bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial infrastructure in the Isolated Rabbit Heart Exposed to Dopamine, Dobutamine, Isoprenaline, G‐Strofanthin, Xamoterol and Hypoxia
Authors: Kjærulf‐Jensen Henrik , Korsgaard Niels , Lindeberg Henning , Vigholt‐Serensen Else
Published: March 2009

Abstract:The isolated spontaneously beating heart was used for comparing the effects of hypoxia and positive inotropic drugs on myocardial ultrastructure. Hypoxia gives a significant decrease in the volume fractions of mitochondrial cristae relative to the total mitochondrial volume (Vvmcristae) and a significant increase in the volume fraction of mitochondrial matrix relative to the total mitochondrial volume (Vvmmatrix), but changes in volume fractions of mitochondria (Vvmitochondria) and myofibrils (Vvmyofibrils) were absent. Significant changes in ultrastructure in hearts treated with dopamine (0.6 μM), dobutamine (90 nM), G‐strofanthin (0.25 μM), xamoterol (32 nM) and isoprenaline (0.15 μM or 15 nM) were absent. Furthermore, myocardial effects in the isolated rabbit heart without exposure to any treatment showed a significantly decrease in oxygen consumption after 90 min. and a significant decrease in frequency of contractions after 120 min. perfusion time, but no change in contractility was seen. We conclude that this experimental model is useful in studies of positive inotropic drugs.
Effects of Foetal Treatment with Methylazoxy methanol on Noradrenergic Synapses in Rat Cerebral Cortex
Authors: Watanabe Masayuki , Kinuya Masayuki , Ohtakeno Shinji , Watanabe Hiromi , Mamiya Gunji
Published: March 2009

Abstract:Methylazoxymethanol (MAM)‐induced cerebral hypoplasia resulted in a significant increase in densities of norepinephrine uptake sites in cerebral cortex, suggsting that norepinephrinergic axon terminals were compressed in the smaller brain volumes. The density of β‐adrenergic receptors in MAM‐lesioned cerebral cortex was decreased probably due to down‐regulation, while there were no changes in the proportions and affinities of agonist high‐affinity sites and agonist low‐affinity sites in the desensitized β‐receptors.
Age, Hypertension and Hypercholesterolaemia Alter Endothelium‐Dependent Vascular Regulation
Authors: Lüscher Thomas F. , Tanner Felix C. , Dohi Yasuaki
Published: March 2009

Abstract:As a source of several vasoactive factors, the endothelium takes part in the regulation of vascular tone. The most important endothelium‐derived vasoactive substances are nitric oxide, prostacyclin, endothelin‐1 and contracting factors requiring the activity of cyclooxygenase. The endothelium is an obvious target organ of cardiovascular risk factors. Accordingly, functional alterations do occur with aging, hypertension and hypercholesterolaemia. All three conditions are associated with a decreased basal and stimulated release of endothelium‐derived nitric oxide. On the other hand, the release of endothelin‐1 appears to increase with age, while the sensitivity to the peptide markedly decreases under the same conditions. In the spontaneously hypertensive rat, acetylcholine and stretch evoke the release of a cyclooxygenase‐dependent endothelium‐derived contracting factor, most likely prostaglandin H2. The circulating levels of endothelin‐1 on the other hand are not increased in experimental and human hypertension. In the porcine coronary circulation, oxidized low‐density lipoproteins selectively reduce endothelium‐dependent relaxations to aggregating platelets, serotonin and thrombin which are mediated by nitric oxide. The alterations of endothelial function occurring with aging, hypertension and hypercholesterolaemia may have important clinical implications for the pathogenesis of cardiovascular disease.
FAILURE OF ADDITION OF LITHIUM TO IMIPRAMINE TO ENHANCE ACTIVITY IN RATS OR MOOD IN NORMAL VOLUNTEERS
Authors: Benjamin Jonathan , Belmaker RH , Berzovsky Yuli , Revasov Arsen , Kofman Ora
Published: March 2009

Lithium powerfully augments the effects of imipramine in resistant depression. We treated four groups of rats for five weeks with (1) saline alone, (2) saline followed by lithium, (3) imipramine alone, and (4) imipramine followed by lithium. There was no augmentation of activity by lithium. Normal human volunteers took imipramine 75 mg daily for three weeks, followed by imipramine 75 mg daily together with lithium 900 mg daily for another ten days. There was no elevation of mood after the addition of lithium. Lithium augmentation of antidepressants apparently requires a pre‐existing neurochemical‐behavioral disturbance.
Serotonin, Carbohydrates, and Atypical Depression
Authors: Møller Svend Erik
Published: March 2009

At least three categories of atypical depression have been described. The hysteroid dysphoria is characterized by repeated episodes of depressed mood in response to feeling rejected, and a craving for sweets and chocolate. Two other issues are characterized by a cyclical occurrence of changes of mood and appetite, i.e., the late luteal phase dysphoric disorder (DSM‐III‐R, appendix), or “the premenstrual syndrome” (PMS), and the major depression with seasonal pattern (DSM‐III‐R), or seasonal affective disorder (SAD). The reactive mood changes are frequently accompanied by features as hypersomnia, lethargy and increased appetite, particularly with a preference for carbohydrates.

Central serotonin pathways participate in the regulation of mood and behavioural impulsivity, and modulate eating patterns qualitatively and quantitatively. Depressives with PMS og SAD benefit, in general, from treatments with serotonin potentiating drugs, suggesting that brain serotonin plays a role in the pathophysiology. Ingestion of carbohydrates increases the plasma ratio of tryptophan to other large neutral amino acids in man and animal, and the serotonin synthesis in the rat brain. Based on these findings it has been suggested that the excessive carbohydrate intake by patients with PMS and SAD reflects a selfmedication that temporarily relieves the vegetative symptoms via an increased central serotonergic activity.
Metabolism of Prednisone in Kidney Transplanted Patients with Necrosis of the Femoral Head
Authors: Lausten Gunnar Sehwarz , Egfjord Martin , Olgaard Klaus
Published: March 2009

Abstract: Interindividual variation of the metabolism of prednisolone and of the susceptibility to glucocorticoids might be possible factors contributing to the development of osteonecrosis after renal allotransplantation. As this aspect has not been properly investigated previously, we compared, in the present study, the metabolism of total and free prednisolone in 6 renal allotransplanted patients who subsequently developed osteonecrosis of the femoral head and the metabolism of 6 matched controls, who did not develop osteonecrosis. There was no difference in age, bodyweight, total serum protein or albumin, or in liver or renal function. The baseline cortisol was 54 ± 23 pg in patients with necrosis, and 102 ± 53 μg/1 in patients without necrosis (n.s.). Likewise there was no difference in the peak concentration of prednisolone (420 ± 43 vs. 394 ± 42 μg/1, n.s.), the bioavailability (0.57 ± 0.09 vs. 0.61 ± 0.05, n.s.) or in the apparent volume of distribution at steady state (Vdss, 0.37 ± 0.09 vs. 0.37 ± 0.04 1/kg, n.s.). The clearance of prednisolone in patients with osteonecrosis was 33% lower (0.79 ± 0.11 vs. 1.18 ± 0.13 ml/min./kg b.wt., P <0.05) and t1/2 was correspondingly 33% longer (246 ± 18 min. vs. 184 ± 15 min., P<0.05) than in patients without osteonecrosis. However, there was no difference in the apparent volume of distribution of free prednisolone (2.07 ± 0.36 vs. 1.69 ± 0.28 1/kg, n.s.), in the t½ (152 ± 30 vs. 107 ± 20 min., n.s.), or in the clearance (7.33 ± 2.12 vs. 7.82 ± 1.18 ml/min./kg) between the two groups. It is, therefore, concluded, that in spite of the reduced metabolic clearance of total prednisolone, the unchanged pharmacokinetics of free prednisolone indicate, that the development of steroid induced osteonecrosis of the femoral head may not be explained by altered pharmacokinetics of prednisone and prednisolone in these patients.
2‐Naphthol Metabolism and Metabolite Transport in the Isolated Guinea Pig Mucosa: Further Evidence for Compartmentation of Intestinal Drug Metabolism
Authors: Sund Reidar Bredo , Lauterbach Fritz
Published: March 2009

Abstract: As an extension of a previous study on the metabolism of 14C‐1‐naphthol (1‐N) by the isolated guinea pig mucosa (Sund & Lauterbach 1986), the isomeric compound 2‐naphthol (2‐N, 50‐130 nmol/ml) has now been examined. 14C‐Labelled drug was added to the luminal or contraluminal fluid bathing the two sides of jejunal or colonic mucosal sheets in a symmetrical set up. After aerobic incubation for 45 min. at 37°, the fluid compartments and the tissue were analysed for parent drug and metabolites. Like I‐N 2‐N was transformed into its sulphate and glucuronide. In the jejunum, 2‐N was more extensively sulphated than 1‐N, whereas in the colon the metabolite profiles (sulphate: glucuronide ratio) of the two isomers were similar. Generally, the metabolism rate of 2‐N, its metabolite profile and metabolite transport pattern (lumen: blood distribution ratio) as well as the tissue accumulation of parent drug and metabolites, depended on the side of drug administration and on the tissue studied. Thus, changing the drug administration had a pronounced impact on the jejunal metabolism and transport, but caused only minor effects in the colon. In summary, this study emphasizes that drug metabolism and metabolite transport differ in the small and large intestine. The data further support the hypothesis that jejunal drug metabolism takes place in two compartments, of which the most active one is accessible from the lumen side and the other from the blood side. The possibility that colonic drug metabolism may also involve compartmentation should be considered although the present study provided very little evidence for this.
Perfluorooctane Sulfonic Acid is a Potent Inducer of Peroxisomal Fatty Acid β‐Oxidation and Other Activities Known to be Affected by Peroxisome Proliferators in Mouse Liver
Authors: Sohlenius Anna‐Karin , Eriksson Anna Messing , Högström Christina , Kimland Malin , DePierre Joseph W.
Published: March 2009

Abstract: Perfluorooctane sulfonic acid is almost as potent as perfluorooctanoic acid in causing increases in peroxisomal fatty acid β‐oxidation, peroxisomal catalase activity, Ω‐hydroxylation of lauric acid, cytosolic epoxide hydrolase activity and cytosolic DT‐diaphorase activity. Octane sulfonic acid was ineffective at doses used for perfluorooctane sulfonic acid and perfluorooctanoic acid. The results support the theory of co‐regulation of these parameters and peroxisome proliferation. The fact that perfluorooctane sulfonic acid causes peroxisome proliferation challenges the hypothesis that the first step in this process is formation of a thioester between the proliferator (the carboxylic group) and coenzyme A.
Increase in Antioxidant Activity in Procainamide‐Treated Rats
Authors: Magner‐Wróbel Krystyna , Toborek Michal , Drózdz Marian , Danch Alojzy
Published: March 2009

Abstract:Recent studies suggest thatin vivoprocainamide oxidation underlies induction of autoimmunity by this drug. Since drug metabolism may be accompanied by generation of reactive oxygen species, plasma and liver thiobarbituric acid reacting substances (TBARS), activity of erythrocyte and liver superoxide dismutase, catalase, selenium‐dependent glutathione peroxidase (Se‐GPX), and plasma antioxidant activity in procainamide treated rats were evaluated. Procainamide administration increased liver lipid peroxide levels, intensified the activity of liver catalase and erythrocyte superoxide dismutase, as well as plasma antioxidant activity. The remaining biochemical parameters in the treated rats were within control values, except for the decreased erythrocyte catalase activity. We conclude, that the increased activity of free radicals observed in the treated rats could contribute to the development of procainamide induced side effects.
Polymorphism of Debrisoquine and Mephenytoin Hydroxylation among Estonians
Authors: Kiivet Raul Allan , Svensson Jan‐Olof , Bertilsson Leif , Sjöqvist Folke
Published: March 2009

Abstract:Debrisoquine and S‐mephenytoin hydroxylation polymorphisms were studied in 156 unrelated native Estonians. The hydroxylation phenotypes were assessed by coadministration of mephenytoin with debrisoquine or dextromethorphan. The frequency of the poor metaboliser phenotype of debrisoquine/dextromethorphan was 4.5% (95% confidence interval 1.2‐7.8%), and that of mephenytoin was 3.9% (95% confidence interval 0.9‐6.9%) among Estonians, which is very similar to what has been reported in other Caucasian populations.
Tolerance to Hexobarbital Induced by Short‐Term Treatments with Diazepam and Tested with an EEG‐Threshold Test in Male Rats
Authors: Carlsson Sten , Wahlström Göran
Published: March 2009

Abstract:Male Mol: SPRD rats were treated with 5 or 20 mg/kg of diazepam for 4 days. The treatment was repeated at two different ages. Diazepam was either dissolved in Intralipid®(KABI, Sweden) or dispersed in gummi arabicum. Tolerance induced by the treatment was tested with an EEG‐threshold technique where hexobarbital was infused intravenously on day 1, 4, 7 and 14 of the abstinence. The threshold was the dose of hexobarbital needed to induce a burst suppression of 1 sec. or more (silent second). After the first diazepam treatment significant increase in the hexobarbital threshold doses were recorded in all but one of the diazepam treated groups. The pattern varied depending on dose, age and solvent. After the second treatment tolerance was seen only when diazepam had been dissolved in Intralipid®. Short term treatment with diazepam can induce crosstolerance to hexobarbital which probably is due to an increased excitation (physical dependence) in abstinence after treatment with diazepam.
Effects of L and D‐carnitine on Brain Energy Metabolites in Mice Given Sublethal Doses of Ammonium Acetate
Authors: Matsuoka Masato , Igisu Hideki
Published: March 2009

Abstract: Previous studies in our laboratory have shown that L‐carnitine suppresses seizures and alterations of brain energy metabolism in mice caused by hyperammonemia. The present study was done to exclude the effects of seizures on brain energy metabolism. When sublethal dose of ammonium acetate (12 mmol/kg b.wt.) was injected to mice, all mice survived without developing seizures, while clear increase of brain ammonia and alterations of brain energy metabolites were seen. In L‐carnitine‐treated animals, the levels of ammonia, AMP and lactate were lower and those of ATP and phosphocreatine were higher than in untreated animals. Treatment with D‐Carnitine also preserved the phosphocreatine level. This indicates that the improvement of brain energy metabolism by L‐carnitine in hyperammonemia is not simply a result of the suppression of seizures, and that the “physiological” function of carnitine may not be the sole mechanism underlying this effect.
Effect of Lovastatin on Cholesterol Absorption in Cholesterol‐Fed Rabbits
Authors: Nielsen L. B. , Stender S. , Kjeldsen K.
Published: March 2009

Abstract: The aim of the present study was to investigate the effect of the hydroxymethylglutaryl (HMG)‐CoA reductase inhibitor lovastatin on some aspects of cholesterol metabolism in cholesterol‐fed rabbits. The plasma cholesterol concentration was markedly lower in lovastatin‐treated rabbits (6 mg/rabbit/day) compared to controls after 36 days of cholesterol‐feeding (x ± S.E.) (19 ± 4 mmol/1, n = 9 versus 153 ± 17 mmol/l, n = 7) (P<0.00001). Intestinal absorption of cholesterol in such rabbits was reduced by 15% in lovastatin‐treated rabbits (n = 21) compared to controls (n = 18) (P<0.025). The results suggest that the hypocholesterolaemic effect of lovastatin in cholesterol‐fed rabbits is associated with a decreased intestinal absorption of cholesterol.
Reduced Turnover of Dopamine and 5‐Hydroxytryptamine in Discrete Dopaminergic, Noradrenergic and Serotonergic Rat Brain Areas after Acutely Administered Medetomidine, a Selective α2‐Adrenoceptor Agonist
Authors: Koulu Markku , Pesonen Ullamari , Koskinen Seppo , Scheinin Harry , Virtanen Raimo , Scheinin Mika
Published: March 2009

Abstract:Monoamine metabolism and turnover were investigated in discrete doparninergic, noradrenergic and serotonergic brain areas in the rat after acute administration of the selective α2‐adrenoceptor agonist, medetomidine. Medetomidine (3, 30 and 100 μg/kg subcutaneously) was given 90 min. before decapitation and discrete brain nuclei were punched from frozen brain slices for the analysis of concentrations of noradrenaline (NA), dopamine (DA), 3,4‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA). In a separate experiment, the accumulation of 3,4‐dihydroxyphenylalanine (DOPA) and 5‐hydroxytryptophan (5‐HTP) was measured after inhibition of L‐aromatic amino acid decarboxylase by NSD 1015: medetomidine (3, 10 and 100 μg/kg subcutaneously) was given 60 min. before NSD 1015 (100 mg/kg intraperitoneally), and the rates of DOPA and 5‐HTP accumulation were determined over 30 min. Finally, the antagonistic effect of idazoxan (1 mg/kg subcutaneously), a selective α2‐adrenoceptor blocking agent, on the medetomidine‐induced changes in monoamine metabolism was investigated. Medetomidine markedly decreased the metabolism and turnover of DA in the nucleus caudatus, but not in the nucleus accumbens or substantia nigra. In all dopaminergic areas, the turnover of 5‐HT was markedly inhibited by medetomidine. These effects were significantly counteracted by idazoxan pretreatment demonstrating the α2‐receptor mediated action of medetomidine. The turnover of 5‐HT was also reduced by medetomidine in the nucleus raphe dorsalis, the A1‐Cl area, locus coeruleus, nucleus tractus solitarius and the A5 area. The accumulation of DOPA was markedly inhibited in the A1‐C1 area, nucleus tractus solitarius and nucleus raphe dorsalis, but not in locus coeruleus. In these brain stem areas the accumulation of DOPA mainly takes place in noradrenergic neurones and thus reflects thein vivorate of synthesis of NA. It is concluded that in spite of the proven α2‐adrenoceptor selectivity and specificity of medetomidine it has marked effects on the metabolism and turnover of other neurotransmitters in addition to NA. This is in agreement with the wide distribution of α2‐adrenoceptors in the central nervous system. Furthermore, it suggests that important interactions take place between different monoaminergic neurones, reducing thein vivoselectivity of drug actions.
Immunological Changes Produced in Rats by Prenatal Exposure to Carbon Monoxide
Authors: Giustino A. , Cagiano R. , Carratù M. R. , De Salvia M. A. , Panaro M. A. , Jirillo E. , Cuomo V.
Published: March 2009

Abstract: Wistar female rats were exposed to relatively mild concentrations of carbon monoxide (CO) (75 and 150 p.p.m.) from day 0 to day 20 of pregnancy. The results show that splenic macrophage phagocytosis of Candida albicans was significantly decreased in 15 and 21 day old male rats exposed to CO (150 p.p.m.) during pregnancy. Moreover, splenic macrophage killing was significantly reduced in 15 day old male pups prenatally exposed to 75 and 150 ppm of CO. Prenatal CO (150 p.p.m.) significantly decreased splenic macrophage O2‐ release in both 15 and 21 day old pups. CO‐induced alterations in the immune system were not observed in 60 day old rats. These findings indicate that gestational exposure to relatively mild concentrations of CO induces in rat offspring reversible immunological changes characterized by an altered splenic macrophage function.
Clinical Pharmacology and Toxicology of Cocaine
Authors: Benowitz Neal L.
Published: March 2009

Abstract:Cocaine abuse has produced a major epidemic health problem in North America in the 1980s. The abuse of cocaine is maintained by the drug's effects on brain reward systems, mediated at least in part by its dopaminergic action. The patterns and consequences of use are best understood by considering the pharmacokinetics (rapid absorption and delivery to the brain, relatively short half‐life) and the pharmacodynamics (intense central and peripheral neural stimulation). Cocaine is used therapeutically as a topical and local anaesthetic. Toxicity occurs primarily in cocaine abusers, but also occasionally after therapeutic dosing. Medical complications reflect primarily excessive central nervous system stimulation and excessive vasoconstriction, the latter resulting in severe hypertension and/or organ ischaemia with associated organ injury. Most deaths that result from medical complications of cocaine intoxication are sudden and occur before medical intervention is possible. Other complications of cocaine abuse with severe personal and social consequences include traumatic deaths and injuries, and reproductive disturbances, as well as transmission of infectious diseases, especially AIDS. Cocaine addiction is clearly a problem, although the number of addicts is unknown. Pharmacologic treatment of cocaine addiction has as yet been unsuccessful. Psychosocial approaches remain the mainstay of therapy.
Atropine and Oxime Treatment in Lethal Soman Poisoning of Anaesthetized Guinea‐pigs: HLö 7 Dimethanesulfonate Versus HI 6 Dichloride
Authors: Worek Franz , Szinicz Ladislaus
Published: March 2009

Abstract:The oxime HI 6 is considered to be effective in soman poisoning and less effective in tabun poisoning. Recently, HLö 7 was shown to reactivate acetylcholinesterase (AChE) inhibited by soman and tabun. Therefore, the efficacy of HLö 7 and HI 6 was compared in soman poisoned guinea‐pigs. Female Pirbright‐white guinea‐pigs were anaesthetized with urethane (1.8 g/kg) and the a. carotis, v. jugularis and trachea were cannulated. After base line measurements soman 0.08 mg/kg (= 5 x LD50) or 0.16 mg/kg (= 10 x LD50) was injected intravenously, 2 min. later the antidotes were applied intravenously: HLö 7 0.03 or 0.1 mmol/kg, HI 6 0.03 or 0.1 mmol/kg, atropine 10 mg/kg, or a combination of atropine and an oxime. Respiratory and circulatory parameters were recorded for 60 min. or until the death of the animal. The injection of 5 x LD50 soman resulted in a rapid respiratory arrest followed by circulatory failure in the soman and soman plus oxime groups (survival time about 7 min). Atropine restored the circulatory parameters to base line but was unable to provide a sufficient respiratory function (survival time 26 min.). The combination therapy with atropine plus HLö 7 or HI 6 improved the respiration sufficiently, restored the circulation completely, and prolonged the survival time to about 50 min. Atropine treatment was insufficient in animals poisoned with 10 x LD50 soman. The combination of atropine and HLö 7 or HI 6 improved respiration, circulation, and survival time to various extent. Despite of the striking therapeutic effect no reactivation of erythrocyte AChE by the antidotes was observed. These results indicate, that the therapy with oximes or atropine alone is insufficient. The treatment with atropine plus HLö 7 or HI 6 proved to be efficient. HLö 7 is considered to be at least as effective as HI 6 in soman poisoning in this guinea‐pig model.
Effects of Six Months’White Spirit Inhalation Exposure in Adult and Old Rats
Authors: Østergaard Grete , Lam Henrik R. , Ladefoged Ole , Arlien‐Søborg Peter
Published: March 2009

Abstract: In two separate experiments in rats the irreversible effects of six months'exposure to white spirit (0, 400 p.p.m., and 800 p,p.m.) were studied. In one experiment the exposure started at the age of three months, in the other the rats were 15 months at the beginning of the exposure. After an exposure‐free period of several months neurobehavioural, pathological, and neurochemical examinations were performed. A marked difference in motor activity between young and aged animals was found. A slight effect on kidney function was seen at 800 p.p.m. No macroscopic or histopathological changes related to dosing were found. The concentrations of noradrenaline, dopamine, and 5‐hydroxytryptamine in various brain regions and in whole brain were irreversibly changed. In conclusion, the study revealed different changes within the CNS, but failed to demonstrate neurobehavioural white spirit‐induced neurotoxicity.
Lactate Accumulation in Isolated Hypoxic Rat Ventricular Myocardium: Effect of Different Modulators of the Cyclic GMP System
Authors: Ljusegren Marie Ekstam , Axelsson Krister L.
Published: March 2009

Abstract:Different agents which are known to increase tissue levels of cyclic guanosine 3′5′‐monophosphate (cGMP), were found to decrease the lactate accumulation induced by hypoxia in isolated, non‐beating rat myocardium from the right ventricle. One μM sodium nitroprusside increased the intracellular cGMP content 4 times during hypoxic conditions, and after 5 min. of hypoxia the intracellular lactate accumulation decreased by about 20%. 0.1 μM atrial natriuretic peptide increased cGMP 10 times during hypoxic conditions and decreased the lactate accumulation by about 40%. The reduction in lactate accumulation was mimicked by 1 mM 8‐Br‐cGMP and by Zaprinast (10 μM), a selective inhibitor of cGMP phosphodiesterase, which reduced lactate accumulation by 60% and 45%, respectively. Glyceryl trinitrate (1 nM and 1 μM) caused a slight increase in lactate accumulation both during normooxic and hypoxic conditions, but had no effect on tissue levels of cGMP. In conclusion, the results indicate that cyclic GMP reduces lactate accumulation in hypoxic, non‐beating rat heart ventricular muscle and suggests that atrial natriuretic peptide, which is released from atrial tissue, may have beneficial metabolic effects on the heart.
Differences in Performance in Three Strains of Rats in a 5‐Choice Serial Reaction Time Task
Authors: Didriksen Michael , Christensen Anne Vibeke
Published: March 2009

Abstract: Possible discrepancies between an albino stock (Wistar), a mixed strain (pigmented/albino, Brown Norwegian x Lewis) and a pigmented strain (Long Evans) of rats in the acquisition and performance of a visual task for attention were investigated. It was expected that Wistar rats were less accurate in performance of the task, considering the visual deficits genetically linked to albinism in rodents. However, Wistar performed with the same accuracy, speed and impulsivity as Long Evans. The Brown Norwegian/Lewis rats had a decreased responding, speed and impulsivity. During task acquisition they responded with the same accuracy as the other two types of rats. After task acquisition they were also less accurate. In conclusion: It seems reasonable to use Wistar rats as well as Long Evans for the present task.
Effect of Nitrous Oxide on Haematopoiesisin Vitro: Biochemical and Functional Features
Authors: Warren D. J. , Christensen B. , Slørdal L.
Published: March 2009

Abstract:Prolonged exposure to nitrous oxide (N2O) can induce dyshaematopoiesis by causing a functional cobalamin‐deficiency state through oxidation of methyl‐cobalamin (vitamin B12). Herein, we demonstrate that N2O exposure of murine bone marrow cellsin vitroresults in both functional and biochemical perturbations. In haematopoietic and bone marrow stromal cells, N2O exposure results in a decrease in methionine synthetase activity with a corresponding increase in homocysteine efflux. In semisolid cultures, N2O inhibits colony formation by cells belonging to the colony forming unit in culture (CFU‐C) compartment. In contrast, N2O‐exposed stromal cell layers maintain the ability to bind and support the differentiation of haematopoietic progenitor cells upon reseeding. Together, these data suggest that the dyshaematopoiesis seen after exposure to N2O is mediated through a direct inhibitory effect on haematopoietic cells.
Drug Treatment of Panic Disorder
Authors: Rosenberg Raben
Published: March 2009

Abstract: Drug treatment of panic disorder is reviewed with focus on recent controlled studies. The efficacy of alprazolam, a triazolobenzodiazepine, and imipramine, a tricyclic antidepressant, has consistently been demonstrated, but there is reasonable evidence that other benzodiazepines or antidepressants might also be effective if equipotent doses are used. Most controlled studies demonstrate drug efficacy on several psychopathological symptoms, including the core symptom panic attacks. Limited evidence indicates that alprazolam may be more efficacious in treating panic attacks than avoidance behaviour, and the reverse when imipramine is concerned. Drug efficacy appears to be most consistently documented in moderately to severely ill panic patients. The benzodiazepines are better tolerated than antidepressants in terms of patient acceptance, and the improvement sets in faster with benzodiazepines. In the presence of depressive symptoms considered secondary to panic attacks and/or agoraphobia, both types of drugs appear efficacious. Difficulty discontinuing high‐dose benzodiazepine treatment remains the most important side effect of the treatment but sedation can, like anticholinergic side effects of the tricyclic antidepressants, be troublesome, thereby diminishing patient compliance. The role of newly developed antidepressants with a more specific mode of action and milder side effects awaits evaluation in controlled trials.
Increased Biliary Transferrin Excretion Following Parenteral Aluminum Administration to Rats
Authors: Klein Gordon L. , Goldblum Randall M. , Moslen Mary Treinen , Pyron Debra L. , Mann Peggy A. , Lee Thomas C. , Alfrey Allen C.
Published: March 2009

Abstract: Aluminum accumulates in the livers of patients receiving either parenteral nutrition or haemodialysis. When given parenterally to rats, aluminum causes cholestasis. However, the mechanism of hepatic aluminum uptake and the fate of aluminum in the liver are poorly understood. We examined the effect of parenteral aluminum administration on biliary excretion of transferrin, the major circulating aluminum‐binding protein. Male Wistar rats were given parenterally aluminum 5 mg/kg/day for 1–14 days. Bile was collected for 3 hr at the end of the study period. Biliary total protein concentration and IgA/total protein were unaffected by up to 14 days of parenteral aluminum administration. However, biliary transferrin excretion increased with duration of aluminum administration up to five‐fold by day 14. Biliary transferrin concentration and transferrin/total protein was higher in aluminum treated rats than controls after 7 and 14 days of study. Hepatic aluminum concentration reached a maximum after 4 days of parenteral aluminum administration, at which time serum bile acid and alanine amino transferase values were not different from controls. Since biliary transferrin is normally derived from the serum, it is likely that aluminum promotes hepatocellular uptake of transferrin and that aluminum enters the hepatocyte bound to transferrin. We postulate that transferrin may direct aluminum to intracellular sites where its toxic effects would be minimized.
Effects of Maternal Dietary Supplementation with Selenite on the Postnatal Development of Rat Offspring Exposed to Methyl Mercury in Utero
Authors: Fredriksson A. , Gårdlund A. Teiling , Bergman K. , Oskarsson A. , Ohlin B. , Danielsson B. , Archer T.
Published: March 2009

Abstract: Female Sprague‐Dawley rats were fed a control standard diet or a selenite (Se) supplemented diet (1.3 p.p.m. Se) for 8 weeks before mating and during gestation and lactation. Blood glutathione peroxidase activity (GSH‐Px) was measured as a biomarker of Se in dames. After mating, the females from two dietary groups were divided into three subgroups (6 groups with 10 animals in each) given 0 (vehicle), 2 or 6 mg/kg methyl mercury (MeHg) by gavage on days 6–9 of gestation. Day 2 post parturition all litters were standardized to 6 pups per litter and remaining pups were used for determination of blood and brain total Hg contents. Behavioural testing was performed at two months of age. The results of the study showed that supplementing the diet with Se partly antagonized some adverse effects of the MeHg such as hypoactivity especially in the high MeHg dose group. There were no changes in physical development or body weight except a tendency to decreased body weight in offspring of mothers exposed to 6 mg Hg/kg. The GSH‐Px activity was significantly increased in animals fed on Se supplemented diet. The dietary Se supplementation resulted in considerably increased concentrations of mercury in the blood of the offspring despite milder signs of CNS toxicity and no increase in brain concentrations of mercury.
Sabeluzole Administration Does not Enhance Fast Axonal Transport in Normal Adult Rat Sciatic Nerve
Authors: Li J.‐Y. , Dahlström A. B.
Published: March 2009

Abstract:Sabeluzole (R58735, Janssen Research Foundation) increased rates of axonal transport in short term tissue culture experiments and in rats with streptozotocin‐induced diabetes. The drug was tested for its subacute (3 days) net effect on axonally transported substances in motor, sensory, and adrenergic axons of normal adult rats. Sabeluzol was given once daily for 3 days, 1 or 10 mg/kg/day intraperitoneally. Immunofluorescence was used to identify transported material. Three or 6 hr after crushing the sciatic nerves, to interrupt anterograde and retrograde intraaxonal transport, cytofluorimetric scanning was used to quantitate accumulated immunoreactive material. Compared with vehicle treated control rats, no clear differences in the net amounts of accumulated material, or in rates of accumulation, were detected in any axonal type. Since the short‐term crush procedure interrupts ongoing axonal transport, the accumulation pattern reflects the transport characteristics in the crushed axons. The absence of clear increases in transport of several substances in this study indicates that sabeluzole did not enhance net axonal transport above control levels in peripheral axons of normal adult rats. Possible reasons for the discrepancy with earlier observations on the effect of sabeluzole on fast axonal transport is discussed.
Identification of the Cephalosporin Human Serum Albumin Binding Sites
Authors: Nerli B. , Pico G.
Published: March 2009

Abstract:We have demonstrated that the cephalosporins which possess heterozyclic pentagonal group substituents bind to the bilirubin binding site on albumin, while the cephalosporins which possess hexagonal hydrocarbon cycle substituents bind to the benzodizepine binding sites (site II) on albumin. No binding of cephalosporins to the so‐called site I and fatty acids binding site on human albumin was demonstrated.
Diazepam Treatment of Pregnant Rats Differentially Affects Interleukin‐1 and Interleukin‐2 Secretion in Their Offspring During Different Phases of Postnatal Development
Authors: Schlumpf Margret , Lichtensteiger Walter , Ramseier Hansruedy
Published: March 2009

Abstract:Treatment of pregnant Long Evans rats with benzodiazepines was found to cause alterations in cellular immune responses in their offspring. We now report on changes in interleukin‐1 (IL‐1) and IL‐2 secretion which were analyzed in rats from birth until 12 weeks. Time‐pregnant rats were treated with diazepam (1.25 mg/kg/day subcutaneously) from gestational day 14 to 20. Lipopolysaccharide‐stimulated release of macrophage‐derived IL‐1 by spleen cells, determined on D10.G4.1 cells, remained in the control range during the preweaning period (postnatal day 6–28), then decreased in prenatally diazepam‐exposed offspring, significantly in males during the postweaning period (postnatal day 34–61) and in both sexes in adults (postnatal day 62–83). Concanavalin A‐stimulated release of T lymphocyte‐derived IL‐2 from spleen cells, determined on CTLL‐2 cells, was reduced in male and female offspring during preweaning (postnatal day 3–28) and postweaning (postnatal day 33–55) periods and normalized in adulthood (postnatal day 60–84). The percentage of IL‐2 receptor expressing (CD25+) cells was unaffected. From these and our earlier data it is evident that prenatal exposure to low doses of benzodiazepines can result in long‐lasting alterations of the cytokine network, as indicated by reduced release of TNF‐α, IL‐1, IL‐6, IL‐2 and interferon‐γ. The concomitant reduction of peripheral type benzodiazepine receptors on macrophages is discussed as a possible link between prenatal treatment and disturbed function.
Interaction of Myeloperoxidase and Elastase Enzyme Activity with the Antihypertensive Agents Hydralazine and Dihydralazine
Authors: Hansson Ann‐Louise , Nässberger Lennart
Published: March 2009

Autoantibodies directed against myeloperoxidase and elastase have been found in patients developing hydralazine‐induced lupus and hydralazine‐induced isolated glomerulonephritis. The aim of this study was to investigate influence of hydralazine and dihydralazine upon myeloperoxidase and elastase enzyme activity. Using a 4‐aminoantipyrin in vitro system, dihydralazine was 2.5 times as potent in inhibiting myeloperoxidase activity as compared to hydralazine. The corresponding Ki‐values were 4 μmM for dihydralazine and 25 μM for hydralazine. When using 2.2′‐azino‐bis‐3‐ethylbenzothiazoline‐6‐sulphonic acid system inhibition was found at lower concentrations. Furthermore, the difference between the compounds was not so pronounced as seen for 4‐aminoantipyrin. The Ki‐values for hydralazine and dihydralazine were 1.2 and 1.4 μM respectively. Complete inhibition was seen for both compounds at concentrations above 7.5 μM. Hydralazine binds to elastase, but neither hydralazine nor dihydralazine inhibited elastase enzyme activity.
Inhibition of Hepatic Microsomal Drug Metabolism by Atracurium Administration in the Rat
Authors: Böhrer H. , Schmidt H. , Bach A. , Martin E. , Kohl B. , Bolsen K. , Goerz G.
Published: March 2009

The muscle relaxant atracurium is known to undergo extrahepatic degradation via Hofmann elimination and ester hydrolysis. The purpose of the present study was to evaluate the effects of atracurium on hepatic P450‐dependent enzyme activities. Thirty‐two male Sprague‐Dawley rats were anaesthetized, mechanically ventilated, and randomly allocated to one of four study groups: group 1 received saline, group 2 atracurium, group 3 vecuronium, and group 4 pancuronium intravenously for a period of 3 hr. Equipotent doses of the muscle relaxants were applied; the doses had been obtained in a pilot study using evoked electromyography. At the end of the study period, the livers were removed and analyzed. All three muscle relaxants may lead to inhibition of hepatic drug metabolism. Atracurium influences hepatic P450, although it is predominantly degraded in extrahepatic tissues. Further studies are needed to evaluate the contribution of the major metabolite laudanosine to this inhibitory action.
Comparison of Cumulative and Non‐Cumulative Administration of Vasoactive Agents in Arterial Smooth Muscle Responsesin Vitro
Authors: Kähönen Mika , Arvola Pertti , Vapaatalo Heikki , Pörsti Ilkka
Published: March 2009

Two methods of determining concentration‐response curves were compared in isolated endothelium‐intact mesenteric arterial rings from Wistar rats: arterial contractile and relaxation responses were elicited by adding compounds cumulatively or introducing a single concentration at a time (non‐cumulative method). The contractile responses induced by high concentrations of K+(20‐125 mM) were comparable between the two methods, whether or not the responses were elicited in the presence of phentolamine (10 μM) and atenolol (10 μM). Noradrenaline (1 nM ‐ 10 μM) likewise induced similar contractions regardless of method of administration, the only exception being the highest concentration (100 μM) which produced lower contractile force when added directly upon resting tension than after cumulative administration. This difference was abolished by atenolol (10 μM). Arterial smooth muscle relaxations induced by endothelium‐dependent (acetylcholine 1 nM ‐ 10 μM) and ‐independent agents (nitroprusside 1 nM ‐ 1 μM, isoprenaline 10 nM ‐ 100 μM) were similar whether the relaxants were added in a cumulative fashion or in a single concentration introduced upon each precontraction. Thus, cumulative and non‐cumulative administration of contractile and relaxing agents give quite comparable results. We conclude that the cumulative method is a reliable and time‐saving way of studying vascular smooth muscle responsesin vitro.
Involvement of Opioid Receptors in Shaking Behaviour Induced by Paraquat in Rats
Authors: Hara Shuichi , Iwata Nobuhisa , Kuriiwa Fumi , Kano Sadao , Kawaguchi Naohiko , Endo Takahiko
Published: March 2009

Paraquat (30‐70 mg/kg intraperitoneally) caused typical shaking behaviour in rats in a dose‐dependent manner. Myoclonus also appeared after the shaking behaviour in several rats treated with the highest dose of paraquat. Morphine (5 mg/kg intraperitoneally, 30 min. before paraquat) significantly reduced the frequency of shaking behaviour. The alleviation by morphine disappeared when naloxone (1.5 mg/kg intraperitoneally 15 min. after morphine) was coadministered. Although there was no histological change in brain slices of paraquat‐treated rats (70 mg/kg intraperitoneally), the fluorescein uptake into brain was increased by the treatment. Morphine prevented the increase of fluorescein uptake, but naloxone failed to antagonize this effect. On the other hand, intracerebroventricularly administered paraquat (25.7 μg/rat) caused tremor in all rats, but not shaking behaviour nor myoclonus. These findings suggest that paraquat administered systemically as well as centrally may be toxic to the brain. Although the actions of paraquat on the brain seem to be complicated, opioid receptors may play a role in the actions.
Gamma‐Vinyl GABA Decreases Voluntary Alcohol Consumption in Alcohol‐Preferring AA Rats
Authors: Wegelius K. , Halonen T. , Korpi E. R.
Published: March 2009

The effect of a GABA transaminase inhibitor, gamma‐vinyl GABA, on the voluntary alcohol consumption of alcohol‐preferring AA rats produced by selective breeding for high alcohol preference, was studied. The rats were first trained to voluntarily drink 10% (v/v) ethanol solution until their ethanol consumption stabilized. Gamma‐vinyl GABA (100, 200 or 500 mg/kg) was then injected intraperitoneally in three groups of rats, with saline‐injected animals serving as a control group. The rats continued to have a free choice between 10% ethanol and plain tap water for five days after the injection, and their ethanol, water and food consumptions were measured daily. Gamma‐vinyl GABA decreased ethanol consumption by the rats in a dose‐dependent way. The consumption remained significantly decreased for three days in the two groups receiving the highest doses, with only a small concomitant tendency to decreased food intake. The results suggest that an increase in brain GABA concentration decreases alcohol drinking, possibly through potentiation of the pharmacological action of ethanol.
Pharmacokinetics of R(+)‐Terodiline Given Intravenously and Orally to Healthy Volunteers
Authors: Hallén Bengt , Gabrielsson Johan , Palmér Lena , Ekström Björn
Published: March 2009

(+)‐Terodiline was given orally (25 mg) and intravenously (12.5 mg) to eight healthy volunteers. The pharmacokinetics of (+)‐terodiline could be described by a one compartment model. The lag time of absorption was 0.6 ± 0.5 hr (mean ± S.D.), the absorption half‐life 0.9 ± 0.5 hr, the time to maximum serum concentration 5.6 ± 2.2 hr and the corresponding maximum serum concentration 62 ± 22 μg/1. The volume of distribution was found to be 372 ± 84 1, the systemic clearance 86 ± 29 ml/min., the mean residence time 81 ± 38 hr and the observed terminal half‐life of elimination 56 ± 26 hr. The urinary excretion of the intravenous dose was 12 ± 6% and the renal clearance 10 ± 5 ml/min. The bioavailability of (+)‐terodiline was 93 ± 19%. The present results indicate that (+)‐terodiline as well as the racemate can be characterized as low clearance long half‐life drugs. One subject was a poor hydroxylator of debrisoquine and exhibited a 3‐fold decrease in clearance and increase in half‐life of (+)‐terodiline relative to extensive metabolizers. Observed pharmacological effects were mild accomodation disturbances and dry mouth, i.e. the same effects as those that may be seen at a corresponding dose of terodiline given as a racemic mixture.
Inhibition of Acetaminophen Oxidation by Cimetidine and the Effects on Glutathione and Activated Sulphate Synthesis Rates
Authors: Dalhoff Kim , Poulsen Henrik E.
Published: March 2009

The aim of the present study was to examine the effects of the hepatotoxic drug, acetaminophen, on the synthesis rates of glutathione, activated sulphate (PAPS, adenosine 3′‐phosphate 5′‐phosphosulphate) and the acetaminophen metabolites, acetaminophen‐glutathione and acetaminophen‐sulphate after inhibition of cytochrome P‐450 drug oxidation by cimetidine in isolated rat hepatocytes. The synthesis rates of glutathione and PAPS were determined simultanously by an established method based on trapping of radioactivity (35S) in the prelabelled glutathione and PAPS pools. Preincubation of the hepatocytes with 60 μg/ml cimetidine for 30 min. did not affect PAPS (1.71 versus 1.78 nmol/106cells) nor glutathione concentration (16.0 versus 16.4 nmol/106cells). The subsequent incubation with 5 mM acetaminophen resulted in decreased PAPS synthesis in the cimetidine treated cells [0.79 × 103versus 0.92 × 103nmol/(106cells · hr)] (P<0.05). There was no difference in PAPS concentration or acetaminophen‐sulphate synthesis [1.73 versus 1.79 nmol/106cells and 13.0 versus 12.9 nmol/(106cells · hr), respectively]. Decreased PAPS synthesis may be related to decreased ATP supply or may be the result of a feed‐back regulation due to diversion of sulphur from glutathione synthesis to sulfoxidation. The glutathione synthesis was not significantly affected by cimetidine treatment [57 × 103versus 27 × 103nmol/(106cells · hr)]. As expected acetaminophen‐glutathione synthesis decreased by 38% [1.66 versus 2.68 nmol/ (106cells · hr)] (P<0.01). Also the glutathione concentration was lower in cimetidine treated cells [15.2 versus 15.9 nmol/ 106cells] (P<0.05). We have previously shown that glutathione synthesis was reduced if substrate availability decreased (acetaminophen concentration lowered). Thus, the unaltered glutathione synthesis observed in the present study in which N‐acetyl‐p‐benzoquinoneimine formation was diminished suggests that cimetidine does not inhibit all acetaminophen metabolites which utilize reduced glutathione.
Protection by Dihydroergocryptine of Glutamate‐Induced Neurotoxicity
Authors: Favit A. , Sortino M. A. , Aleppo G. , Scapagnini U. , Canonico P. L.
Published: March 2009

Dihydroergocryptine is a hydrogenated ergot derivative with pharmacological actions mainly related to its dopaminomimetic activity. Here we report that dihydroergocryptine can protect cultured rat cerebellar granule cells against glutamate‐induced neurotoxicity, assessing cell viability with the fluorescein diacetate‐propidium iodide technique. Dihydroergocryptine antagonized both the neuronal death produced by acute exposure to a toxic glutamate concentration as well as the normal age‐dependent degeneration in culture. The effect of dihydroergocryptine might be mediated by a scavenger action as suggested by the fact that the compound in a concentration‐dependent manner reduced the formation of intracellular peroxides produced in cerebellar granule cells by exposure to 100 μM glutamate. This action is apparently not mediated entirely by interactions with the dopamine D2receptors. The neuroprotective action suggests that dihydroergocryptine might be a potential useful drug in the therapy and/or prophylaxis of acute and chronic neurodegenerative diseases related to excitotoxic damage.