakazawa Saburo , Tomita Tadao
Published: March 2009

Abstract:A protease inhibitor, gabexate (ethyl‐p‐6‐guanidinohexanoyloxy benzoate), was found to have an antimuscarinic action in muscle strips of the guinea‐pig gastric fundus. Gabexate reversibly inhibited carbachol‐induced contractions in the presence of prostaglandin synthesis inhibitors (indomethacin or meclofenamate) with a pA2of 5.66 for the circular and 5.25 for the longitudinal muscle. The effect was not affected by tetrodotoxin. Gabexate also inhibited contractions produced by prostaglandin E2(PGE2) (21.7 ± 7.3% with 30 μM, n = 12). The inhibition was markedly potentiated by anticholinesterase, diisopropyl fluorophosphate, but converted to contraction by atropine. In the absence of PGE2, gabexate produced no mechanical response on its own even after atropine application. Treatment with hemicholinium, an acetylcholine synthesis inhibitor, also converted the relaxant effect of gabexate, applied during PGE2‐induced contraction, to contraction. Gabexate also inhibited contracture induced by 30 mM K+weakly (13 ± 2% with 30 μM, n=5). This relaxation was abolished by atropine, without converting to contraction. PGE2and excess K+are likely to release acetylcholine from nerve fibres. These results suggest that the inhibitory effect of gabexate is mainly due to the muscarinic receptor blocking action. In addition, gabexate has a potentiating action on the prostaglandin‐induced contraction.
Function of the Auditory System, the Visual System, and Peripheral Nerve and Long‐Term Combined Exposure to Toluene and Ethanol in Rats
Authors: Nylen Per , Hagman Maud , Johnson Ann‐Christin
Published: March 2009

Abstract: Male pigmented rats (n=36) were exposed to toluene and/or ethanol (1000 p.p.m. toluene in the inhaled air 21 hr/day, and 5.7‐8.0% ethanol in the drinking water continuously) during 8 weeks. Electrophysiological recordings were made 1 week after the exposure. Auditory sensitivity (auditory brainstem response) was reduced only after exposures including toluene. At 20 kHz, ethanol antagonized toluene‐induced loss of auditory sensitivity (P<0.05). Flash evoked potentials were not affected in any group. In peripheral nerve, exposures containing ethanol were followed by increased amplitudes of nerve and muscle action potentials. Exposures including toluene were followed by an increase in liquid consumption.
Prenatal Toxicity of Heptachlor in Albino Rats
Authors: Amita Rani B. E. , Krishnakumari M. K.
Published: March 2009

Abstract:Exposure of the cyclodiene insecticide heptachlor at 1/8 and 1/4 LD50to male and female albino rats before mating affected fertility in both sexes. A decrease in implantations, serum oestrogen and progesterone levels and increase in resorptions in the females was observed. However, no histological changes were observed except for few atretic follicles in the treated females. In males, a dose‐dependent significant decrease in the sperm count and coagulating gland fructose levels was observed, with marginal degeneration of seminiferous tubules. These results are indicative of the prenatal toxicity of heptachlor in male and female rats.
Ethanol Inhibits Acetate Metabolism in Rat Hepatocytes
Authors: Knudsen Charlotte T. , Quistorff Bjørn , Grunnet Niels
Published: March 2009

Abstract:The metabolism of acetate at concentrations of 1, 2.5, 5 and 10 mM was investigated in freshly isolated hepatocytes from 48 hr fasted, female rats in the absence and presence of 10 mM ethanol. The maximal capacity for acetate metabolism was 0.85 μmol/(108cells · min). Ethanol caused a 20% decrease in the apparent Vmaxfor acetate metabolism and an increase in the apparent Km for acetate from 3.0 to 4.6 mM. At physiological concentration of acetate (~ 1 mM) and in the absence of an inhibitory effect of ethanol, the capacity for acetate metabolism was 15–20% of the rate of acetate formation from ethanol and the inhibitory effect of ethanol further reduced it to 10–15%. The results thus explain the well‐known but hitherto not understood fact that only a small fraction of acetate produced in the liver during ethanol oxidation is further metabolized by the liver, while the majority is exported for oxidation in other tissues. Finally, a new method for calculation of liver acetate uptake in the presence of ethanol is presented.
Tropisetron and Octreotide Reduce Serotonin‐Induced Fluid Hypersecretion in Pig Jejunum
Authors: Hansen Mark Berner
Published: March 2009

Abstract:In vitrodata suggest that the serotonin receptor subtype 4 (5‐HT4) mediate part of the serotonin (5‐HT)‐induced intestinal secretion. This study elucidates the involvement of the intestinal 5‐HT4receptor subtype and the anti‐diarrhoeal therapeutic potentials of tropisetron and octreotide in 5‐HT‐induced intestinal hypersecretionin vivo.The effects of intraluminal 5‐HT, 5‐methoxytryptamine, and tropisetron (ICS 205‐930), and subcutaneous octreotide (SMS 201‐995) on fluid hypersecretion (accumulation) was studied in tied‐off loops in pig jejunum. 5‐HT, 5‐methoxytryptamine (5‐HT4agonist), and tropisetron (5‐HT3/5‐HT4antagonist) all induced a dose‐dependent hypersecretion. Low doses of tropisetron reduced, while high doses of tropisetron enhanced the 5‐HT and 5‐methoxytryptamine responses. Taking into account the hypersecretory effect by itself, tropisetron seemed to completely block the hypersecretory effects of 5‐HT and 5‐methoxytryptamine. Finally, octreotide reduced the hypersecretory effect of 5‐HT, maximally by 30%. These results suggest the involvement of the intestinal 5‐HT4receptor subtype in 5‐HT‐induced hypersecretion in pig jejunumin vivo.Furthermore, this study demonstrates a potential therapeutic value for octreotide in 5‐HT‐related diarrhoeagenic disorders in the pig.
Comparison of High Affinity Binding of3H‐Proadifen and3H‐(‐)‐Cocaine to Rat Liver Membranes
Authors: Ross Svante B.
Published: March 2009

Abstract:The characteristics of the binding of3H‐proadifen to rat liver membranes were studied and compared to those of3H‐cocaine. It was found that3H‐proadifen was bound reversibly with high affinity (KD=1.8 ± 0.5 nM) and large capacity (Bmax=2010 ± 340 pmol/g wet tissue) to liver membranes. The corresponding values for the3H‐cocaine binding were 3.5 nM and 1000 pmol/g wet tissue. The binding of3H‐proadifen was mainly localised to the microsomal fraction. The number of binding sites was not increased by treatment of rats with phenobarbitone. With 1 μM CdCl2in the incubation buffer it was possible to differentiate between two3H‐cocaine binding sites with Kd values of 1.6 and 7.7 nM and Bmaxvalues of 280 and 940 pmol/g wet liver tissue. S‐(‐)‐Alaproclate inhibited the binding of3H‐proadifen and3H‐cocaine with high affinity (IC50=2.2 nM and 0.4 nM, respectively). The R‐enantiomer was 100 to 300 times less potent. Cocaine inhibited the binding of3H‐proadifen (IC50= 10 nM) and proadifen that of3H‐cocaine (IC50= 1 nM). There was a high correlation coefficient (rr=0.972; P<0.01; n=12) in the Spearman rank test between the inhibitory potencies of compounds examined in both systems. Besides some potent alaproclate analogues a couple of compounds had moderately high affinity (IC50= 100–500 nM): chloroquine, phenoxybenzamine, amitriptyline, ajmaline, remoxipride, imipramine and (‐)‐alaprenolol. CdCl2, ZnCl2and CuCl2inhibited the binding of both ligands with low Hill coefficients, indicating heterogeneous binding sites. The inhibition curve of Cd2+on the cocaine binding was biphasic with a high affinity part around 50 nM and a low affinity part at 15 μM. The similarity of the characteristics of the binding of these ligands with that of3H‐alaproclate is discussed. It is suggested that all three compounds bind to the same sites, although additional binding sites seem to exist for proadifen.
Metoclopramide Inhibits the Cytotoxicity of Cisplatin and Enhances the Cytotoxicity of Epirubicin
Authors: Motlagh Parviz Behnam , Henriksson Roger , Grankvist Kjell
Published: March 2009

Abstract: During cancer treatment, the use of antiemetics are often needed due to induction of nausea and vomiting by antineoplastic drugs. Some antiemetics have however been afflicted with cytotoxic effects during chemotherapy. The influence of the commonly used antiemetic metoclopramide on the cytotoxicity of epirubicin and cisplatin was tested on fibroblasts (V79) and lung cancer cells (P31) in vitro. The clonogenic survival of fibroblast and lung cancer cells were reduced when the cells were exposed to epirubicin or cisplatin. Metoclopramide (0.5 or 5 mg/l) enhanced epirubicin‐induced toxicity to both fibroblast and lung cancer cells, but inhibited the cytotoxicity of cisplatin. The demonstrated effect of metoclopramide on cells in vitro and the fact that metoclopramide is used as a routine antiemetic during cancer treatment, may indicate that a possible clinical interaction with the antineoplastic action of cancer treatment drugs should be given attention.
Role of Cyclic AMP in Stimulation‐Evoked Release of3H‐Noradrenaline from Rabbit Isolated Ear Artery
Authors: Abrahamsen Jan , Nedergaard Ove A.
Published: March 2009

Abstract:The possible involvement of cyclic AMP in the stimulation‐evoked3H‐overflow from rabbit isolated ear artery preloaded with3H‐noradrenaline was studied. Cyclic AMP (10–5–3x10–4M), 8–bromo‐cyclic AMP (3x10–4M) and adenosine (10–5–3X10–4M) enhanced stimulation‐evoked3H‐overflow. Dibutyryl‐cyclic AMP (10–5–3x10–4M) had no effect. Theophylline (3X10–5M) and the phosphodiesterase inhibitor AH 21–132 (3X10–5M) did not alter the enhancement of3H‐overflow caused by either cyclic AMP or adenosine. Forskolin (3X10–6M) and the phosphodiesterase inhibitors ICI 63 197 (10–4M) and AH 21–132 (3x10–6–3x10–5M) increased stimulation‐evoked3H‐overflow. Forskolin (10–6M) enhanced the effect of ICI 63 197 (3x10–5M) but it did not alter the effect of AH 21–132. It is concluded that cyclic AMP is involved in the stimulation‐evoked release of noradrenaline from postganglionic sympathetic nerves in the rabbit ear artery.
Effects of Sulfhydryl Compounds on the Accumulation, Removal and Cytotoxicity of Inorganic Mercury by Primary Cultures of Rat Renal Cortical Epithelial Cells
Authors: Endo Tetsuya , Sakata Masakatsu
Published: March 2009

Abstract:The effects of sulfhydryl compounds on the accumulation, removal and cytotoxicity of inorganic mercury (Hg) were investigated in primary cultures of rat renal cortical epithelial cells. The compounds investigated were 2, 3–dimercapto‐succinic acid, 2, 3–dimercapto‐1‐propanol, D‐penicillamine, glutathione (GSH) and L‐cysteine. In the accumulation experiment, the cells were co‐incubated with Hg and the above compounds for 30 min. (short‐term) or 18 hr (long‐term). In the removal experiment, cells incubated with Hg were further incubated with the above compounds for 30 min. In both experiments, the alleviative effect of the compounds on the cytotoxicity was estimated by the uptake of neutral red or by cell growth. 2, 3–Dimercaptosuccinic acid had the highest antidotal effects except for Hg removal. 2, 3–Dimercapto‐1‐propanol exerted the least antidotal effects in the short‐term, as well as in the long‐term experiments, 2, 3–dimercapto‐1‐propanol increased the Hg accumulation and the cytotoxicity despite its removal of most of the Hg. Although D‐penicillamine, L‐cysteine and GSH did not increase the Hg removal in the long‐term experiment other antidotal effects were seen.
Inhibition by Lithium of Neomycin‐Induced Release of N‐Acetyl‐β‐glucosaminidase in the Rat Heart
Authors: Dehpour Ahmad Reza , Samini Morteza , Ghafourifar Pedram , Kyani Homayoun
Published: March 2009

Abstract:The effects of neomycin, lithium and concurrent therapy of these drugs on subcellular distribution of lysosomal enzyme, N‐acetyl‐β‐glucosaminidase (NAG) in the heart was studied. Released activity of NAG was used as a marker for assessing myocardial lysosomal integrity. The activity of NAG was determined in non‐sedimentable and sedimentable fractions after centrifugation of the tissue extracted for assessment of the subcellular distribution of the lysosomal enzyme. Daily intraperitoneal injection of 100 mg/kg/day of neomycin increased the ratio of the non‐sedimentable activity (free) to the non‐sedimentable plus sedimentable activities (total) of NAG. Daily intraperitoneal injection of lithium decreased the total activity of NAG but did not affect the ratio of free: total activities of the enzyme. Lithium in doses of 2 and 4 mM/kg/day one hour prior to neomycin reduced the neomycin‐induced enhancement of the ratio of free: total activity of NAG. Neomycin like other aminoglycosides altered the acidic phospholipid metabolism in lysosomal membranes and/or impairment of some important lysosomal functions. In this regard, the protective effects of lithium may be due to interference of this ion with phosphoinositide cycle.
Purinoceptors in the Nervous System*
Authors: Fredholm Bertil B.
Published: March 2009

Abstract:The purine nucleoside adenosine and the purine nucleotide ATP play different roles in the nervous system. Adenosine acts on a family of G protein coupled receptors, collectively called adenosine receptors or P1purinoceptors. Four members of this family have been cloned and pharmacologically characterized: A1A2a, A2band A3. Their distribution, pharmacology and biological roles are briefly discussed. In particular, the evidence that adenosine acting at A1receptors regulates the release of several neurotransmitters and that adenosine acting at A2areceptors modulates dopaminergic transmission is summarized. ATP acts on receptors called P2purinoceptors, which appear to fall into at least two main families – G protein coupled receptors and intrinsic ion channels. Their subclassification is becoming clearer as receptors are cloned and new selective agonists and/or antagonists are becoming available. There is an interesting potential for development of drugs targeted at purines or their receptors.
Release of3H‐5‐Hydroxytryptamine from Isolated Rabbit Aorta
Authors: Gouliaev Alex H. , Nedergaard Ove A.
Published: March 2009

Abstract:The main aim of the present investigation was to study systematically the passive and stimulation‐evoked release of3H‐5‐hydroxytryptamine (3H‐5‐HT) from rabbit isolated aorta. This was accomplished by preloading rings of aorta with3H‐5‐HT (10–6M) and then monitoring by fractional collection the basal3H‐outflow and stimulation‐evoked3H‐overflow. The basal3H‐outflow from aorta preloaded with 10–6M of either3H‐5‐HT or (‐)‐3H‐noradrenaline (3H‐NA) leveled off about 100 min. after the onset of wash‐out and remained almost constant thereafter (100–240 min.). The basal3H‐outflow from tissue preloaded with3H‐5‐HT was almost 3‐fold higher (70–240 min.) than that seen after preloading with3H‐NA. Cocaine (3x10–5M) did not alter the basal3H‐outflow (15–240 min.) from tissue preloaded with3H‐5‐HT, while pargyline (5X10–4M) decreased it by about 66% (100–240 min.). Electrical‐field stimulation (S1S7, 200 mA, 600 pulses, 0.5 msec, 3 Hz) were applied to the tissue. The initial stimulation‐evoked3H‐overflow from aorta preloaded with3H‐5‐HT was higher than the subsequent ones (S1‐S7: 100, 35, 35, 35, 35, 37, and 40%). Similar results to these were obtained with tissues preloaded with3H‐NA. The stimulation (S1‐S7; 200 mA; 600 pulses, 0.5 msec, 3 Hz)‐evoked3H‐overflow increased in an apparent linear manner with the amount of current used (50–200 mA). This was also the case for number of pulses (100–900) in the stimulus. The stimulation‐evoked3H‐overflow depended in part on the stimulation frequency: unchanged at 2–4 Hz; small increase at 8 Hz; and a 15‐fold increase at 16 Hz relative to 2 Hz. Tetrodotoxin (10–6M) decreased the stimulation‐evoked3H‐overflow from aorta preloaded with3H‐5‐HT (S2‐S6) by about 60%, while S1was not affected. The inhibitory effect of tetrodotoxin was fully reversed by washing the aorta with drug‐free salt solution. Omission of Ca2+from the salt solution reduced the stimulation3H‐overflow by 47–57% (S2‐S6) while S1was unaffected. 6‐Hydroxydopamine markedly increased the stimulation‐evoked3H‐overflow from3H‐5‐HT preloaded rings (180–323% of control). Pargyline (5x10–4M), cocaine (3x10–5M) and removal of endothelium did not alter the stimulation‐evoked3H‐overflow evoked by stimulation (S1‐S6) of aorta preloaded with3H‐5‐HT. It is concluded that3H‐5‐HT can be released by electrical‐field stimulation as a “false transmitter'’from rabbit isolated aorta. Most of the release is probably of neuronal origin. However, some of the stimulation‐evoked3H‐overflow is derived from extraneuronal sites.