bluuebunny/crossref_metadata_2025 huggingface dataset:
Disposition of 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) in Mice before and after Monoamine Oxidase and Catecholamine Reuptake Inhibition
Authors: Lydén‐Sokolowski Annika , Larsson Bengt S. , Lindquist Nils Gunnar
Published: March 2009

Abstract: The distribution of radioactivity in pigmented mice after a single intravenous injection of 1‐(3H) methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (3H‐MPTP) was studied by quantitative whole body autoradiography and liquid scintillation counting. Pretreatment with the monoamine oxidase inhibitors clorgyline, pargyline and deprenyl, or the catecholamine reuptake inhibitor nomifensine was performed 30 min. prior to the 3H‐MPTP administration. A high uptake of radioactivity was observed in the striatum, nucleus accumbens, midbrain area and locus coeruleus, and also in the adrenal medulla. This uptake was inhibited by deprenyl or pargyline pretreatment, but not after clorgyline or nomifensine pretreatment. An extensive uptake which was not influenced by deprenyl or pargyline treatment was found in the melanin‐containing tissues of the eye. This accumulation is due to the melanin affinity of MPTP and its metabolites. A comparatively rapid elimination from the brain of MPTP and its metabolites was observed, which may be due to the lack of neuromelanin in mice.
Pharmacokinetics of 7‐Hydroxy‐methotrexate and Methotrexate in the Rat
Authors: Slørdal L. , Jæger R. , Kjæve J. , Aarbakke J.
Published: March 2009

Abstract: To investigate the pharmacokinetics of the active metabolite of methotrexate (MTX), 7‐hydroxy‐methotrexate (7‐OH‐MTX), 1 mg/kg of the compound was administered as single intravenous bolus injections to 6 unanaestetized rats. For comparison, 1 mg/kg of the parent drug MTX was given to the same number of animals. Venous blood samples were drawn at intervals for a total of 120 min., and thereafter the rats were sacrificed and tissue samples were obtained from the brain, lungs, liver, kidneys, testes, fat, and muscle. Pharmacokinetics of 7‐OH‐MTX and MTX were biphasic, with a significantly (P < 0.05) smaller central compartment of distribution (Vc) and a longer second phase half‐life (t1/2(β)) for 7‐OH‐MTX. MTX tissue concentrations exceeded those of 7‐OH‐MTX in all tissues examined. The highest 7‐OH‐MTX concentrations were found in renal tissue. It is implied that 7‐OH‐MTX is less extensively distributed than the parent compound.
Pharmacokinetics of Biosynthetic and Pituitary Human Growth Hormones in Rats
Authors: Jørgensen Karin Damm , Monrad J. D. , Brøndum L. , Dinesen B.
Published: March 2009

Abstract: The pharmacokinetics of biosynthetic and pituitary human growth hormones (B‐hGH and P‐hGH) was compared in rats. Normal and hypophysectomized male and female rats were subcutaneously and intramuscularly injected with 100 μg/kg B‐hGH and P‐hGH and intravenously with 60 μg/kg B‐hGH and P‐hGH. A statistically significantly smaller distribution volume and a slower metabolic clearance rate (MCR) was found for B‐hGH compared to P‐hGH. A statistically significantly smaller distribution volume and MCR was found for hypophysectomized rats compared to normal rats. The plasma half lives were estimated to be about 3–7 min. (α1/2) and 29 min. (β1/2). The plasma levels of hGH were higher after subcutaneous compared to intramuscular administration. The data imply that an extensive local degradation took place at the subcutaneous and intramuscular injection sites. Comparative tissue distribution studies were performed with radioiodinated B‐hGH and P‐hGH. No differences were observed between the growth hormones. It was found that most of the labelled TCA precipitable material was cleared through the liver. The females cleared relatively more through the liver than the males, while the males cleared relatively more through the kidneys.
Effects of the Benzazepine SCH 23390 on Prolactin Release from Isolated Pituitary
Authors: Navarra P. , Del Carmine R. , Ragazzoni E. , Vacca M. , Preziosi P.
Published: March 2009

Abstract:The benzazepine, SCH 23390 (10−5M), is able to block D2anterior pituitary receptors and their interaction with a maximal concentration of dopamine (10−7M) in an experimental setting involving superfused pituitary slices and prolactin release by lactotrophs as a functional model of such receptors; this finding which correlates nicely with binding studies and drug‐induced hyperprolactinaemia supports a SCH 23390 D1dose‐related selectivity; given at doses higher than those inducing behavioural changes, the compound may affect D2receptor‐driven functions, e.g. prolactin secretion.
Effect of Cadmium Chloride on Hepatic Lipid Peroxidation in Mice
Authors: Andersen Helle Raun , Andersen Ole
Published: March 2009

Abstract: Intraperitoneal administration of cadmium chloride to 8–12 weeks old CBA‐mice enhanced hepatic lipid peroxidation. A positive correlation between cadmium chloride dose and level of peroxidation was observed in both male and female mice. A sex‐related difference in mortality was not observed but at a dose of 25 μmol CdCl2/kg the level of hepatic lipid peroxidation was higher in male mice than in female mice. The hepatic lipid peroxidation was not increased above the control level in 3 weeks old mice, while 6 weeks old mice responded with increased peroxidation as did 8–12 weeks old mice. The mortality after an acute toxic dose of cadmium chloride was the same in the three age groups. Pretreatment of mice with several low intraperitoneal doses of cadmium chloride alleviated cadmium induced mortality and lipid peroxidation. The results demonstrate both age dependency and a protective effect of metallothionein induction on cadmium chloride induced hepatic lipid peroxidation.
Selenium Deficiency and Cardiac Electrophysiological and Mechanical Function in the Rat
Authors: Ringstad Jetmund , Tande Pål M. , Norheim Gunnar , Refsum Helge
Published: March 2009

Abstract: Earlier studies have shown that selenium and vitamin E are important in maintaining normal cardiac function. The present study was designed to test the effect of sole selenium deficiency on electrophysiological and mechanical characteristics of the rat heart. Male weanling rats were fed a standardized vitamin E adequate but selenium deficient diet, or a control diet. Deficiency of selenium was verified by direct (tissue selenium analyses) and indirect (glutathione‐peroxidase tissue analyses) methods. In vivo electrocardiographic recordings as well as in vitro electrophysiological and mechanical recordings did not reveal abnormalities in any of the two groups. In conclusion, earlier studies have shown that the combined deficiency of selenium and vitamin E leads to abnormal cardiac function. Selenium deficiency alone, however, does not appear to significantly affect cardiac function in the rat.
Psychomotor Performance of Patients with Rheumatoid Arthritis: Cross‐Over Comparison of Dextropropoxyphene, Dextropropoxyphene plus Amitriptyline, Indomethacin, and Placebo
Authors: Saarialho‐Kere Ulpu , Julkunen Heikki , Mattila Mauri J. , Seppälä Timo
Published: March 2009

Abstract: Actions on performance of dextropropoxyphene (DXP) alone and in combination with amitriptyline (AMI), indomethacin (IN), and placebo were compared in 15 patients with rheumatoid arthritis. The patients were on their prescribed maintenance regimen excluding analgesics. In four randomized test sessions at two‐week intervals, they received double blind and crossover single oral doses of DXP 130 mg, IN 50 mg, DXP 65 mg+AMI 25 mg or placebo, each after two days'pretreatment with the same drug. Objective and subjective effects were measured at baseline and 2 and 4 hours after drug administration. DXP impaired critical flicker discrimination, symbol copying and body balance without modifying tracking, choice reactions or attention. It rendered the subjects elated, muzzy, mentally slow and calm. Actions of AMI + DXP were about the same. IN impaired body balance and critical flicker recognition. Plasma concentrations of DXP were moderate to high whilst those of IN and AMI were fairly low. We conclude that therapeutic doses of DXP and IN are relatively safe in regard to driving skills. Small doses of AMI may not enhance the mild psychomotor effects of DXP. Earlier single dose studies carried out with healthy volunteers might have overestimated the decremental effects of analgesics on psychomotor performance.
Sensory Irritation and Pulmonary Irritation of C3–C7 n‐Alkylamines: Mechanisms of Receptor Activation
Authors: Nielsen Gunnar Damgård , Vinggaard Anne Marie
Published: March 2009

Abstract: Sensory irritation due to inhalation of a series of alkylamines was estimated from the decrease in respiratory rate in normal (non‐cannulated) mice (American standard method E 981–84, 1984). The irritation effects rapidly reached stable levels. The concentration‐response relationships followed Michaëlis‐Menten equations. The maximum response decreased with increasing chain length. The concentrations depressing the respiratory rate by 50% (RD‐50) were 184, 121, 97, 51, and 27 p.p.m. for n‐propylamine, n‐butylamine, n‐pentylamine, n‐hexylamine, and n‐heptylamine, respectively. It is suggested that the receptor is activated partly by the amines and partly by hydroxide ions. The nose has a scrubbing effect, which partly protects the lungs against water soluble irritants. Pulmonary irritation was estimated from the decrease in respiratory rate in tracheally cannulated mice. The plateau‐level of the response was reached slowly. The respective concentrations depressing the respiratory rate by 50% (tRD‐50) were 416, 300, 128, 66, and 36 p.p.m. for the C3–C7 n‐amines. It is suggested that the pulmonary receptor environment is lipophilic and the receptor, probably the J‐receptor, is activated chemically by the amines. The sensory and pulmonary irritation data were used to estimate workplace exposure limits (TLV's) which protect against these effects.
A One Year Follow‐Up Study of the Distribution of 14C‐Clodronate in Mice and Rats
Authors: Mönkkönen Jukka
Published: March 2009

Abstract: The distribution of 14C‐clodronate (dichloromethylene bisphosphonate) was studied in mice and rats by whole‐body autoradiography and by measuring the 14C‐activities in various tissues up to one year after a single intravenous dose. The results indicate that the deposition of clodronate in bone tissue of mice and rats is extremely strong and long lasting; in both animals, high radioactivities were measured even 12 months after the administration. In spleen, thymus, and small intestine of mice, 14C‐activity could be detected 12 months after dosing. Small amounts of radioactivity were also detected in spleen of rats for 12 months, although much less than in spleen of mice. The results suggest that clodronate accumulates to some extent in the reticuloendothelial system of animals. They suggest further that the animal species should be carefully considered when interpreting the distribution kinetics of bisphosphonates, especially their accumulation in the reticuloendothelial system.
Effects of Postpuberal Castration on Dopamine Receptor Sensitivity in the Male Rat Brain
Authors: Klint Thorsten , Megaart Viveka , Mud Per‐Olof , Wijkström Agneta , Ahlenius Sveo
Published: March 2009

Abstract: In order to study the effects of castration of brain dopamine @A) receptor sensitivity, the effects of apomorphine on locomotor activity and striatal DA synthesis, as assessed by the dihydroxyphenylalanine (DOPA) accumulation after NSD‐1015 treatment, were examined in normal and castrated male Sprague‐Dawley rats pretreated with reserpine (5 mg/ kg ‐ 18 hrs). There was an enhanced locomotor response to apomorphine (0.05‐0.1 mg/kg) in castrated animals, as compared to sham operated controls. Furthermore, the increase in DOPA accumulation produced by the reserpine treatment was antagonized to a greater extent by apomorphine in the castrated animals. These results indicate an enhanced DA receptor sensitivity at both pre‐ and post‐synaptic sites.
Effects of Treatment with Phenobarbitone or Isoniazid on Hepatotoxicity Due to Prolonged Subanaesthetic Halothane Inhalation
Authors: Plummer John L. , de la M. Hall Pauline , Jenner Mark A. , Cmielewski Patricia L. , Llsley Anthony H. , Cousins Michael J.
Published: March 2009

Abstract:Rats were exposed to halothane vapour, 50 p.p.m., or air for a period of four weeks. Within each exposure group, some animals drank plain water, some received water plus phenobarbitone, while some received water plus isoniazid. Halothane exposure resulted in increased serum bromide concentrations and liver injury evidenced by increased serum alanine aminotransferase activity, focal hepatocellular necrosis and fatty change. Administration of isoniazid reduced halothane metabolism by 33% as assessed by serum bromide concentrations, and completely blocked the injurious effects of halothane on the liver, suggesting that halothane metabolism plays a role in halothane hepatotoxicity under these conditions. Administration of phenobarbitone partially prevented the increase in serum alanine aminotransferase activity and hepatocellular necrosis due to halothane. In contrast to isoniazid, phenobarbitone led to a slight increase in halothane metabolism. However, phenobarbitone also caused an increase in liver size, such that the amount of halothane metabolised per gram of liver was reduced by phenobarbitone treatment. These results suggest that metabolism of halothane is an important factor in liver injury due to prolonged, subanaesthetic halothane exposure.
Ontogenic Development of 7‐Ethoxycoumarin and 7‐Ethoxyresorufii 0‐Deethylase in the Rat and Effect of Monoclonal Antibodies
Authors: Pacifici G. M. , Park S. S. , Gelboin H. W. , Rane A.
Published: March 2009

Abstract: The O‐deethylase activities with 7‐ethoxycoumarin (ECDE) and 7‐ethoxyresorufin (ERDE) as substrates were investigated in the liver microsomal fraction of newborn, 1 week, 2 weeks, 1 month and 2 months old rats. The rates of 0‐deethylation of both substrates were lowest in newborn rats at which stage the specific activities (pmol x rnin.‐l x mg‐1 protein; mean± S.D.) of ECDE and ERDE were 19.0 ± 0.2 and 6.0 ± 0.5, respectively. In 1 week old animals, the rate of ECDE had reached the highest values (270 ± 81 pmol x min.‐1 x mg‐1 protein). Thereafter, it decreased to a minimum (70.9 ±14.8 pmolmin.‐1 x mg‐1 protein) at 2 months of age. The rate of ERDE reached the highest activity (129 ± 7.1 pmol x min.‐1 x mg‐1 protein) in 1 month old animals. The effects monoclonal of antibodies (MAb), on ECDE and ERDE were studied. The MAb were raised against 3‐methylcholanthrene (MAb 1‐7‐1) or phenobarbital (MAB 2‐66‐3) induced rat liver microsomal cytochrome P‐450. Only the former antibodies were inhibitory to the 0‐deethylation of 7‐ethoxyresorufin. This reaction was inhibited to a similar extent (by 31‐33%) in rat liver microsomes from 1 week and 2 months old animals. None of the antibodies exerted any effect on the O‐deethylation of 7‐ethoxycoumarin.
Tissue and Subcellular Localizations of 3H‐CyclospoMe A in Mice
Authors: Bäckman Lars , Brandt Ingvar , Appelkvist Eeva‐Liise , Dallner Gustav
Published: March 2009

Abstract: The tissue and subcellular localizations of 3H‐cyclosporine A after administration to mice were determined with whole‐body autoradiography and scintillation counting of lipid extracts of tissues and subcellular fractions. The radioactivity was widely distributed in the body and the pattern of distribution after oral or parenteral administration was the same, except that tissue levels were generally lower after oral administration. Pretreatment of the animals with a diet containing cyclosporine A for 30 days before the injection of radioactive cyclosporine A did not change the pattern of distribution substantially. No significant radioactivity was found in the central nervous system, except for the choroidal plexus and the area postrema region of the brain. In pregnant mice no passage of radioactivity from the placentas to fetuses was observed after a single injection. 3H‐cyclosporine A and/or its metabolites showed a high affinity for the lympho‐myeloid tissues, with a marked long‐term retention in bone marrow and lymph nodes. There was massive excretion in the intestinal tract after parenteral administration, and the liver, bile, pancreas and salivary glands contained high levels of radioactivity. In the kidney radioactivity was confined to the outer zone of the outer kidney medulla. In liver homogenates no quantitatively significant binding of 3H‐cyclosporine A and/or its metabolites to cellular molecules such as proteins, DNA, phospho‐ or neutral lipids was found. After lipid extraction with organic solvents, almost all radioactivity was recovered in the organic phase.
Extrahepatic Sites of Metabolism of Halothane in the Rat
Authors: Ghantous Hunan , Löfberg Boël , Tjälve Hans , Danielsson Bengt R. G. , Dencker Lennart
Published: March 2009

Abstract:Rats were given14C‐halothane intravenously and whole‐body autoradiography with freeze‐dried sections, or with sections extracted in trichloroacetic acid, water, and organic solvents, was carried out to trace tissues accumulating halothane metabolites.In vitroincubations of tissue homogenates were performed to examine the capacity by the various organs to form tissue‐bound14C from the14C‐halothane. Autoradiography of isolated organs after incubation with14C‐halothane was performed to study the tissue localization of halothane metabolites formed underin vitroconditions. A localization of halothane metabolites was observed in several extrahepatic tissuesin vivo, and thein vitroexperiments showed a capacity by the same tissues to transform14C‐halothane to metabolites that bind strongly to tissue components. In addition to the liver, the other tissues shown to have a marked halothane‐metabolizing capacity were the nasal mucosa, lateral nasal gland, mucosa of the tongue, cheek, soft palate (but not the hard palate), pharynx, larynx, oesophagus, and the tracheo‐bronchial mucosa. Thein vivodata obtained indicated a diffusion of the halothane over the walls of the large intestine and the caecum, followed by the formation of apparently reductive metabolites by intestinal microbes and a binding of the metabolites to the intestinal contents. The localization of halothane metabolites in the upper alimentary and respiratory pathways is correlated to the presence of cytochrome P‐450 at these sites.
Relaxation of Bovine Mesenteric Artery Induced by Glyceryl Trinitrate is Attenuated by Pertussis Toxin
Authors: Ahlner Johan , Axelsson Krister L. , Ekstram‐Ljusegren Marie , Friedman Richard L. , Gnindström Nils , Karlsson Ja Olof G. , Andersson Rolf G. G.
Published: March 2009

Abstract:Low concentrations (< 1 nM) of glyceryl trinitrate (GTN) induced a considerable relaxation of bovine mesenteric arteries (BMA) brought to sustained contraction by the addition of phenylephrine. The concentration‐response curve of GTN showed a biphasic pattern with a high and a low affinity component. Pretreatment with pertussis toxin (IAP) attenuated the high affinity relaxant component, but not the low affinity component or the relaxation induced by NaNO2. A polyclonal antibody to IAP counteracted the effect of the toxin on the GTN‐response. Low concentrations of GTN increased the cGMP level in BMA via activation of the high affinity pathway. This effect was also inhibited in preparations pretreated with IAP. It is suggested from the present study that GTN induces relaxation of vascular smooth muscle via two separate pathways, the high affinity pathway might involve a receptor‐complex interaction with a regulatory protein.
Deactivation of Sulindac‐Sulphide by Human Renal Microsomes
Authors: Eriksson L.‐O. , Boström H.
Published: March 2009

Abstract:The renal metabolism of sulindac‐sulphide was studied in subcellular fractions from human kidney. It was shown that renal microsomes, in the presence of NADPH, effectively catalyzed the sulphoxidation of sulindac‐sulphide. Also the mitochondrial fraction catalyzed the reaction but at a ten‐fold lower rate than the microsomes. Carbon monoxide, metyrapone and n‐octylamine did not inhibit renal sulphoxidation of sulindac‐sulphide and the reaction could occur in a monooxygenase containing fraction free from NADPH‐cytochrome P‐450 reductase. Hydroxylation of lauric acid was studied in microsomes and in the purified monooxygenase containing fraction under the same experimental condition as sulindac‐sulphide sulphoxidation. Lauric acid is a substrate known to be metabolized by a renal cytochrome P‐450 to 11 and 12‐hydroxylated products. This reaction was sensitive to carbon monoxide and did not occur in the absence of NADPH cytochrome P‐450 reductase. Based on these results we conclude that cytochrome P‐450 plays at the most a limited role in human kidney metabolism of sulindac‐sulphide. In contrast, sulphoxidation of sulindac‐sulphide was substantially reduced in the presence of methimazole suggesting a role of the flavin‐containing monooxygenase in the renal biotransformation of sulindac‐sulphide in man.
Sodium Dependent Uptake of 3H‐Choline in the Cerebral Cortex of Ageing Male Rats
Authors: Sirviö Jouni , Hervonen Antti , Riekkinen Paavo J.
Published: March 2009

Abstract: Uptake of 3H‐choline and the binding of 3H‐hemicholinium‐3 in the cerebral cortex was investigated in male Wistar rats of different ages. The effect of Al3+‐ions on 3H‐choline uptake was also studied. Na‐dependent high affinity uptake of 3H‐choline and 3H‐hemicholinium binding were lower in 10‐ to 11‐month‐old rats than in 3‐ to 4‐month‐old rats. There was no further decline in these parameters from 10‐ to 11‐month‐old to 24‐ to 25‐month‐old rats. Al3+‐ions had no effect on the uptake of 3H‐choline. The present study supports the hypothesis that there is a relationship between Na‐dependent high affinity uptake of 3H‐choline and the binding of 3H‐hemicholinium in the crude synaptosomal fraction of the rat cerebral cortex.
Tumour Promotion Related Effects by the Cyclodiene Insecticide Endosulfan Studied in Vitro and in Vivo
Authors: Flodström Sten , Wärngård Lars , Hemming Helena , Fransson Ronny , Ahlborg Ulf G.
Published: March 2009

Abstract: The cyclodiene insecticide endosulfan is structurally related to the tumour promoting pesticides chlordane and heptachlor. Divergent conclusions have been reported regarding the carcinogenic activity of endosulfan. In this study we have investigated if endosulfan and four of its metabolites possess tumour promotion related effects. Two in vitro test systems detecting inhibition of intercellular communication were used; the Chinese hamster lung fibroblast (V79) metabolic cooperation assay and a scrape loading/dye transfer assay using rat liver WB epithelial cells. At non‐cytotoxic concentrations, technical grade endosulfan, analytical grade endosulfan (α‐ and β‐isomers and an αβ‐isomer mixture) and endosulfan‐sulfate inhibited gap junctional communication in both assay systems. In addition, the metabolite endosulfan‐ether was effective in the rat liver WB epithelial cells. Endosulfan was also studied for enhancement of γ‐glutamyl transpeptidase positive enzyme altered foci incidence in partially hepatectomized, nitrosodiethylamine‐initiated male Sprague‐Dawley rats. However, endosulfan administered orally (1 or 5 mg/kg/day) five days a week for ten weeks did not enhance enzyme altered foci incidence. These apparently contradictory results with regard to possible tumour promoting activity of endosulfan are discussed in relation to metabolism, systemic toxicity and tissue/species specificity in tumour promotion.
Action of Mercurials on Activity of Partially Purified Soluble Protein Kinase C from Mice Brain
Authors: Inoue Y. , Saijoh K. , Sumino K.
Published: March 2009

Abstract: The enzymatic activity of soluble protein kinase C from mice brain was inhibited by mercuric chloride (II) (HgCl2) and organic mercurials, i.e. methyl mercury, phenyl mercury and p‐chloromercuribenzoic acid (PCMB). The IC50 was 0.08 μM for HgCl2 and about 1 μM for organic mercurials. Sulfhydryl blocking reagents such as 5,5′‐dithiobis‐2‐nitrobenzoic acid (DTNB) and N‐ethylmaleimide (NEM) were less potent but nevertheless inhibited the enzymic activity of protein kinase C. The Hill coefficients of HgCl2, DTNB and NEM were close to unity whereas the values for organic mercurials were 1.3 to 1.5. The inhibition was of a non‐competitive type with respect to Hl histone. 3H‐PDBu binding activity was also inhibited by all of the reagents in a non‐competitive manner. Mercurials apparently bind to sulfhydryl groups of protein kinase C to inhibit the enzymatic activity.
Stimulation‐Induced Changes in Cyclic Nucleotide Content by Isolated Rat Parotid Acid: Effects of Calcium
Authors: Glenert Ulla , Nauntofte Birgitte
Published: March 2009

Abstract:In the present study we investigated the relation between receptor activation and the acinar formation of cyclic nucleotides as a function of time, including effects of calcium. The experiments were performed using collagenase‐isolated rat parotid acini and the cyclic nucleotide content was determined using a specific CAMP binding protein and cGMP antibody. Under physiological conditions, activation of β‐adrenoceptors increased CAMP content 27 fold within 60 sec. This response was not dependent upon the presence of extracellular calcium nor could it be mimicked by the calcium ionophore A23187. The adrenaline‐induced activation of the α‐adrenergic receptors lead to a 19% increase in cGMP content within 15 sec. This response was abolished in the absence of extracellular calcium. Pure activation of the α‐l‐adrenoceptors by phenylephrine resulted in a 62% increase in cGMP content within 15 sec. Finally, carbachol‐induced activation of the cholinoceptors lead to a 50% transient increase in cGMP content within 7 sec. In rile absence of calcium (EGTA present), the basal cGMP level was increased and in addition, the carbachol‐induced cGMP formation was slower in onset and amounted to only 23% within 60 sec. The carbachol‐induced cGMP formation could be mimicked by the calcium ionophore A23187 or by addition of calcium to acini preincubated in a calcium free buffer containing A23187. In conclusion, stimulation‐induced formation of cyclic nucleotides under various conditions proved to be very rapid, well regulated, and sensitive processes.
Tissue Distribution of Inducible Aldehyde Dehydrogenase Activity in the Rat after Treatment with Phenobarbital or Methylcholanthrene
Authors: Vasiliou Vasilis , Marselos Marios
Published: March 2009

Abstract: Two genetically distinct substrains of the Wistar rat (RR and rr) were used to study the tissue distribution of the inducibility of aldehyde dehydrogenase (ALDH). The RR substrain is responsive to phenobarbital (PB), as far as the induction of the hepatic ALDH activity is concerned, whereas the rr substrain is deprived of this biochemical property. Both substrains, however, respond to treatment with methylcholanthrene (MC), exhibiting a uniform increase of the ALDH activity in the liver. It is known that PB and MC induce two different isozymes of the hepatic cytosol. The effect of PB (1 g/l in drinking water, for 12 days) on the inducibility of ALDH in extrahepatic tissues was examined in the RR substrain. On the contrary, MC was given (50 mg/kg x 4, intraperitoneally) to rr animals. The activity of ALDH was found to be induced by PB in the liver and the intestinal mucosa, when measured with NAD and propionaldehyde (P/NAD) or phenylacetaldehyde (Ph/NAD). An increase of the activity was also noticed when ALDH was measured with NADP and benzaldehyde (B/NADP). In rr animals, MC induced the B/NADP activity in the liver, the intestinal mucosa, the kidneys, the lungs, the spleen, the brain, the urinary bladder and the heart. The effect of MC on various tissues was less distinct, when ALDH was measured as P/NAD or Ph/NAD activity. It is concluded, that PB and MC not only induce different types of ALDH activity, but they also reveal differences in the tissue distribution of the inducibility of ALDH.
The Involvement of Dopamine D1and D2Receptors in the Locomotor Stimulation Produced by (+)‐Amphetamine in Naive and Dopamine‐Depleted Mice
Authors: Ross S. B. , Jackson D. M. , Edwards S. R.
Published: March 2009

Abstract:The interaction between (+)‐amphetamine and dopamine (DA) D1and D2receptors was investigated. In naïve mice, i.e., mice with intact stores of DA, both the selective D1antagonist SCH23390 and the selective D2antagonist spiperone blocked the locomotor stimulation produced by (+)‐amphetamine. The selective D1agonist SKF38393 (6 mg/kg intraperitoneally) did not produce a consistent dose‐dependent effect on the response to (+)‐amphetamine in naïve mice. In mice depleted of DA with reserpine 24 hr before a challenge with (+)‐amphetamine, neither SCH23390 nor spiperone were completely effective in blocking (+)‐amphetamine. A combination of spiperone plus SCH23390 was, however, more effective than either drug alone, although significant activity remained even after the combination. In mice pretreated with reserpine and various doses of α methyl‐p‐tyrosine (αMPT, intraperitoneally), the degree of stimulation produced by (+)‐amphetamine was dependent on the amount and frequency of αMPT dosage – the higher and more frequent the dose, the more effective the blockade. In these animals, both SKF38393 and the selective D2agonist quinpirole potentiated the stimulation induced by (+)‐amphetamine when the dose of αMPT was not maximal. However, in those animals pretreated with reserpine plus two doses each of 400 mg/kg αMPT, neither SKF38393 nor quinpirole were effective in potentiating (+)‐amphetamine. Nevertheless, when SKF38393 and quinpirole were administered simultaneously to these mice, marked locomotor stimulation occurred implying that the pretreatment itself had not rendered the mice incapable of locomotion. The data indicate that (+)‐amphetamine produces excitation in naïve mice by an indirect action on D1and D2receptors, both of which must be stimulated for activation to occur. In animals depleted of DA with less than optimal doses of αMPT, (+)‐amphetamine could still release enough DA to stimulate D1and D2receptors, as either SKF38393 or quinpirole could potentiate the excitation induced by (+)‐amphetamine. However, in mice pretreated with the highest doses of αMPT, (+)‐amphetamine was virtually inactive even when combined with either a D1or a D2agonist, implying a lack of released DA available for receptor stimulation.
Selective Inactivation of Dopamine D1and D2Receptors in 6‐Hydroxydopamine‐Lesioned Rats: Evidence that the Effect of D1and D2Agonists can be Expressed in the Absence of the Heterologous DA Receptor
Authors: Arnt J. , Hyttel J.
Published: March 2009

Abstract:EEDQ (N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline) markedly decreased the density of dopamine (DA) D1and D2receptors in the lesioned and normal striatae of rats lesioned unilaterally with 6‐hydroxy‐DA. By treatment with either the D1antagonist SCH 23390 or the D2antagonist raclopride, together with EEDQ selective inactivation of D2and D1receptors, respectively, are obtained. In rats with decreased density of D1receptors the circling behaviour response to the D1agonist SK&F 38393 was markedly inhibited 24 hours after EEDQ treatment, whereas the similar response to the D2agonist pergolide was unchanged. In rats with decreased density of D2receptors the effects of pergolide and the partial D2agonist (‐)‐3‐PPP were antagonized, while the effect of SK&F 38393 was unchanged. These results indicate that the effect of D1and D2agonists can be expressed in the absence of normal densities of the heterologous DA receptor. In contrast, the responses from homologous DA receptors, mediating the circling behaviour from the denervated side of the brain, are highly sensitive to the inactivating effect of EEDQ.
On the Topically Effective Ocular Hypotensive Properties of ICI 147,798, a Natriuretic β‐Adrenoceptor Antagonist, in Rabbits
Authors: Kau S. T. , Limp G. L.
Published: March 2009

Abstract:The ocular antihypertensive effects of ICI 147,798, a natriuretic, non‐selective β‐blocker lacking local anaesthetic and intrinsic sympathomimetic activities, were evaluated in unanaesthetized rabbits with water‐load‐induced ocular hypertension. The racemate was approximately 20 times more potent as a β‐blocker than its d‐isomer. The magnitude of reductions in intraocular pressure (IOP) elicited by both compounds was equal following topical administration of an equal dose‐concentration (100–300 μl, 0.5% or 0.75%) to one or both eyes, and the activities were similar to those obtained with timolol. A five‐hour duration of the IOP lowering effect was achieved by ICI 147,798 and timolol in this rabbit model. ICI d‐147,798 exhibited a shorter duration, which could be prolonged by increasing the concentration of the ophthalmic solution. Timolol caused a pronounced reduction of isoproterenol‐induced tachycardia after a single dose (200 μl, 0.5%) or by repeating the dose twice a day for four consecutive days. Following the same dose regimen, neither ICI 147,798 nor its d‐isomer significantly altered the heart rate response produced by isoproterenol. These findings indicate that ICI 147,798, while effective as a potential antiglaucoma agent, does not display the characteristics of β‐blockers on heart rate effects noted with timolol. The results also cast some doubt on the contention that the IOP lowering effect of certain β‐blockers is predominantly determined by specific blockade of β‐adrenoceptors.
A Model System for Studying the Bioavailability of Intestinally Administered Microcystin‐LR, A Hepatotoxic Peptide from the Cyanobacterium Microcystis aeruginosa
Authors: Dahlem Andrew M. , Hassan Aslam S. , Swanson Steven P. , Carmichael Wayne W. , Beasley Val R.
Published: March 2009

Abstract: Sprague‐Dawley rats were used to evaluate a model system for studying the hepatotoxicity caused by microcystin‐LR (MCYST‐LR), a toxin produced by the cyanobacterium (blue‐green alga) Microcystis aeruginosa, and for evaluating the in vivo therapeutic potential of cholestyramine resin (CTR) which was found to bind the toxin in vitro. Female rats were treated with either toxin or an equivalent volume of the saline vehicle by direct administration into the lumen of an in situ isolated ileal loop. Male rats were dosed with toxin as described above, and then animals were dosed in the ileal loop with either cholestyramine resin (CTR, 50 mg/rat) or an equivalent vehicle. The survivors in both studies were killed six hours after dosing and hepatotoxicity was assessed by change in relative liver weights. In all groups given toxin alone, there was a significant increase in liver weight and males and females were equally susceptible. Liver weights of the toxin plus CTR treated rats were similar to those in vehicle‐treated rats. When the toxin was administered into a similarly isolated jejunal loop, liver weight was significantly less than that found when an equivalent dose was administered into the ileal loop suggesting an intestinal site specificity for toxin absorption.
Chelation in Metal Intoxication XXIX: α‐Mercapto‐β‐aryl Acrylic Acids as Antidotes to Mercury (II) Toxicity
Authors: Kachru D. N. , Khandelwal S. , Sharma B. L. , Tandon S. K.
Published: March 2009

Abstract: α‐Mercapto‐β‐(2‐furyl) acrylic acid (MFA), α‐mercapto‐β‐(phenyl) acrylic acid (MPA), α‐mercapto‐β‐(2‐hydroxyphenyl) acrylic acid (MHA), α‐mercapto‐β‐(4‐methoxyphenyl) acrylic acid (MMA), β‐1,2‐phenylene di‐α‐mercapto acrylic acid (1, 2‐PDMA) and β‐1, 4‐phenylene di‐α‐mercapto acrylic acid (1, 4‐PDMA) enhanced faecal excretion and reduced liver, spleen and blood burden of inorganic mercury when administered (0.5 m mol/kg, in two split doses) 24 hr after Hg (II) (1 mg/kg) in rats. MFA, MPA, MHA and MMA were also effective in lowering renal Hg mainly from the cytosol, without any significant increase in urinary excretion of Hg. The results indicate that all the mono‐mercapto acrylic acids including MFA were more effective than di‐mercapto acrylic acids and act through the mechanism characteristic of thiol chelators, that is, mobilization of Hg as their complexes, contrary to the reported observation that MFA acts through the induction of metallothionein.
A Simple Method for Shell‐less Cultivation of Chick Embryos
Authors: Jakobson Åke M. , Hahnenberger Rudolph , Magnusson Anneli
Published: March 2009

Abstract: The chorio‐allantoic membrane of explanted chick embryos can be used for the study of vascular development and of the vascular response to drugs and to tissue implants or tissue extracts. Three different types of vials for shell‐less cultivation of chick embryos were compared in terms of short‐term survival. Plastic cups with rounded bottoms were superior to Petri dishes and polyethylene film bags, in that they combined a high survival rate of the embryos with a possibility of using a large number of embryos in each experiment. With the use of plastic cups this method is simple, reliable and inexpensive.
Effects of Tetraethylthiuram Disulfide on the Toxicokinetics of Cadmium in Mice
Authors: Andersen Ole , Grandjean Philippe
Published: March 2009

Abstract: This study examines the effects of tetraethylthiuram disulfide (TTD; disulfiram, Antabuse®) on the toxicokinetics in mice of 109Cd‐labelled cadmium chloride, as determined by whole‐body and organ gamma‐counting. At the highest single dose of orally administered CdCl2, i.e. 70 μmol/kg, orally administered TTD enhanced the inhibitory effect of CdCl2 on intestinal motility and increased the fractional whole‐body retention of the dose of cadmium chloride, indicating enhanced intestinal cadmium absorption. Also, TTD induced extensive changes in organ distribution of absorbed cadmium; the relative hepatic and testicular deposition was reduced, while the relative deposition in heart, spleen, lungs, brain and carcass was increased. In a prolonged exposure experiment where CdCl2 was added to the drinking water and TTD to the feed, TTD increased the intestinal absorption of cadmium by more than four‐fold as compared to the controls. Further, decreased deposition was seen in the carcass and increased deposition in intestines and liver. In a third experiment, oral doses of TTD given twice weekly had no influence on the rate of excretion of aged cadmium depots, and also the organ distribution was unchanged. Thus, the effect of TTD on cadmium metabolism seems to be exerted only during intestinal absorption and the distribution phase immediately thereafter.
Cardiovascular Function Measured by Ultrasound Doppler in Healthy Young Men after Ingestion of Dextropropoxyphene Napsylat
Authors: Lang‐Jensen T. , Thisted B. , Krantz T. , Serensen M. B. , Jacobsen E. , Angelo H. R.
Published: March 2009

Abstract: In a double blind cross‐over study 10 healthy male volunteers were given either 300 mg dextropropoxyphene napsylat (DP) or placebo daily for 16 days. The serum levels of DP and the metabolite nordextropropoxyphene were measured on day 3, 6 and 16. Haemodynamic measurements were made on day 1 and day 16, both at rest and during exercise. The measurements were made non‐invasively, with a pulsed ultrasound Doppler. Blood pressure, heart rate, velocity, cardiac output, left cardiac work, increased during work, but showing no significant differences between the groups. The systolic time intervals were also measured by the ultrasound Doppler. The preejection period increased significantly in the DP‐group, whereas the ratio preejection period/left ventricular ejection time which reflects the contractility of the heart did not differ significantly. It is concluded that DP taken daily in a normal dose for 16 days did not affect the heart function in healthy young men.
Treatment of Experimental Acute Uranium Poisoning by Chelating Agents
Authors: Ortega Arturo , Domingo José L. , Gómez Mercedes , Corbella Jacinto
Published: March 2009

Abstract:Sixteen chelating agents were examined to determine their relative efficacy as antidotes in acute uranyl acetate intoxication in mice after subcutaneous administration. Chelators were administered intraperitoneally to male Swiss mice at a dose equal to one‐fourth of their respective LD50 and the therapeutic effectiveness was calculated. Eight compounds resulted in a significant enhancement of the survival rate: Tiron, gallic acid, DTP A, p‐aminosalicylic acid, sodium citrate, EDTA, 5‐aminosalicylic acid and EGTA. Therapeutic indices (TI) were then determined for these chelating agents. Tiron (TI: 158), gallic acid (TI: 116) and DTPA (TI: 44.9) were the most effective antidotes. In subsequent experiments, uranyl acetate dihydrate was administered subcutaneously (10 mg/kg) in a 24 hr excretion and distribution study. The previous eight chelators were given intraperitoneally ten min. after the uranium administration. 5‐Aminosalicylic acid and tiron were consistently the most effective in increasing the urinary and faecal excretion of uranium respectively. A decrease of the uranium concentration in kidneys and bone was also noted with tiron. Tiron appears to be the most effective agent of those tested in the prevention of acute uranium intoxication.
Comparison of Intra‐ and Extrasynaptosomal Monoamine Oxidase‐A and ‐B Activities in the Striatum and Frontal Cortex of Two Mice Strains with Different Sensitivities to the Neurotoxic Actions of 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine
Authors: Stenström Anders , Sundström Erik , Fowler Christopher J.
Published: March 2009

Abstract: Conditions for the assay of the intra‐ and extrasynaptosomal rates of deamination of dopamine and noradrenaline by the two forms of monoamine oxidase (MAO) have been determined in striatal and frontal cortical homogenates, respectively, from C57 BL/6 mice. The activities obtained were compared with the corresponding activities found for NMRI mice, a strain less sensitive to the neurotoxic effects of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) than the C57 BL/6 strain. In both strains, the intra‐ and extrasynaptosomal deamination of dopamine in the striatal homogenates was brought about predominantly by MAO‐A. No significant differences between the two strains were found for the intra‐ or extrasynaptosomal MAO‐A or ‐B activities towards dopamine in striatal homogenates. On the other hand, the striatal dopamine concentrations were higher in the C57 BL/6 mice than in the NMRI mice. The concentrations of the dopamine metabolites DOPAC and HVA were similarly higher, suggesting that the rate of turnover of dopamine is the same for the two strains. In frontal cortical homogenates, MAO‐A predominated in the deamination of noradrenaline both intra‐ and extrasynaptosomally. The extrasynaptosomal rates of deamination of noradrenaline were similar in the two mice strains, whereas the intrasynaptosomal MAO‐A activity was significantly higher for the C57 BL/6 mice. These results concur with and extend to the noradrenergic system the conclusion previously made by Jossan et al. (1987) for the dopaminergic system that although MAO‐B activity is necessary for expression of MPTP neurotoxicity, it is not the rate‐limiting step for the development of the neurotoxic effects.
Effects of Perinatal Treatment with Lead and Disulfiram on ALAD Activity in Blood, Liver and Kidney and Urinary ALA Excretion in Rats
Authors: Oskarsson Agneta
Published: March 2009

Abstract: Disulfiram, which is metabolized to diethyldithiocarbamate, is known to greatly influence the tissue distribution of lead (Pb) and potentiate the toxic effect of lead in the central nervous system. Effects on δ‐aminolevulinic acid dehydratase (ALAD) activity and urinary δ‐aminolevulinic acid (ALA) excretion were studied in rats pre‐ and postnatally exposed to lead and disulfiram, singly or in combination. Pregnant rats were treated with lead (0.25% Pb in the drinking water), with disulfiram (0.1 mmol/kg orally twice a week) or with both lead and disulfiram from day 1 of pregnancy until weaning. After parturition the disulfiram was given subcutaneously directly to the offspring. ALAD activity in blood was inhibited to a similar extent in the group treated with lead alone and in the group treated with lead and disulfiram (7 and 10% of control activity, respectively). Liver and kidney ALAD activities were not affected by the combined treatment with lead and disulfiram. However, urinary excretion of ALA was increased twice as much in the group treated with lead and disulfiram as in the group treated with only lead. The haematocrits were also significantly more depressed after combined exposure to lead and disulfiram. Two weeks after cessation of exposure ALAD activity in blood was inhibited to 47% of control activity in both the lead‐ and the lead plus disulfiram‐treated groups. At this time there was no effect due to treatment on urinary ALA excretion or haematocrit. The results indicate that disulfiram probably influences the effects of lead on ALAD activity at the site of haem synthesis in the bone marrow. It is suggested that a lipophilic lead‐diethyldithiocarbamate complex is formed in vivo, resulting in a higher uptake of lead in the bone marrow with subsequent effects on haem biosynthesis.
Decrease in the Number of Muscarinic Receptors in Rat Pancreas after Chronic Alcohol Intake
Authors: Grönroos Juha M. , Kaila Timo , Aho Heikki J. , Nevalainen Timo J.
Published: March 2009

Abstract: The effect of eight months of alcohol intake on the number and affinity of muscarinic receptor sites in the rat pancreatic tissue were measured by using N‐3H‐methylscopolamine (NMS) as a radioligand. There were no differences in the receptor affinities for NMS between the alcohol‐exposed and age‐matched control animals, but the number of muscarinic receptor sites was 60 percent lower in the alcoholic animals. The present experimental model is consistent with altered food and water intake as consequences of chronic alcoholism and thus changes in food and water consumption may participate in mediating the effects of chronic alcohol intake on NMS binding sites. We suggest that the previously reported marked alcohol‐induced increase in pancreatic acetylcholine levels, which has been proposed to play a crucial role in the pathogenesis of acute alcoholic pancreatitis, may be a secondary phenomenon induced by increased resistance at the muscarinic receptor level.
Tissue Distribution of Glyceryl Trinitrate and the Effect on cGMP Levels in Rat
Authors: Torfgård Kristina , Ahlner Johan , Axelsson Krister L. , Norlander Björn , Bertler Åke
Published: March 2009

Abstract: In order to study distribution in tissue, rats were treated subcutaneously with glyceryl trinitrate, GTN, (50 mg/kg). The concentrations of GTN were measured in plasma, brain, heart, adipose tissue and aortic tissue at different sampling times by a gas chromatographic method with electron‐capture detection. The peak GTN‐concentration was reached after 2 hours in all tissues examined. The highest concentration of GTN was found in adipose tissue, where the level was approximately forty times higher than in plasma. The concentration of GTN in brain, heart and aortic tissue was about 2–3 times as high as in plasma. The cGMP level was measured in heart and brain. An increase of the cGMP level was found in brain 2 hours after GTN administration. No cGMP increase was found in heart tissue. The results indicate a substantial distribution of GTN to tissue, and an increase of cGMP in brain. The distribution of the substance in the tissues as shown, might have both pharmacokinetic and pharmacodynamic implications.
Transferrin Microheterogeneity in Rats Treated Chronically with Ethanol
Authors: Stibler Helena , Beaugé Françoise , Bjørneboe Anders , Aufrère Gilles
Published: March 2009

Abstract: The microheterogeneity of rat serum transferrin was analyzed by isoelectric focusing and immunofixation from Wistar rats chronically treated with ethanol either by inhalation (4 weeks) or by a liquid diet (6 weeks) and from pairfed controls. In spite of the length of ethanol exposure, a daily ethanol intake of 13–18 g/kg b.wt. and BAC levels of 1.0–4.1 g/l, no transferrin abnormality similar to that found in human alcoholics was observed. It is apparent that these two common animal models for chronic high ethanol consumption are not suitable for experimental studies of ethanol‐associated effects on transferrin.