bluuebunny/crossref_metadata_2025 huggingface dataset:
Two Weeks Inhalation Exposure to 4‐terf‐Butyltoluene Causes Persistent Changes in Visually Evoked Potentials in Rats
Authors: Lund Soren P. , Simonsen Leif , Fries Adolf S.
Published: March 2009

Abstract: The effects of repeated exposure to 20 p.p.m. 4‐tert‐butyltoIuene (CAS No. [98‐51‐1]) 6 hr/day for 14 days on the function of the intact nervous system were examined by measurements of flash evoked potentials in Wistar rats. The exposure to 4‐tert‐butyltoluene induced changes in the amplitudes of the flash evoked potentials. The changes were significantly different from controls on day 2, 19 and 26 after cessation of the exposure, but not on day 5 and 12. No significant difference in body weight gain between groups was found during the experiment. These results indicate that repeated exposure to 20 p.p.m. 4‐tert‐butyltoluene causes persistent changes in the function of the central nervous system measured as changes in the flash evoked potential. A reevaluation of the present TLV‐value of 10 p.p.m. for 4‐tert‐butyltoluene is suggested.
Enhancement of Cytosolic and Microsomal Glutathione S‐Transferase Activities in Liver and Small Intestine from Female Rats During Lactation
Authors: Luquita M. G. , Catania V. A. , Sánchez Pozzi E. J. , Mottino A. D.
Published: March 2009

Abstract:The influence of lactation on hepatic and intestinal glutathione S‐transferase activities in mother rats was studied. Cytosolic and microsomal activities were assessed 7, 14 and 21 days after delivery, using 1‐chloro‐2, 4‐dinitroben‐zene as substrate. Cytosolic and microsomal activities from liver and small intestine determined 7 dayspost partumdid not differ from those of virgin female rats. The hepatic cytosolic activity was significantly increased with respect to that of virgin females 14 days after delivery and tended to revert to the control value on day 21 of lactation, whereas the intestinal activity was increased on day 14 and remained augmented even 21 dayspost partum. Although the respective microsomal activities showed percent increases higher than those of the cytosolic enzymes, they both exhibited a similar pattern of stimulation in response to lactation.
The Effect of Zidovudine and 2′3'‐Dideoxyinosine on Human Trophoblast in Culture
Authors: Esterman Abbie L. , Rosenberg Carl , Brown Tom , Dancis Joseph
Published: March 2009

Abstract: Trophoblast from term and first trimester placenta, maintained in culture, were exposed to 20 μmoles/1 zidovudine or 2′3'dideoxyinosine. Several indices of function were measured and compared to control trophoblast in parallel culture. The results from individual placentas were examined by Student's t‐test and cumulative results by ANOVA. Neither zidovudine or 2′3'‐dideoxyinosine had statistically significant effects on the function of term trophoblast, following a 48 hr exposure to the drug as indicated by hCG secretion, protein synthesis and glucose consumption. In one of five placentas exposed to zidovudine, progesterone secretion was reduced as compared to its control but remained in the high range. Zidovudine had no significant effect on cultured trophoblast isolated from first trimester placenta even after prolonged exposure to the drug for eleven days. Both term and first trimester trophoblast in culture tolerate prolonged exposure to high concentrations of zidovudine or 2′3'‐dideoxyinosine. Human trophoblast in culture provides a safe in vitro model for the screening of drugs intended for use during pregnancy.
Cyclosporin A in Fat Emulsion Carriers: Experimental Studies on Pharmacokinetics and Tissue Distribution
Authors: Tibell A. , Lindholm A. , Sawe J. , Chen G. , Norrlind B.
Published: March 2009

Abstract:In the commercially available intravenous formulation of Cyclosporin A (Sandimmun®), polyoxyethylated castor oil (Cremophor®EL) is used as a solubilizing agent. We have recently reported that the acute nephrotoxic effect of this preparation was alleviated by replacing Cremophor®EL with a soybean oil‐based fat emulsion in a rat model. To further explore the potential of fat emulsions as carriers for cyclosporin A, data on the in vivo pharmacokinetics and tissue distribution are required. In this study in pigs, the pharmacokinetics of soybean oil‐cyclosporin A was compared to that of Sandimmun®. The two formulations seemed bioequivalent, as there were no significant differences in the systemic clearances, volumes of distribution or elimination half‐lives. Moreover, the tissue distributions of soybean oil‐cyclosporin A and Sandimmun® were compared in rats. These studies also included two additional lipid‐based carriers: one based on iodized ester of poppy seed oil and the other on a liposomal preparation. The tissue distributions were found to be similar regardless of the carriers used. Fat emulsion carriers seem to offer possibilities for preparing better tolerated intravenous formulations of cyclosporin A while maintaining the same characteristics concerning pharmacokinetics and tissue distribution.
Effects of Aminoglycoside Antibiotics on Cholinergic Autonomic Nervous Transmission
Authors: Said A. A. , Matsuki N. , Kasuya Y.
Published: March 2009

Abstract:The effects of eight aminoglycoside antibiotics, gentamicin, neomycin B, ribostamycin, dibekacin B, kanamycin A, streptomycin, tobramycin and amikacin, and two non‐aminoglycoside antibiotics, tetracycline and ampicillin, on cholinergic autonomic nervous transmission were studied using isolated guinea‐pig ileum preparation. The aminoglycoside antibiotics blocked the transmurally elicited twitches of the ileum in a concentration‐dependent manner. The blocking effect of aminoglycosides was biphasic, i.e., an initial reduction followed by a spontaneous partial recovery. Dibekacin was the most potent parasympathetic inhibitor, followed by neomycin B, tetracycline, gentamicin, streptomycin, kanamycin A, tobramycin, ribostamycin, and amikacin. Ampicillin had no blocking effect. The tested antibiotics did not affect acetylcholine (ACh)‐induced contraction of the ileum, except for high concentrations of neomycin B, gentamicin, and streptomycin. The three antibiotics shifted the dose‐response curves for ACh to the right without affecting the maximal contraction. Naloxon, yohimbine, hexamethonium and choline chloride failed to eliminate the blocking effect of the antibiotics on twitches of the ileum induced by transmural stimulation. However, increase of the extracellular Ca ion concentration virtually abolished the blockade. Dibekacin blocked the evoked but not the spontaneous release of ACh and shifted the dose‐response curve of CaCl2‐dependent transmurally elicited contractions of the ileum to the right. These results suggest that the site for the block of aminoglycosides is mainly the cholinergic nerve terminal, where they reduce the available Ca ions required for the release of ACh.
Effects of Teratogenic Exposures to Zn2+, Cd2+, Ni2+, Co2+, and Cu2+ on Metallothionein and Metallothionein‐mRNA Contents of Xenopus Embryos
Authors: Sunderman Jr. F. William , Plowman Marilyn C. , Kroftova Olga S. , Grbac‐Ivankovic Svetlana , Foglia Lisa , Crivello Joseph F.
Published: March 2009

Abstract: Xenopus laevis embryos were analyzed for metallothionein by silver‐saturation assay and metallothionein‐mRNA by reverse transcriptase/polymerase chain reaction following exposures to the following metal chlorides at levels that caused >95% malformations and <7% mortality: Zn2+ (300 μM); Cd2+ (18 μM); Ni2+ (56 μM); Co2+ (1,800 μM); and Cu2+ (5.6 μM). At the beginning of the exposures (stages 8), metallothionein‐mRNA and metallothionein levels averaged 2.0X106 copies/embryo and 19 pmol/embryo, respectively. In control embryos at stages 26, 36,42, and 46, metallothionein‐mRNA content averaged 9, 37, 104, and 97 copies X106 /embryo, and metallothionein content averaged 6, 11, 15, and 18 pmol/embryo. In Zn2+‐exposed embryos at the same stages, metallothionein‐mRNA content averaged 116*, 11,400*, 3,210*, and 14 copiesX106/embryo and metallothionein content averaged 10, 18*, 46*, and 90* pmol/embryo; in Cd2+‐exposed embryos, metallothionein‐mRNA content averaged 22, 7, 170*, 1,783*, and 240 copies X106/embryo and metallothionein content averaged 8, 14, 33*, and 56* pmol/embryo, respectively (*plt;0.05 versus controls). Exposure‐response curves (Cd2+, 1–18 μM; Zn2+, 3–300 μM) indicated that Cd2+ was 3‐ to 5‐times more potent than Zn2+, based on metallothionein‐mRNA response at stage 36 and metallothionein response at stage 46. In Ni2+‐, Co2+‐, or Cu2+‐exposed embryos, metallothionein‐mRNA and metallothionein contents did not differ significantly from controls. This study shows that (1) metallothionein‐mRNA is greatly elevated in Zn2+‐ and Cd2+‐exposed embryos at stage 36 and declines to control levels by stage 46, while metallothionein content increases progressively from stage 26 to 46; and (2) elevated metallothionein‐mRNA and metallothionein levels may contribute to malformations induced by Zn2+ or Cd2+, but are unlikely to account for the teratogenic effects of Ni2+, Co2+, or Cu2+.
Glutathione S‐Transferases as a Cefpiramide Binding Protein in Rat Liver
Authors: Guji Atsuko , Nishiya Hajime , Aoki Masumi , Ohyatsu Isao , Yamaguchi Morimichi , Tokumura Yasuaki , Sugiyama Hajime , Miyashita Taku , Ono Yasuo , Kunii Otohiko
Published: March 2009

Abstract:To clarify the intrahepatical transport mechanism of cefpiramide, we investigated effects of various agents mainly excreted into the bile by several different mechanisms on the biliary excretion of cefpiramide in rats. Sulfobromophthalein, indocyanine green, bilirubin and probenecid, known to be bound to glutathione S‐transferases (GST) (EC 2.5.1.18) in liver cytosol, reduced the biliary excretion of cefpiramide, while neither secretory IgA, which is transported via vesicles in the liver, nor colchicine, which inhibits movements of vesicles, had any effect on the excretion of cefpiramide. Propranolol and metoprolol, metabolized by mixed function oxidases, had no effect on the biliary excretion of cefpiramide. In the chromatography of liver cytosol, the amount of sulfobromophthalein or benzylpenicillin bound to the GST fraction decreased in the presence of cefpiramide or probenecid. The study showed that cefpiramide was transported in the liver without relation to mixed function oxidases or vesichle‐mediated transporting system, but in relation to GST which binds cefpiramide, sulfobromophthalein, benzylpenicillin and probenecid, indicating an important role of GST in the cefpirami de excretion into the bile.
The Promoting Action of Magnesium Lithospermate B on the Kinin‐Prostaglandin E2 System in the Kidney
Authors: Chung Hae Young , Kim Jung Sun , Chung Han Young , Yokozawa Takako , Oura Hikokichi
Published: March 2009

Abstract: The effect of magnesium lithospermate B purified from Salviae Miltiorrhizae Radix on the kinin‐prostaglandin E2 system was investigated using kidney slices and isolated kidney microsomes. Magnesium lithospermate B markedly increased the amount of thiobarbituric acid‐reactive substances produced by incubation of arachidonic acid in renal slices. Enhancement of arachidonic acid‐mediated oxygenation of 1, 3‐diphenylisobenzofuran was also observed in renal microsomes from rats treated with magnesium lithospermate B, indicating an increase of prostaglandin biosynthesis. Furthermore, magnesium lithospermate B significantly increased the synthesis of prostaglandin E2 in renal slices, but the magnesium lithospermate B‐mediated response was blunted with kinin antagonist. On the basis of the above results, it is apparent that magnesium lithospermate B exerts an influence on the prostaglandin system via kinin receptors.
Malnutrition and Pharmacokinetics of Penicillin in Ethiopian Children
Authors: Bolme P. , Eriksson M. , Paalzow L. , Stintzing G. , Zerihun G. , Woldemariam T.
Published: March 2009

Abstract: Penicillin was given to 104 children with different nutritional status, normal, underweight, marasmus and kwashiorkor. Penicillin was given either intravenously, intramuscularly or orally and the plasma concentration was followed at regular times after administration. There was a significantly decreased plasma clearance of penicillin in all malnourished groups compared to the normal weight‐for‐age group. The half‐lives of penicillin were, however, not significantly different between the nutritional groups. This was explained by the fact that also the volume of distribution was decreased in the malnourished group with a net result that the half‐life was unchanged. The bioavailability was decreased if penicillin was given to non‐fasting individuals. The greatest difference between fasting and non‐fasting was seen in the severely malnourished children with marasmus and kwashiorkor. Therefore, it is advised that, if penicillin is given orally to very sick and undernourished children, the dose should be increased and preferably be given in the fasting state.
Kinetics and Inhibition by Fluvoxamine of Phenacetin O‐Deethylation in V79 Cells Expressing Human CYP1A2
Authors: Jensen Klaus Gjervig , Poulsen Henrik Enghusen , Doehmer Johannes , Loft Steffen
Published: March 2009

Abstract: The kinetics of phenacetin O‐deethylation and its inhibition by fluvoxamine was investigated in a V79 cell line (V79MZh1A2) transfected with human CYP1A2. In four sets of experiments the apparent Km values for phenacetin O‐deethylation ranged from 35 to 95 μM and the Ki for fluvoxamine‐mediated inhibition of the reaction ranged from 2.7 to 14.5 nM, i.e. comparable to values obtained in human liver microsomes. The kinetic performance of the V79MZh1A2 cell line demonstrates its usefulness as an analytical tool in a variety of toxicological and drug metabolism studies involving CYP1A2.
High Throughput Assays of Cloned Adrenergic, Muscarinic, Neurokinin, and Neurotrophin Receptors in Living Mammalian Cells
Authors: Messier Terri L. , Dorman Christine M. , Braüner‐Osborne Hans , Eubanks David , Brann Mark R.
Published: March 2009

Abstract:Many receptors stimulate proliferation of NIH 3T3 cells in a ligand dependent fashion. Based on this observation, we developed a high throughput assay of cloned receptor pharmacology. In this assay, receptors are transiently co‐expressed with the marker enzyme β‐galactosidase. Receptors that induce cellular proliferation select and amplify the cells that also express the marker, thus the ability of ligands to alter receptor activity are reported as changes in enzyme activity. In the present study, we used this assay to evaluate the ability of agonist ligands to stimulate four cloned receptors. The agonists phenylephrine, carbachol, substance P and nerve growth factor selectively stimulated cells transfected with the α‐1b adrenergic, m4 muscarinic, NK1 neurokinin and trkA neurotrophin receptors, respectively. These data demonstrate that a high throughput colorimetric assay performed in 96 well plates can be used to evaluate the pharmacology of ligands for cloned receptors belonging to a wide range of functional and pharmacological classes.
Effects of Lead and Mercury on Histamine Uptake by Glial and Endothelial Cells
Authors: Huszti Zsuzsanna , Balogh István
Published: March 2009

Abstract: The effects of lead and mercury on [3H]‐histamine uptake by cultured astroglial and endothelial cells of rat brain were studied. Experimental data showed that both metal ions inhibited the uptake in both cell types of concentrations as low as 1–10 μM. The effects were consistent with non/competitive inhibitions. With either lead or mercury exposure, the inhibition of the uptake was greater in astroglial than in cerebral endothelial cells. Contrary to the above findings, 100 μM of mercuric chloride produced stimulation of histamine uptake and this stimulation was much more pronounced in cultured cerebral endothelial cells than in astroglial cells. Inhibition of [3H]‐histamine uptake by lead acetate and mercuric chloride was considered to be association with a loss of the transmembrane Na+ and/or K+ gradient while stimulation of the uptake by high concentration of mercury might be related to a direct effect on histamine transporter. It is noteworthy, that cultured astroglial cells, derived from neonatal rat brain, are much more sensitive to the toxic effects of these heavy metal ions than cultured endothelial cells derived from the brain capillaries of the same species of animals.
Is there any Cross‐Antagonism between μ‐Opioid and α2‐Adrenergic Receptors in the Rat Spinal Cord?
Authors: Kontinen Vesa K. , Kalso Eija A.
Published: March 2009

Abstract:A functional connection, evidenced by synergism and cross‐tolerance, seems to exist between the μ‐opioid and the α2‐adrenergic receptors in the superficial dorsal horn of the rat spinal cord. In this study possible cross‐antagonism between these systems was studied by intrathecal administration of morphine 2.5 μg or dexmedetomidine 1.25 μg 15 min. after subcutaneous injection of naloxone 1.0 mg/kg or atipamezole 3.0 mg/kg in the morphine group and 4.0 mg/kg or 1.0 mg/kg in the dexmedetomidine group, respectively. No cross‐antagonism of the antinociceptive effect was seen either in the tail flick or in the hot plate test at 15, 30, 45 and 60 min. from the pretreatment.
Differences in Brain 5‐HT Transporter Dissociation Rates among Animal Species
Authors: Erreboe Inge , Plenge Per , Mellerup Erling T.
Published: March 2009

Abstract: The potential of using receptor‐ligand dissociation rates as a model for investigating molecular changes in receptors was tested using the dissociation of [3H]citalopram, [3H]paroxetine and [3H]imipramine from the brain 5‐HT transporter of four different species (mouse, rat, pig and man). Since the dissociation rates of each of the three ligands differed in most of the species investigated, receptor‐ligand dissociation rate constants would seem to be a sensitive measure of receptor conformation. The model could be useful in the search of structural variation in receptors whether attributable to genetic factors or to posttranslational modification.
Different β‐Adrenergic Receptor Density in Different Rat Skeletal Muscle Fibre Types
Authors: Jensen Jørgen , Brørs Odd , Dahl Hans A.
Published: March 2009

Abstract: The effects of adrenaline on skeletal muscle differ between fibre types. The aim of the present study was to investigate the β‐adrenoceptor density, affinity and subtype in rat skeletal muscles with different fibre type composition. β‐Adrenoceptors were determined in cryostat sections to avoid methodological problems with variable recovery, using the non‐selective β‐adrenoceptor ligand [3H]CGP‐12177 and β1 and β2‐selective cold ligands CGP 20712A and ICI 118,551. In the presence of protease inhibitors [3H]CGP‐12177 binding was stable, saturable, reversible, and displaceable. Scatchard analysis of binding saturation data was compatible with a single class of specific binding sites. Binding site density (Bmax) was higher (P<0.02) in adult soleus (9.38 ± 1.13 fmolxmg protein–1) than in adult extensor digitorum longus (4.74 ± 0.39 fmolxmg protein–1), whereas the dissociation constants (Kd), 0.37® pL 0.05 and 0.31 ± 0.04 nM for soleus and extensor digitorum longus, respectively, were not significantly different. For young rats (5–6 weeks), Bmax was 11.21 ± 0.33 and 5.45 ± 0.11 fmolxmg protein–1 (P<0.05), and Kd was 0.27±0.02 and 0.24±0.04 nM for soleus and epitrochlearis, respectively. These results correspond to a receptor density of 2 and 1 pmolxg w.wt.–1 in muscles containing mainly type I and type II fibres, respectively. Displacement studies with CGP 20712A and ICI 118,551 were compatible with mainly β2‐adrenoceptors, but 7–10% β1‐adrenoceptors were present in both types of muscle. In conclusion, the receptor density is twice as high in muscles containing mainly type I muscle fibres compared to muscles containing mainly type II fibres, and this may explain some of the different effects of adrenaline between the two muscle fibre types.
Immunosuppression, Macroencapsulation and Ultraviolet‐B Irradiation as Immunoprotection in Porcine Pancreatic Islet Xenotransplantation
Authors: Sandberg J.‐O. , Olsson N. , Johnson R. C. , Hellerström C. , Andersson A.
Published: March 2009

Abstract: Membrane encapsulation or ultraviolet‐B irradiation, with or without mild immunosuppressive treatment, was applied in order to prolong the survival of xenogeneic porcine foetal pancreatic grafts. Non‐diabetic C57BL/6 mice were transplanted with porcine islet‐like cell clusters, either membrane‐encapsulated in the epididymal fat pad, or non‐encapsulated under the kidney capsule. The animals were treated with daily subcutaneous injections of either cyclosporin A (12.5 mg/kg b.wt.), 15‐deoxyspergualin (5.0 mg/kg b.wt.), ethyl (E)‐6‐(1, 3‐dihydro‐4‐hydroxy‐6‐methoxy‐7‐methyl‐3‐oxo‐5‐isobenzofuranyl)‐4‐methyl‐4‐hexenoate. (RS‐61443) (70 mg/kg b.wt.) or with cyclophosphamide (70 mg/kg b.wt.) every second day. A fulminant mononuclear cell infiltration was observed 14 days after transplantation both around the subcapsular graft and outside the membranes in the saline treated control group. The membrane had pores of 0.45 μm and was designed to allow macromolecule transport but prevents cells from crossing. Therefore, xenoantigens can escape from the membrane implants and cause an immune reaction. A significantly weaker mononuclear cell infiltration was, however, seen when the membrane barrier was combined with 15‐deoxyspergualin, cyclophosphamide or RS‐61443 treatment but the morphology of the encapsulated ICC was not improved. The best subcapsular, non‐encapsulated graft survival was obtained in animals treated with 15‐deoxyspergualin or cyclophosphamide and the graft insulin content measurements confirmed the morphological data. There was no prolongation of islet‐like cell cluster graft survival under the kidney capsule after ultraviolet‐B irradiation alone (650 J/m2 for 90 sec), and no synergistic effect was observed when ultraviolet‐B irradiation was combined with 15‐deoxyspergualin therapy (2.0 mg/kg b.wt.). It is concluded that neither membrane encapsulation with membrane that allow xenoantigen escape from the implants nor ultraviolet‐B irradiation are able to prolong discordant xenograft survival in mice. However, such an effect may be obtained by repeated administration of 15‐deoxyspergualin or cyclophosphamide.
Atropine Reverses Antinociception Induced by 2,5‐Hexanedione in Rats
Authors: Pereira M. E. , Rocha J. B. T. , Izquierdo I.
Published: March 2009

Abstract: 2,5‐Hexanedione is a n‐hexane metabolite with neurotoxic properties. We have previously demonstrated that acute administration of 2,5‐hexanedione causes analgesia in the tail‐flick test in rats. In the present investigation, we examined the possible involvement of a cholinergic component in the 2,5‐hexanedione‐induced antinociception, since literature data indicate that this hexacarbon compound may act as a competitive inhibitor of acetylcholinesterase and that cholinesterase inhibitors are analgesic to rodents. Rats were treated with saline or with 5 or 25 mg/kg atropine (intraperitoneally) 10 min. before the injection of vehicle or 800 mg/kg 2,5‐hexanedione (intraperitoneally). 2,5‐Hexanedione caused a significant increase in tail‐flick latencies at 10, 30, 60 and 90 min. after hexacarbon injection. Atropine (5 or 25 mg/kg) partially reversed the analgesia caused by 2,5‐hexanedione at 60 and 90 min. When effects of 2,5‐hexanedione on brain acetylcholinesterase was assessed in vitro, the results demonstrated that a competitive component is involved in enzyme inhibition. Taken together, these data support the involvement of a cholinergic (muscarinic) component in 2,5‐hexanedione‐induced analgesia.
Effect of Renal Ischaemia on Organic Compound Transport in Rabbit Kidney Proximal Tubule
Authors: Kim Yong Keun , Woo Jae Suk , Kim Young Hee , Jung Jin Sup , Kim Bong Seon , Lee Sang Ho
Published: March 2009

Abstract:This study was carried out to determine the effect of renal ischaemia on transport systems for organic compounds in the rabbit kidney proximal tubule. Ischaemia for 30 or 60 min. induced glucosuria and phosphaturia, which was accompanied by polyuria and natriuresis. The Na+‐dependent uptake of glucose, succinate and L‐glutamate by brush‐border membrane vesicles was not altered by 30 or 60 min. of ischaemia, while the H+/tetraethylammonium antiport was significantly inhibited after 30 min. of ischaemia. When the duration of ischaemia was extended to 120 min. the uptake of glucose and succinate by brush‐border membrane vesicles was also significantly attenuated, but the L‐glutamate uptake was not altered. The uptake of glucose, succinate and L‐glutamate by basolateral membrane vesicles was not impaired even with 120 min. of ischaemia, suggesting that transport systems for organic compounds in the brush‐border membrane are more sensitive to ischaemia than those in the basolateral membrane. Ouabain‐sensitive oxygen consumption in renal cortical slices was not depressed by 60 min. of ischaemia. When kidneys were reperfused for 60 min. following 60 min. of ischaemia, the Na+‐glucose and Na+‐succinate cotransport and the H+/tetraethylammonium antiport were not different from the control, but the recovery of alkaline phosphatase was significantly reduced. When kidneys were subjected to ischaemia for 60 min., a loss of brush‐border microvilli and plasma membrane was observed after 5 or 60 min. of reflow in the proximal convoluted tubule. After 3 hr of reflow, focal necrosis appeared although the microvilli were partially regenerated. These results indicate that renal ischaemia induces selective impairments of transport systems in the rabbit renal proximal tubule, and that the glucosuria and phosphaturia induced by transient ischaemia are results, at least in part, from a diminution of brush‐border surface area rather than a direct defect in the function of the membrane transport systems.
Transplacental and Lactational Exposure to Mercury in Hamster Pups after Maternal Administration of Methyl Mercury in Late Gestation
Authors: Nordenhäll Kerstin , Dock Lennart , Vahter Marie
Published: March 2009

Abstract: Pregnant Syrian golden hamsters were given a single oral dose of 203Hg‐labelled methyl mercury (MeHg), 1.6 μmol/kg body weight, on day 12 of gestation. The uptake, retention and tissue distribution of 203Hg in the dams and pups was studied by γ‐counting during the following three weeks. The average transplacental transfer of 203Hg was 1.1% of the administered dose per pup, corresponding to 11% of the administered dose to a whole litter. This was considerably more than in our previous studies when the dams were treated on gestational day 2 (1.3%) or 9 (4.6%). The amount of 203Hg transferred to each pup in utero was independent of the litter size. The average additional transfer of 203Hg to a litter via milk was 1.7% of the administered dose. In the pups, the content of 203Hg in the liver and brain decreased, while the content in the kidneys and pelt increased during the second and third week. The highest amount of 203Hg was generally found in the pelt, which indicated that unweaned hamster pups primarily excrete MeHg by binding to hair. The chemical form of mercury in the liver and kidneys of the pups was determined by ion‐exchange separation of inorganic Hg and MeHg followed by γ‐counting. The amount of inorganic Hg in the liver of the pups remained constant throughout the experiment, while it increased in the kidneys after one week due to the demethylation of MeHg. The inorganic Hg in the liver of newborn pups was probably due to maternal demethylation of MeHg and transplacental transfer of inorganic Hg. This hypothesis was supported by the observed transplacental transfer of inorganic Hg in pregnant dams administered 203HgCl2 on day 12 of gestation.
Screening of Potential Transport Systems for Methyl Mercury Uptake in Rat Erythrocytes at 5° by Use of Inhibitors and Substrates
Authors: Wu Guang
Published: March 2009

Abstract:The current study was designed to screen the potential transport systems for methyl mercury (MeHg) uptake by isolated erythrocytes from rats at 5°. Several inhibitors and substrates were used to test which potential transport system might be involved in MeHg uptake. Probenecid was used to test the organic anion transport system, valinomycin was used to test the effect of the membrane potential, D‐glucose and cytochalasin B were used to test the facilitated diffusive D‐glucose transport system and colchicine and vinblastine were used to test the microtubule system. The effects of Ca++, Mg++and Na+on MeHg uptake have been examined. Ouabain, ATP and glucose were used to test the active transport system, cysteine for the cysteine‐facilitated transport system, glycine for system Gly, DL‐methionine for system L, and MeHgCl and 4′,4‐diisothiocyano‐2′,2‐stilbenedisulfonic acid (DIDS) for the Cl‐ion transport system. The results showed that MeHg uptake might be involved in the following transport systems at 5°: 1) organic anion transport system; 2) facilitated diffusive D‐glucose transport system; 3) cysteine‐facilitated transport system; 4) Cl‐ion transport system. Moreover, the transport systems for MeHg uptake were sensitive to the membrane potential. Although the mechanisms of interaction of transport systems have not been fully clarified, evidence has been presented which support the existence of several simultaneous transport systems for MeHg uptake.
Quantitative and Qualitative Distribution of Mercury in Organs from Arctic Sledgedogs: An Atomic Absorption Spectrophotometric and Histochemical Study of Tissue Samples from Natural Long‐Termed High Dietary Organic Mercury‐Exposed Dogs from Thule, Greenland
Authors: Hansen Jens C. , Danscher Gorm
Published: March 2009

Abstract: Organs from 10 sledgedogs fed methyl mercury‐containing organs and meat from predatory marine animals also eaten by humans in the Thule district of Greenland, were examined histochemically for cellular distribution of mercury, and the organ concentrations of mercury were quantified by atomic absorption spectrometry (total Hg). In selected organs the methyl mercuric level was determined by gaschromatography. The highest concentration of total mercury was found in mesenterial lymph nodes followed by liver and kidneys, which indicates that the lymphatic system might play an important role in the regulating transport of mercury to target organs. The concentrations were age‐related, and the results suggest that demethylation takes place in all organs except skeletal muscles, but lowest in CNS. The distribution of mercury at cellular and subcellular levels was studied by the autometallographic technique. The atomic absorption spectrometric and autometallographic results were in good agreement. The brain mean concentration in the oldest group was 438 μg/kg, a level much lower than what has been reported to cause effects in the human central nervous system. However, if humans over a period of e.g. 50 years eat Arctic marine meat and accumulate mercury in the same way as dogs, the possibility that this may have health implications cannot be entirely excluded.
Regional Differences in Cerebral Noradrenaline Turnover in Mice Withdrawn from Repeated Morphine Treatment and Tolerance to the Effects of Acute Morphine
Authors: Airio Juha , Attila Martti , Ahtee Liisa
Published: March 2009

Abstract:The effects of morphine withdrawal and challenge doses (10 or 30 mg/kg) on the α‐methyl‐p‐tyrosine (αMT)‐induced noradrenaline (NA) depletion as well as on the free 3‐methoxy‐4‐hydroxyphenylethylene glycol (MOPEG) concentration were studied in various brain areas of NMRI mice. Morphine was given subcutaneously 3 times daily for 5 days followed by 1 or 3 days'withdrawal. In morphine withdrawn mice the αMT‐induced NA depletion and the free MOPEG concentrations were differentially altered. At 1‐day withdrawal the αMT‐induced NA depletion was retarded and the NA concentration was elevated in the forebrain area indicating reduced release of NA. Simultaneously, however, the free MOPEG concentration was significantly elevated in the forebrain area and in the lower brain stem suggesting enhanced NA turnover. No withdrawal‐induced changes were found in the hypothalamic NA turnover. Acute morphine elevated the free MOPEG concentration and accelerated the αMT‐induced NA depletion in all brain areas of control mice but not in mice withdrawn for 1 day from repeated morphine treatment. At 3 days'withdrawal, however, the 30 mg/kg morphine dose slightly accelerated the NA depletion in the forebrain area. These results show that morphine withdrawal differentially alters the αMT‐induced NA depletion and the free MOPEG concentration in various mouse brain areas. These effects are relatively modest suggesting that in mice the noradrenergic mechanisms play a minor role in morphine withdrawal syndrome. However, in all brain areas of the morphine‐withdrawn mice tolerance was found towards the NA turnover and release accelerating effect of acute morphine.
Effects of Diabetes, Insulin Treatment, and Osmolality on Contractility of Isolated Rat Resistance Arteries
Authors: Nielsen Henrik , Bonnema Steen J. , Flyvbjerg Allan
Published: March 2009

Abstract:The effects of osmolality, diabetes, and insulin‐treatment on microvascular contractility were examined in mesenteric resistance arteries (internal diameter approximately 250 μm) isolated from streptozotocin‐induced diabetic rats, streptozotocin‐induced diabetic rats treated with 1–3 U insulin/day during the week before being killed, and age‐ and sex‐matched control rats. Vessels were mounted in a microvascular myograph for isometric tension recording and responses were generated in physiological salt solutions with varying amounts of glucose or mannitol added. The passive response (expressed as the diameter the vessels would maintain if relaxed and exposed to a transmural pressure of 100 mmHg), the maximal response to noradrenaline, and the response produced by partial depolarization with 50 mmol/l potassium were not dependent on glucose or mannitol concentrations of the bathing medium; also, these responses were not dissimilar in vessels from the three groups of rats tested. The sensitivity to noradrenaline, however, was inversely related to the concentration of glucose (P<0.01) and mannitol (P<0.01) of the bathing medium without significant differences in slopes of regression lines between rat groups. Moreover, vessels from streptozotocin‐induced diabetic rats were less sensitive to noradrenaline than were vessels from control rats; vessels from insulin‐treated streptozotocin‐induced diabetic animals had the lowest sensitivity to noradrenaline. These data suggest that osmolality, diabetes, and insulin‐treatment independently affect microvascular sensitivity to the endogenous neurotransmitter, noradrenaline.
Calcipotriol: A New Drug for Topical Psoriasis Treatment
Authors: Kragballe Knud
Published: March 2009

Abstract: Vitamin D is best known for its role in the regulation of calcium and bone metabolism. The effects of the biologically active form of vitamin D, 1,25‐dihydroxyvitamin D3 (1,25 (OH)2D3), are mediated by binding to a specific intracellular vitamin D receptor, which is present in most tissues including the skin where it regulates the growth of epidermal cells. Calcipotriol is a synthetic analogue of 1,25(OH)2D3. In vitro the activity of calcipotriol is comparable to that of 1,25(OH)2D3. In vivo, however, the risk of calcipotriol changing calcium metabolism is greatly reduced. Animal studies have established that calcipotriol is 100–200 times less calcaemic than 1,25 (OH)2‐D3. This low calcaemic activity is mainly due to the rapid metabolism of calcipotriol. This pharmacological profile makes calcipotriol an ideal candidate for topical treatment of hyperproliferative skin disorders, such as psoriasis. This paper reviews the clinical experience with calcipotriol in psoriasis patients.
Effect of p‐Chlorophenylalanine and α‐Methyltyrosine on the Antinociceptive Effect of Antidepressant Drugs
Authors: Sierralta F. , Pinardi G. , Miranda H. F.
Published: March 2009

Abstract:The role of para‐chlorophenylalanine and α‐methyl‐DL‐p‐tyrosine in the antinociceptive effects of the intracerebroventricular administration of the antidepressant drugs clomipramine, zimelidine, imipramine and maprotiline was studied using the acetic acid writhing test in mice. The results demonstrated an antinociceptive effect for all these antidepressants. Pretreatment with para‐chlorophenylalanine significantly reduced the antinociception induced by the ED50's of imipramine and maprotiline, and did not modify the effects of zimelidine and clomipramine, pretreatment with α‐methyltyrosine did not modify the antinociception induced by these drugs except maprotiline. Pretreatment with para‐chlorophenylanine plus α‐methyltyrosine significantly reduced the antinociceptive effect of all the antidepressants tested. The main finding of the present study is that the association of para‐chlorophenylanine plus α‐methyltyrosine reduced the antinociceptive action of all the antidepressants. This means that critical levels of both 5‐HT and NA are responsible for mediating the antinociceptive effects of antidepressants on the writhing test in mice.
Angiotensin Receptors in the Brain
Authors: Höhle Susanne , Blume Annegret , Lebrun Christine , Culman Juraj , Unger Thomas
Published: March 2009

Abstract:Angiotensin receptors have recently become a focus of scientific interest due to the recent development of specific receptor ligands which allow to distinguish between various angiotensin II receptor subtypes, notably the angiotensin II type 1 receptor (AT1) and angiotensin II type 2 receptor (AT2). Although both receptors belong to the seven transmembrane domain receptor family they feature less than 35% homology and differ in their signal transduction mechanisms and in the effects mediated. In the brain, both angiotensin receptor types and probably some further subtypes are present and have been localized in distinct regions. In the adult brain, the AT1receptor dominates by far and is responsible for most of the known central actions of angiotensin peptides, for example blood pressure increase, release of vasopressin from the pituitary gland, natriuresis, drinking and induction of immediate early genes in distinct brain areas. Some of the AT2receptor‐mediated effects have been shown to be enhanced by blockade of AT2receptors in the brain suggesting that the central AT2receptor can exert an inhibitory control on AT1receptor‐mediated actions in the brain.
Changes in Serotonin Metabolism during Treatment with the Aldehyde Dehydrogenase Inhibitors Disulfiram and Cyanamide
Authors: Beck Olof , Helander Anders , Carlsson Sten , Borg Stefan
Published: March 2009

Abstract: The effect of the aldehyde dehydrogenase inhibitors disulfiram (Antabuse®) and cyanamide (calcium carbimide, Dipsan®) on the metabolism of serotonin measured as relative amounts of the metabolites 5‐hydroxyindole‐3‐acetic acid and 5‐hydroxytryptophol in urine were studied in alcoholic patients. Sixteen out of 23 patients receiving drug therapy showed elevated excretion of 5‐hydroxytryptophol. However, there was a marked, 15‐fold, variability in 5‐hydroxytryptophol excretion rate between patients. A high degree of variability was also seen in another group of patients studied before and after introduction of drug therapy. When patients were followed during the dose interval, a time‐dependent response after each single dose could be observed. The disulfiram response lasted over the course of several days whereas the response to cyanamide lasted for less than 12 hr. It is concluded that treatment with disulfiram and cyanamide affects serotonin metabolism leading to increased production of 5‐hydroxytryptophol, but there is a marked inter‐individual variability in degree of response.
Intraplatelet Free Calcium and Calcium‐Regulating Hormones in Plasma are Not Related to the Antihypertensive Effect of Nifedipine in Hypertensive Pregnancy
Authors: Manninen Auli , Wuorela Heikki , Laippala Pekka , Vapaatalo Heikki
Published: March 2009

Abstract: Intracellular free calcium regulates contraction‐relaxation processes in vascular smooth muscle. We compared intraplatelet free calcium ([Ca2+]i) and pH ([pH]i) in hypertensive pregnant women to those in normotensive pregnant and non‐pregnant women. Plasma parathormone and vitamin D metabolite were simultaneously assessed. In hypertensive pregnancy, [Ca2+]i tended to be lower than in normotensive pregnant (P=0.08) and non‐pregnant subjects (P=0.06). In hypertensive pregnancy, 1,25 (OH)2 vitamin D in plasma was in the same range as in non‐pregnant women and significantly lower than in normotensive pregnancy (p<0.01). The other two vitamin D metabolites, parathormone and [pH]i were equal in the three groups. A five‐day nifedipine treatment (10 mg t.i.d.) increased [Ca2+]i in hypertensive pregnant (P<0.05) and normotensive non‐pregnant subjects (P=0.06), whereas [pH]i (P<0.05) and 25 (OH) vitamin D (P<0.05) decreased in the former and 24,25 (OH)2 vitamin D increased in the latter group (P<0.05). Initial [Ca2+]i did not correlate with blood pressure in any group. The antihypertensive effect of nifedipine did not correlate with any variable measured. In conclusion, [Ca2+]i and calcium‐regulating hormones seem not to be related to the antihypertensive effect of nifedipine in hypertensive pregnancy. In this type of hypertension, intraplatelet calcium may not reflect calcium balance in smooth muscle cells regulating vascular tone and blood pressure.
Interaction of the Chiral Forms of Ketamine with Opioid, Phencyclidine, σ and Muscarinic Receptors
Authors: Hustveit Olav , Maurset Atle , Øye Ivar
Published: March 2009

Abstract:In order to elucidate the mechanisms of action of ketamine, we have investigated the binding of the chiral forms of ketamine to opioid (μ, δ and κ), phencyclidine, σ and muscarinic receptors and we have performed detailed concentration‐response experiments in the guinea‐pig ileum preparation. The affinity ratios for the chiral forms at phencyclidine, μ and κ receptors correlated with the potency ratio of the chiral forms in the ischaemic pain test found previously. The affinities were highest for phencyclidine receptors. The affinities for muscarinic receptors were lower than for phencyclidine receptors by a factor of about 10–20. The concentration‐response experiments revealed one opioid (naloxone sensitive) and one non‐opioid component. The two component are very close, which explains why other authors have reported that naloxone antagonizes the ketamine effect only partly. The concentrations of naloxone necessary to shift the opioid part of the curves indicate that ketamine is a κ agonist in the guinea‐pig ileum preparation. We conclude that the analgesic effect of ketamine in humans is most probably mediated via phencyclidine receptors, although a κ effect can not be excluded. Binding to κ and muscarinic receptors may contribute to the psychotomimetic side effects seen during recovery from ketamine anaesthesia.
Multiple Effects of Salicylaldoxime on Rat Cardiac Action Potentials
Authors: Chunlei Han , Sellin Lawrence C.
Published: March 2009

Abstract:The effect of salicylaldoxime, 2‐(OH)C6H4CH=NOH, on the resting membrane potential and action potential characteristics was studied using isolated right ventricular strips from rat heart. Salicylaldoxime (1–3 mM) reversibly hyperpolarized the cells, increased action potential amplitude, decreased the maximal rate of rise (Vmax) and prolonged duration. The prolongation of the action potential produced by 1 mM salicyaldoxime could not be reversed with isoprenaline (10 μM). Salicyalaldoxime (0.3–1 mM) had no effect on the Ca2+‐dependent slow action potential for periods up to 60 min. Initial exposure to 3 mM salicylaldoxime produced no changes in the slow action potential, but after 30 min. there was a gradual reduction in amplitude. This effect was completely reversible within 10–15 min. of washout. These data suggest that salicyaladoxime can block Na+, K+and Ca2+currents in rat cardiac muscle. Furthermore, it appears that the slow inward Ca2+current, as measured by the slow action potential, may be sensitive to a dephoshorylating action of this oxime.
Effects of Nicardipine on Lipid Peroxidation in Rabbits Given 2% Cholesterol Diet
Authors: Ismail Nafeeza M. , Jaarin Kamsiah , Vasudevan S. K. , Hashim Suhaimi
Published: March 2009

Abstract Nicardipine has been shown to have an anti‐atherogenic effect in rabbits given a 2% cholesterol diet. Current evidence suggests that lipid peroxidation plays an important role in atherogenesis. This study examines the effect of nicardipine on lipid peroxidation in rabbits given a 2% cholesterol diet, 8 of these rabbits given nicardipine 0.5 mg/kg twice daily intramuscularly for ten weeks while the remaining untreated 6 were controls. After ten weeks, serum malondialdehyde in the control group was significantly higher compared to their baseline levels (P<0.05). However, there was no increase in serum malondialdehyde in the nicardipine group after 10 weeks. The area of Sudan IV positive intimal lesions (atherosclerotic plaques) were significantly decreased (P<0.01) in the treated group compared to the control group. The aortic tissue content of cholesterol and diene conjugates were also decreased in the nicardipine group (P<0.01). These findings suggest a possible link between nicardipine and lipid peroxidation in mediating its antiatherogenic effects.
In vitro Effect of Avarone and Avarol, a Quinone/Hydroquinone Couple of Marine Origin, on Platelet Aggregation
Authors: Belisario Maria Antonietta , Maturo Mariavalentina , Avagnale Gennaro , Rosa Salvatore De , Scopacasa Francesco , Caterina Maurizio De
Published: March 2009

Abstract: We investigated the effect on human platelet aggregation of the naturally occurring quinone/hydroquinone couple, avarone and avarol. Avarone exerted antiplatelet activity both on platelet‐rich plasma and, to a greater extent, on washed platelets. The quinone inhibited the platelet aggregatory process with all the agonists used. The highest inhibitory potency occurred with arachidonic acid or A23187 as stimulating agents. In the case of agonists such as adenosine 5'diphosphate, platelet‐activating factor or U46619, the antiaggregatory effect was more pronounced on the second wave. Inhibition of the aggregatory process paralleled thromboxane B2 formation. Avarol also exerted antiplatelet activity, even though its inibitory potency was much lower than that of avarone.