bluuebunny/crossref_metadata_2025 huggingface dataset:
Lithium Does Not Alter ADP‐Ribosylation of Gi/Go Catalyzed by Pertussis Toxin in Rat Brain
Authors: Odagaki Y. , Koyama T. , Yamashita I.
Published: March 2009

Abstract:The influences of lithiumin vitroandex vivoon the ADP‐ribosylation of Gi/Go catalyzed by pertussis toxin (islet‐activating protein, IAP) were investigated in cerebral cortical and hippocampal membranes from rats. Incorporation of [32P]ADP‐ribose into 40–4. kDa band catalyzed by IAP was markedly reduced by the addition of non‐hydrolyzable GTP analogue, guanosine 5′‐O‐(3‐thiotriphosphate) (GTPγS) or guanosine 5′‐(β, γ‐imido)triphosphate [Gpp(NH)p], in the presence of MgCl2but not in the absence of MgCl2. The amounts of IAP‐catalyzed ADP‐ribosylation of Gi/Go in the presence of 100 μM guanosine 5′‐O‐(2‐thiodiphosphate) (GDPβS) and 50 mM EDTA and in the absence of MgCl2were in proportion to the protein contents between 30 and 60 μg/tube, suggesting that the determination of [32P]ADP‐ribosylation could be used quantitatively within this limited range. Addition of LiClin vitrodid not affect the IAP‐mediated ADP‐ribosylation of Gi/Go up to the concentration of 5 mM. The values of ADP‐ribosylation of Gi/Go in the presence of 100 μM GTPγS were reduced by MgCl2concentration‐dependently. However, this inhibitory effect of MgCl2was not influenced by 2 mM LiClin vitro.Furthermore, chronic treatment with a diet containing 0.2% lithium carbonate did not alter the [32P]ADP‐ribosylation of Gi/Go catalyzed by IAP.
The Behavioural Response to Intrathecal Serotonin is Changed by Acute but not by Repeated Treatment with Zimelidine or Metergoline
Authors: Eide Per Kristian , Joly Norma Mjellem , Lund Anders
Published: March 2009

Abstract:The behavioural response to intrathecal serotonin (5‐HT) was examined in mice after acute and after withdrawal of repeated treatment with the 5‐HT uptake inhibitor zimelidine or the 5‐HT receptor antagonist metergoline. Intrathecal 5‐HT elicits a response consisting of biting or licking of the lower part of abdomen and reciprocal hindlimb scratching, indicative of nociceptive stimulation. Acute injection of zimelidine (20 mg/kg) significantly increased the response to intrathecal 5‐HT (0.25‐1 μg) whereas a single dose of metergoline (5 mg/kg) completely blocked the response to intrathecal 5‐HT (2 μg). The behavioural response to intrathecal 5‐HT (0.25‐2 μg) was not significantly changed 48 hr after withdrawal of repeated treatment with zimelidine (2 × 10 mg/kg/day for 14 days) or metergoline (2 × 2.5 mg/kg/day for 14 days). In the present experiments acute zimelidine appeared to increase nociceptive responsiveness, whereas metergoline had the opposite effect. This study does not provide evidence that long‐term treatment with zimelidine or metergoline leads to adaptive changes in the response to spinal cord 5‐HT receptor stimulation.
Level of Clodronate in Bone after Single and Repeated Subcutaneous Injections in Rats
Authors: Österman Thua , Laurén Leena
Published: March 2009

Abstract: The levels of clodronate in bone and plasma were determined in rats after subcutaneous injection of a mixture of unlabelled and 14C‐labelled disodium clodronate as a single dose (25 mg/5 μCi/kg or of 125 mg/25 μCi/kg), and as repeated doses (25 mg/5 μCi/kg) once or five times a week for five weeks. The level of clodronate in bone increased dose‐dependently. However, during repeated administration some saturation in bone was observed. The accumulation of clodronate in femur was higher than in ankle. No clear differences in concentration of clodronate in bone could be seen after different dosage schedules when the total doses were the same.
Genotoxicity of Acrylic Bone Cements
Authors: Jensen Jørgen Steen , Sylvest Annette , Trap Birna , Jensen Jørn C.
Published: March 2009

Abstract: The genotoxicity of conventional polymethylmethacrylate (PMMA) and a new formulation of bone cement: methylmethacrylate/n‐decylmethacrylate/isobornylmethacrylate (MMA/DMA/IBMA) were tested by micronucleus test and reverse mutation assays of Salmonella typhimurium (Ames test). In extracts from cement pellets (37°, 72 hr) with water and water/ethanol the concentration of MMA was reduced by 13–1. times with the new formulation and the concentrations of accelerators were reduced by 4‐5 times. New chemical constituents (DMA, IBMA, dihydroxy‐ propyl‐p‐toluidine) were found in negligible concentrations. In the micronucleus test all three cement brands were found non‐mutagenic and in the Ames test scattered increased revertant ratios were found without differences between the three brands. The new formulation does not possess any increased risk of genotoxicity.
Transport Kinetics of Glucose and Alanine in Renal Brush‐Border Membrane Vesicles of Cadmium‐Intoxicated Rabbits
Authors: Lee H. Y. , Kim K. R. , Park Y. S.
Published: March 2009

Abstract: Changes in transport kinetics of D‐glucose and L‐alanine were studied in renal luminal membrane vesicles isolated from cadmium‐intoxicated rabbits. Cadmium intoxication was induced by subcutaneous injections of CdCl2 at a dose of 2 mg Cd/kg/day for 2‐3 weeks. Brush‐border membrane vesicles were prepared from renal outer cortex and outer medulla by Percoll gradient centrifugation. Cadmium intoxication resulted in a marked attenuation of Na+‐dependent transports of D‐glucose and L‐alanine in both outer cortical and outer medullary brush‐border membrane vesicles, and this was due to reduction in Vmax and not Km. Similar results were obtained in normal vesicles directly exposed to free cadmium. These results suggest that in long‐term cadmium‐exposed animals free cadmium ions liberated in the proximal tubular cytoplasm may directly impair brush‐border membranes thereby reducing capacity of Na+‐dependent transport systems for glucose and amino acids.
2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD) and Related Compounds as Antioestrogens: Characterization and Mechanism of Action
Authors: Safe S. , Astroff B. , Harris M. , Zacharewski T. , Dickerson R. , Romkes M. , Biegel L.
Published: March 2009

Abstract:In the female Sprague‐Dawley rat uterus 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and related compounds exhibited a broad spectrum of antioestrogenic responses. For example 2,3,7,8‐TCDD inhibited the 17β‐oestradiol‐induced uterine wet weight increase, peroxidase activity, oestrogen and progesterone receptor levels, epidermal growth factor (EGF) receptor binding, and EGF receptor and c‐fos protooncogene mRNA levels. The aryl hydrocarbon (Ah) receptor was identified in the rat uterus and the antioestrogenic activities of TCDD and related compounds were structure‐dependent. In parallel studies, the effects of TCDD as an antioestrogen in MCF‐7 human breast cancer cells was also investigated. TCDD inhibited the 17β‐oestradiol‐induced proliferation of these cells and the secretion of the 34‐, 52‐ and 160‐kDa proteins. Treatment of MCF‐7 cells with 1 nM [3H]‐β‐oestradiol resulted in a rapid accumulation of nuclear oestrogen receptor (ER) complexes. Pretreatment of the cells with TCDD caused a rapid decrease in nuclear ER binding activity and immunoreactive protein; moreover, the structure‐dependent potencies of TCDD and related compounds as antioestrogens were similar to their Ah receptor binding affinities. TCDD also caused a decrease in nuclear ER levels in wild‐type Ah‐responsive Hepa lclc7 cells but was inactive in Ah non‐responsive mutant Hepa lclc7 cells. Moreover, in the wild‐type cells, both antinomycin D and cycloheximide blocked the effects of TCDD. 6‐Methyl‐1,3,8‐trichlorodibenzofuran (MCDF) has previously been characterized as a TCDD antagonist in rodents and in transformed rodent cell lines. However, like TCDD, MCDF also exhibited a broad spectrum of antioestrogenic activities in both the female Sprague‐Dawley rat uterus and MCF‐7 cells. MCDF is relatively non‐toxic compared to TCDD and is being investigated as a compound which may be clinically useful for the treatment of mammary cancer.
The Use of 2,4,5,2′,4′,5′‐Hexachlorobiphenyl (6‐CB) as an Unmetabolizable Lipophilic Model Compound
Authors: Mühlebach S. , Wyss P. A. , Bickel M. H.
Published: March 2009

Abstract:2,4,5,2′,4′5′‐Hexachlorobiphenyl (6‐CB) ‐ a polychlorinated biphenyl (PCB) congener resitant to metabolism in most species ‐ has become a major residue in the biosphere including human adipose tissue. Its use as a model of unmetabolizable lipophilic compounds and as a tool intoxicokineticsin the last two decades is reviewed. This extremely water‐insoluble compound is transported in plasma by albumin and lipoproteins. Binding to these plasma proteins appears to be important for uptake and release processes in different tissues. The redistribution kinetics of 6‐CB as well as its pronounced adipose tissue storage and a very slow excretion with the faeces has been established in long‐term animal studies. Excretion is strongly influenced by an increasing or diminishing adipose storage compartment size. Other minor pathways of elimination, e.g., via hair, become also important in the absence of metabolism and renal excretion. 6‐CB has revealed the possibility of an almost quantitative transfer of the maternal body burden to the offspring via milk. The use of 6‐CB in studies with tissue preparationsin vitrois providing insight into transport mechanisms of uptake and release.
Relative Liver Tumour Promoting Activity and Toxicity of some Polychlorinated Dibeiizo‐p‐dioxin‐ and Dibenzofuran‐Congeners in Female Sprague‐Dawley Rats
Authors: Wærn Fredrik , Flodström Sten , Busk Leif , Kronevi Tony , Nordgren Ingrid , Ahlborg Ulf G.
Published: March 2009

Abstract:The polychlorinated dibenzo‐p‐dioxins/dibenzofurans 1,2,3,7,8‐pentachlorodibenzo‐p‐dioxin (PeCDD), 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and 2,3,4,7,8‐pentachlorodibenzofuran (PeCDF) were studied for liver tumour promoting activity in a medium‐term altered foci assay in nitrosamine‐initiated female Sprague‐Dawley rats. The congeners under study were administered by weekly subcutaneous injections at three dose levels for 20 weeks. Evaluation of γ‐glutamyl‐transpeptidase (GGT+), altered hepatic foci development, showed that all congeners studied acted as potent promoters of hepatocarcinogenesis. TCDD and PeCDD were virtually equipotent as enhancers of foci development while PeCDF displayed approximately ten per cent of the activity of the dioxins. Analysis of the dioxin‐ and furan‐congeners by gas chromatography/mass spectroscopy (GC/MS) technique showed that the retention of PeCDD and PeCDF in liver tissue was approximately 7 and 20 times, respectively, as high as the retention of TCDD. Based on the concentration of the respective congener in liver tissue, PeCDD and PeCDF were 0.14 and 0.007 times as active as TCDD as promoters of foci development. The dose related enhancement of GGT+foci development induced by the PCDD/PCDF congeners was accompanied by an increased incidence of histological changes in the liver.
Effects of Dietary Supplementation with Vitamin E, Riboflavin and Selenium on Central Nervous System Oxygen Toxicity
Authors: Boadi W. Y. , Thaire L. , Kerem D. , Yannai S.
Published: March 2009

Abstract:We attempted to modify the resistance of rats to hyperbaric oxygen (HBO)‐induced central nervous system (CNS) toxicity, by increasing the tissue antioxidant potential through dietary factors. Groups of rats were fed excesses of vitamin E (VIT E) alone or in combinations with riboflavin (RIB), selenium (Se) or both, for 30 days. A control group was maintained on an unsupplemented diet. On the 23rd day animals to be exposed were implanted with chronic electrodes for electrocorticographic (ECoG) recording. Later, each group was divided into two subgroups, of which one was exposed to 4.5 atmospheres absolute (ATA) of 100% oxygen (O2) for 30 min., hereafter referred to as “exposed”, noting the time of appearance of first electrical discharge (FED) in their ECoG. The remaining subgroups were left unexposed. Forty‐eight hours later, all animals were sacrificed and some of their tissues were analyzed for glutathione (GSH). The GSH level in the liver, brain, lungs and blood of all experimental subgroups were significantly higher than in the control unexposed counterparts. Combinations of RIB and/or Se with VIT E failed to show a greater increase in GSH over VIT E alone. This increase was, however, not accompanied by a meaningful delay in the appearance of FED. Forty‐eight hours post‐exposure, the brain GSH levels of all exposed subgroups were still lower than the respective pre‐exposure levels. Yet, in the treated exposed subgroups the GSH levels observed 48hr after exposure were already higher than in the untreated unexposed controls. Thus, the dietary factors studied may enhance the reparative potential of oxidative tissue injury, but do not afford increased resistance of the brain to HBO, as judged by the respective FED times.
Action of Mercurials on3H‐cAMP Binding to the Regulatory Subunit‐II of cAMP‐Dependent Protein Kinase
Authors: Saijoh Kiyofumi , Inoue Yuhiko , Katsuyama Hironobu , Sumino Kimiaki
Published: March 2009

Abstract:Binding of the regulatory subunit type II (RII) of adenosine 3′,5′‐cyclic monophosphate (cAMP) dependent protein kinase was inhibited by Hg2+with an IC50 value of 0.31 μM. Methyl mercury, p‐chloromercuribenzoic acid (PCMB), and 5,5′‐dithiobis‐2‐nitrobenzoic acid (DTNB) also inhibited cAMP binding with IC50 values of 70–80 μM for organic mercurials and 130 μM for DTNB. Addition of 1 mM 2‐mercaptoethanol and 1 M cysteine to the assay mixture reversed these inhibitions. N‐ethylmaleimide (NEM) showed little effect on the binding. On the other hand, Hg2+and methyl mercury markedly suppressed enzymatic activity of the catalytic subunit. The IC50 value was 0.13 μM for Hg2+and 0.15 μM for organic mercurials. Scatchard plots of kinetic analysis data for the cAMP binding revealed a noncompetitive type of inhibition by mercurials and DTNB. It is suggested that blockade of sulfhydryl groups resulted in the inhibition of cAMP binding to the RII subunit, which might result in preserving the association of the RII subunit and the catalytic subunits and in preventing further inactivation of the catalytic subunit by Hg2+.
Stereoselective Efflux of (E)‐10‐Hydroxynortriptyline Enantiomers from the Cerebrospinal Fluid of Depressed Patients
Authors: Bertilsson Leif , Otani Koichi , Dahl Marja‐Liisa , Nordin Conny , Åberg‐Wistedt Anna
Published: March 2009

Abstract:In 5 patients treated with nortriptyline or amitriptyline for at least 9 months, the cerebrospinal fluid (CSF)/plasma ratio for 10‐hydroxynortriptyline (10‐OH‐NT) ranged from 0.085 to 0.172, which is similar to the ratio previously measured in patients treated for 3 weeks. In 4 other patients treated with racemic (E)‐10‐OH‐NT, the mean concentration ratio between (‐)‐ and (+)‐(E)‐10‐OH‐NT was 3.56 in plasma, 2.39 in plasma ultrafiltrate and 1.42 in CSF (oneway ANOVA; P<0.001). The mean free fraction in plasma determined by ultrafiltration for (‐)‐(E)‐10‐OH‐NT was 28.9±S.D.1.1% and for the (+)‐enantiomer 43.7±0.8% (P<0.001) confirming the difference in protein binding shown previously in healthy subjects. There was a correlation between the concentration of 10‐OH‐NT (sum of enantiomers) in CSF and plasma ultrafiltrate (r = 0.96; n = 7; P<0.001). The concentration in CSF was, however, only about 50% of that in the plasma ultrafiltrate and this seems to be due to a stereoselective transport of (E)‐10‐OH‐NT out from the CSF. The secretion from the CSF is more pronounced for the (‐)‐compared to the (+)‐enantiomer, which is consistent with the stereoselectivity of the renal secretion of these compounds.
Age‐ and Sex‐Dependent Dichlorovinyl Cysteine (DCVC) Accumulation and Toxicity in the Mouse Kidney: Relation to Development of Organic Anion Transport and β‐Lyase Activity
Authors: Darnerud Per Ola , Gustafson Anne‐Lee , Törnwall Ulrika , Feil Vernon J.
Published: March 2009

Abstract:The age‐ and sex‐dependent changes in mouse kidney accumulation and toxicity ofS‐1,2‐dichlorovinyl cysteine (DCVC) was investigated. The results were compared to developmental changes in the basal activities of organic anion transportin vitro(PAH uptake) and of cysteine conjugate β‐lyase (substrate: benzothiazolyl cysteine). Following14C‐DCVC (5 mg/kg body wt. orally), the renal14C‐accumulation increased with age, whereas the degree of tubular DCVC lesions was about the same at all time points. Regarding the sex differentiation in adult mice, both the kidney14C‐accumulation levels and the kidney lesion (5 mg/kg DCVC) were most accentuated in the female mouse. However, at a higher dose (25 mg/kg), the male kidney was most affected. Changes in the anion transport and β‐lyase activities did not directly mirror the age‐dependent increase in kidney radioactivity. Sex differences in anion transport and β‐lyase activities were also seen, the former activity being highest in the male mouse and the latter in the female. The conflicting results of14C‐accumulation and histopathology in developing mice, may be explained by the ongoing development of the kidney; increase in the number of functionally active nephrons may result in an increased14C‐accumulation (in d.p.m./mg wet wt.) but still the same degree of lesion, when estimated per nephron. In the adult mice, the higher susceptibility of the female may be correlated to the higher β‐lyase activity in the same sex. Regarding the inversed results at a higher dose, rate limitations of transport and bioactivation systems may play a role.
Pharmacokinetics of Alprazolam in Geriatric Patients with Neurotic Depression
Authors: Dehlin O. , Kullingsjö H. , Lidén A. , Agrell B. , Moser G. , Olsen I.
Published: March 2009

Abstract: The pharmacokinetics of alprazolam was studied in 10 geriatric patients (5 males, 5 females) with neurotic depression during a 6‐week period. After 0.5 mg of alprazolam on Day 1 the mean elimination half‐life was 11.1 hr and Cmax 12.3 ng/ml. The pharmacokinetic evaluation on Day 1 (t 1/2, tmax) did not differ significantly from the evaluation on Day 42. The mean daily dosage on Day 42 was 1.6 mg alprazolam. The concentrations of the metabolites α‐OH alprazolam and 4‐OH alprazolam were less than 10% of that of alprazolam. All the patients improved clinically. The most common side effect was drowsiness, more often during the first week than the last week.
Suppression of the Luteinizing Hormone Surge by Chlordimeform in Ovariectomized, Steroid‐Primed Female Rats
Authors: Goldman Jerome M. , Cooper Ralph L. , Edwards Tammy L. , Rehnberg Georgia L. , McElroy W. Keith , Hein Joy F.
Published: March 2009

Abstract: The midcycle surge of luteinizing hormone (LH) from the pituitary provides the physiological trigger in the mammalian female for the process of ovulation. Accordingly, any agent that compromises the LH surge could function as a reproductive toxicant. Since ovariectomized (OVX) rats implanted with oestradiol capsules will exhibit daily afternoon surges, such animals can serve as a useful model for the investigation of toxicant‐induced alterations in this functional hormonal event. The acaricide chlordimeform (CDF) has previously been found to decrease serum LH, probably by altering the hypothalamic noradrenergic transmitter control of LH secretion. Consequently, the present study focused on the effect of acute CDF administration on the appearance of the induced LH surge. Single intraperitoneal injections of CDF (0, 10, 25, 50 mg/kg) in OVX, oestradiol‐implanted female Long‐Evans rats approximately 5 hr prior to the expected surge caused a complete suppression at 25 and 50 mg/kg. Ten mg/kg had no effect on surge amplitude, but advanced the LH peak by 2 hr. The observed suppression did not persist beyond the day of CDF administration. Earlier dosing at 11 or 18 hr prior to the surge was without effect. Since CDF has been found to elevate serum corticosterone (CORT), 10 mg CORT/rat were given at different times prior to the surge. Twenty hr after administration only a partial lowering was seen; 5 hr exposure were ineffective. This indicates that an indirect adrenal effect was not the principal route, but may accompany an action of CDF on the hypothalamic mechanisms regulating the surge and becomes evident after more prolonged exposure.
Pharmacokinetics of Metrifonate and its Rearrangement Product Dichlorvos in Whole Blood
Authors: Abdi Yakoub Aden , Villén Tomas
Published: March 2009

Abstract: Six male healthy volunteers were given single oral doses of 7.5 mg/kg of metrifonate and concentrations of metrifonate and dichlorvos were determined in whole blood using a standardized sampling procedure. Blood was collected in test tubes containing equal volumes of 0.74 M phosphoric acid for the determinations of metrifonate and dichlorvos with gas chromatography and mass spectrometry at different time points for up to 24 hr. Cholinesterases were also determined in blood haemolyzed with water. Metrifonate was quickly absorbed with a Cmax of 50.5±18.9 μmol/l which was obtained between 0.17 to 1 hr after drug intake. Mean whole blood t1/2, Cl0 and AUC were 2.07±0.24 hr, 0.34±0.06 l/hr/kg and 89.2±16 μmol.hr/l respectively. The concentrations of dichlorvos closely followed those of metrifonate with a constant ratio of 0.01 to 0.02. The concentrations of metrifonate were detectable for up to 8 hr but those of dichlorvos had fallen below the level of determination by this time. Both plasma and red blood cell cholinesterases were readily inhibited and were still low after 24 hr. None of the volunteers complained of side effects.
Spinal Antinociception by Dexmedetomidine, a Highly Selective α2‐Adrenergic Agonist
Authors: Kalso Eija A. , Pöyhiä Reino , Rosenberg Per H.
Published: March 2009

Abstract:The antinociceptive effects of dexmedetomidine, a highly selective new α2‐adrenoceptor agonist, were evaluated in rats after intrathecal, intraperitoneal and subcutaneous administration. Antinociception was tested using the tail‐flick method. Both 3 and 6 μg of intrathecal dexmedetomidine produced maximal antinociception within 10 min. The effect lasted for up to 6 hr. The smaller dose of 1.5 μg produced a mean antinociception of 50% (of the maximum possible effect, MPE%) which lasted for about 2 hr. Subcutaneous atipamezole, a specific α2‐adrenergic antagonist completely abolished the antinociception produced by intrathecal dexmedetomidine. When given intraperitoneally, dexmedetomidine produced on average a 50% antinociceptive effect with the highest dose of 60 μg/kg. The lower doses of 10 and 30 μg/kg were ineffective. After subcutaneous administration a maximal effect was achieved with 120 μg/kg, a 70% effect, on average, with 60 μg/kg and a short lasting effect of 60% with 30 μg/kg. In conclusion, dexmedetomidine is a very potent antinociceptive agent when given intrathecally to rats.
Renal Effects of α‐Adrenoceptor Blockade During Furosemide Diuresis in Conscious Rats
Authors: Petersen J. S. , Shalmi M. , Abildgaard U. , Christensen N. J. , Christensen S.
Published: March 2009

Abstract:Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non‐selective α‐adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide‐induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n=6) was compared with time control animals (n=9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n=9), 0.3 (n=6), 1.0 (n=7) and 3.0 mg/kg/hr (n=6). Phentolamine infusion reduced noepinephrine‐induced increase in blood pressure at all three dose levels (n=5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose‐dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose‐dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FELi) increased to 65±3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52±3% during furosemide alone. At steady‐state conditions (120–180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume‐depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FELi=48±2% versus 39±1%> in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular α‐adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide‐induced volume contraction.
Stereoselective Pharmacodynamic Action of (+)‐S‐12967 and (—)‐S‐12968, Isomers of a New Slow Acting 1, 4‐Dihydropyridine Derivative with Calcium Channel Agonistic and Antagonistic Effects on Rat Aorta
Authors: Poulsen S. H. , Nyborg N. B. C. , Mikkelsen E. O.
Published: March 2009

Abstract:The effects of (+)‐S‐12967 and (—)‐S12968, isomers of a new dihydropyridine (1, 4‐DHP) derivative [2(7‐amino 2, 5‐dioxaheptyl) 3‐ethoxycarbonyl 4‐(2, 3‐dichlorophenyl) 5‐methoxycarbonyl 6‐methyl 1, 4‐dihydropyridine] were studied on contractile responses of isolated thoracic aortas from rats and compared to that of nifedipine. The maximal relaxant effect of both isomers was reached in about 2 hr whereas the maximal relaxant effect to nifedipine was obtained within 30 min. The two 1, 4‐DPH isomers and nifedipine had a far more potent inhibitory effect on potassium (K+) than on noradrenaline (NA) induced contractions. They shifted the K+, Ca2+and NA‐concentration response‐curves to the right and depressed the maximal vessel response to these agonists. Nifedipine was about 10 times more potent than the (—)‐isomer which again was about 100 times more potent that the (+)‐isomer. In contrast to nifedipine (–)‐S‐12968 and (+)‐S‐12967 had a dual action on K+and Ca2+‐induced contractions as both isomers in low concentrations, 3×10–9M and 3×10–7M, respectively, shifted the K+‐concentration response curves to the left and increased the maximal response. In K+‐depolarized preparations they increased the response to low Ca2+‐concentrations without affecting the maximal vessel response at the highest Ca2+‐concentrations. The result indicates that (+)‐S‐12967 and (—)‐S‐12968 possess Ca2+‐agonistic as well as Ca‐antagonistic properties. Compared to nifedipine both isomers are slow acting vasodilators. Their action as regards their potency is stereoselective and the (—)‐isomer is more potent than the (+)‐isomer.
Evidence for Distinct Phencyclidine and SKF10047 Receptors Following Detergent Treatment of Rat Brain Membranes
Authors: Grynne B. Hougens , Holmen Aa. T. , Maurset A.
Published: March 2009

Abstract:In order to compare characteristics of benzomorphan and phencyclidine receptors, binding of the ligands [3H]SKF10047 and [3H]phencyclidine (PCP) was measured in intact rat synaptosomal membranes and in membranes treated with a detergent (CHAPS, a twitterionic derivative of cholic acid). Ligand binding was quantified in the particle containing fractions and in particle‐free supernatants. About 20% of the SKF binding sites could be solubilized from the membranes by CHAPS under the conditions used here, while all PCP binding sites remained associated to particles. This observation and the inhibition patterns found for the two ligands indicate that the PCP receptors and the SKF receptors as delineated in this paper are indeed separate.
Acute and Long Term Effects of 1‐Methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) in Tests of Nociception in Mice
Authors: Rosland Jan Henrik , Hunskaar Steinar , Broch Ole Jacob , Hole Kjell
Published: March 2009

Abstract:Acute and long term changes in nociception after administration of 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) 80 mg/kg (four injections of 20 mg/kg given at two hr intervals) were investigated in mice. MPTP caused shivering, lacrimation, salivation, teeth chattering and fur erection a few minutes after drug injection, but all these behavioural changes were normalized within 30 min., when the first behavioural testing was performed. No significant alteration in general behaviour, sensorimotor performance or body temperature could be detected at the time of nociceptive testing. The acute effects of MPTP on nociception were a reduced response latency in the tail flick test and a prolonged response latency compared to controls in the constant temperature hot plate test. No significant effects of MPTP were found in the increasing temperature hot plate test. The long term effects were a reduced response latency both in the tail flick test and the constant temperature hot plate test, indicating that the MPTP induced lesions of dopaminergic pathways result in hyperalgesia. In the increasing temperature hot plate test and the formalin test, no significant long term changes were demonstrated. Seven days after injection, the dopamine content was reduced to 62% of control values in striatum, to 51% in the rest of the forebrain, and to 41% in the spinal cord. Noradrenaline levels were only slightly and transiently reduced. Serotonin levels were not affected 7 days after injection, but 14 days after injection, a great increase was found in the forebrain and in the spinal cord. The results suggest that dopaminergic systems tonically inhibit nociception. A functional adaptation starts to take place about one week after lesion, making an investigation of the time course important in studies of the functional effects of MPTP induced lesions.
Multiple‐Dose Sodium Polystyrene Sulfonate in Lithium Intoxication: An Animal Model
Authors: Linakis James G. , Eisenberg Marc S. , Lacouture Peter G. , Maher Timothy J. , Lewander William J. , Driscoll James L. , Woolf Alan
Published: March 2009

Abstract: Previous work in our laboratory has demonstrated that sodium polystyrene sulfonate (SPS) significantly lowered serum lithium (Li) concentrations when administered in a single oral dose after an oral dose of lithium in a mouse model. The present study was designed to determine whether: 1) repetitive doses of SPS are effective in lowering serum lithium concentrations, 2) the effect of SPS on lithium concentration is dose related and 3) SPS enhances the elimination of lithium. Mice (N=144) were given orogastric LiCl (250 mg/kg) and then divided into 4 groups: Controls received water 0, 30, 90, 180, and 360 min. after LiCl; the Full‐Dose SPS Group received SPS (5 g/kg/dose) at equivalent times; the Half‐Dose SPS Group received SPS (2.5 g/kg/dose) at the same times; and the Elimination Group received water at 0 and 30 min. after LiCl and SPS at 90, 180 and 360 min. after LiCl. Subgroups of each group were sacrificed at 1, 2, 4 and 8 hr post‐treatment and serum analyzed for lithium concentrations. Statistical analyses revealed that, when compared to Controls: 1) SPS significantly lowered serum lithium concentrations; 2) this effect was dose‐related; 3) repetitive dosing of SPS appears to enhance the elimination of lithium.
Clinical Responses in Relation to Blood Acetaldehyde Levels
Authors: Johnsen Jon , Stowell Allan , Morland Jerg
Published: March 2009

Abstract:A study was undertaken to examine the relationship between blood acetaldehyde levels and clinical responses in volunteers receiving the anti‐alcohol drugs disulfiram and calcium cyanamide. In the first part of this study volunteers received different doses of disulfiram (125 mg and 500+250 mg), of calcium cyanamide (25 mg, 50 mg and 100 mg) and of ethanol (0.2 g/kg orally and 0.5 g/kg intravenously). The ensuing interactions ranged from no reaction at all to an intense hypotensive cyanamide‐ethanol reaction (CER). A blood acetaldehyde concentration‐effect relationship was suggested. In the second part of this study seven subjects received 50 mg of calcium cyanamide 4 hr prior to an intravenous ethanol dose of 0.2 g/kg. The maximum blood level of acetaldehyde ranged from 16 to 241 μM. Aversive interactions started to occur at acetaldehyde levels around 40–60 uM. Changes in flushing reaction and diastolic blood pressure appeared best to reflect changing blood acetaldehyde levels. As a rule, however, the expected cyanamide‐ethanol and disulfiram‐ethanol reactions are more clearly registered as an increase in acetaldehyde levels than as the ensuing physiological responses.
Preferential Stimulation of Locomotor Activity by Ventral Tegmental Microinjections of (—)‐Nicotine
Authors: Leikola‐Pelho Taru , Jackson David M.
Published: March 2009

Abstract:In the present study the effect of acutely administered (—)‐nicotine on locomotor activity was measured after direct bilateral microinjections into the nucleus accumbens (Acb) or into the ventral tegmental area (VTA) of rats. Intrategmental (—)‐nicotine (either 0.02 or 2 μg/side) increased locomotor activity, the effect being greatest after the lower dose. The stimulation began almost immediately and was shortlasting with peak activity occurring at 30 min. after injection. Intra‐accumbal (—)‐nicotine (either 0.02, 2 or 20 μg/side) caused only a marginal short enhancement of activity which was not dose‐dependent. The time course of enhanced activity was similar to that observed after intrategmental injection. Our results indicate that the nicotine‐induced hyperlocomotion may arise primarily from activation of VTA nicotinic cholinoceptors (nAchRs), whereas activation of the accumbal nAchRs is less significant in regard to this effect.
Intestinal Absorption of Inorganic Mercury in Rat
Authors: Piotrowski Jerzv K. , Szymańska Jadwiga A. , Skrzypińska‐Gawrysiak Malgorzata , Kotelo Jolanta , Sporny Stanislaw
Published: March 2009

Abstract: 203Hg‐Mercuric chloride was administered intragastrically to female rats. The absorption rate evaluated for a broad range of doses was found constant for low and medium range, and higher for high doses. Mercury was determined in internal organs and intestines. The time‐course of intestinal mercury indicated that a deposit formed initially in the mucosa was further absorbed into the circulation. No indication was found of a protection mechanism based on exfoliation of the mucosal deposits of metal.
A Method for Simultaneous Evaluation of Drug‐Effects on Excitability and Inotropy in Isolated Cardiac Preparations
Authors: Lange‐Asschenfeldt Henning , Mescheder Axel , Mohr Klaus
Published: March 2009

Abstract:A method is described which allows determination of the threshold of excitability of electrically stimulated, regularly contracting isolated cardiac preparations. The force of the contraction (CF) is isometrically recorded and serves as feed‐back signal indicating effective stimulation. The pulse intensity is decreased monoexponentially as long as contractions are elicited. If the mechanical response does not occur, the pulse intensity is immediately reset to the initial high value and the pulse is delivered with a latency of a few milliseconds. A stimulus intensity just below threshold is recorded as the rectangular pulse threshold (RPT). The method was applied in order to compare the effects of a number of antiarrhythmic drugs including the β‐blocker propranolol on the electrical excitability (1/RPT) and on the contractility of guinea pig left atria stimulated at 3 Hz. In general, the drugs depressed excitability and contractility concomitantly. The rank order of potency with respect to the reduction of excitability was: aprindine > propafenone > propranolol > quinidine > mexilitine > lidocaine. The Ca‐antagonist verapamil reduced contractile force most powerful but had no effect on excitability. Presumably, RPT reflects sodium‐channel function. In conclusion, the described method offers an easily operable test of drug effects on the excitability threshold and the contractility of isolated cardiac preparations.
Cathinone, a Natural Amphetamine
Authors: Kalix Peter
Published: March 2009

Abstract:Cathinone is an alkaloid that has been discovered some fifteen years ago in the leaves of the khat bush. This plant grows in East Africa and in southern Arabia, and the inhabitants of these regions frequently chew khat because of its stimulating properties. Cathinone, which is S(–)‐α‐aminopropiophenone, was soon found to have a pharmacological profile closely resembling that of amphetamine; indeed, in a wide variety ofin vitroandin vivoexperiments it was demonstrated that cathinone shares the action of amphetamine on CNS as well as its sympathomimetic effects; thus, for example, drug‐conditioned animals will not distinguish between cathinone and amphetamine. These various observations were confirmed by a clinical experiment showing that cathinone also in humans produces amphetamine‐like objective and subjective effects. Finally, it was demonstrated that cathinone operates through the same mechanism as amphetamine, i.e. it acts by releasing catecholamines from presynaptic storage sites. Thus, much experimental evidence indicates that cathinone is the main psychoactive constituent of the khat leaf and that, in fact, this alkaloid is a natural amphetamine.
Receptor Subtypes in Opioid and Stimulant Reward
Authors: Self David W. , Stein Larry
Published: March 2009

Abstract:Studies of the behaviourally‐reinforcing actions of opioid and stimulant drugs of abuse are reviewed in an attempt to identify their reward‐related brain receptors. We focus on data generated by drug self‐administration, brain stimulation reinforcement, and conditioned place preference paradigms. A consistent body of evidence supports a role for μ and δ, but not K, receptors in opioid reward. Stimulant reward apparently involves both D1and D2receptors; the data favour D2mediation of stimulant drug reinforcement with a permissive or modulatory role for D1receptors. The reward‐relevant opioid and dopamine receptors, as well as the cannabinoid (marijuana) receptor, share the ability to couple Giproteins that mediate inhibition of adenylate cyclase and stimulation of K+conductance. These signal transduction mechanisms thus may be generally implicated in the reinforcing properties of diverse drugs of abuse.
Acute Neurobehavioural Toxicity of Trichothecene T‐2 Toxin in the Rat
Authors: Sirkka Ulla , Nieminen Sakari A. , Ylitalo Pauli
Published: March 2009

Abstract:The acute effects of single oral doses, 0.4 and 2.0 mg/kg, of trichothecene T‐2 mycotoxin on behaviour, motor performance and nociception were studied in male Wistar rats. Both doses are sublethal and did not cause overt acute signs of intoxication. In the open field test, 2.0 mg/kg of T‐2 toxin increased motionlessness and decreased sniffing (P<0.05) 4 hr after the administration. The higher dose shortened step‐through latencies in the test trial of the 24‐hr passive avoidance test (two‐way shuttle box). The exponential data analysis showed that, in those rats that did not learn to avoid the dark (unsafe) compartment of the box, the retention after 2.0 mg/kg of T‐2 toxin was only 25% of that in controls (P<0.001). T‐2 toxin had no effect on motor coordination in the rotarod test and in the bridge walking test 7–8 hr after administration. T‐2 toxin had no effect on nociception in the hot place test 8.5 hr after administration. The results suggest that T‐2 toxin has some inactivating effects on behaviour of rats, and it seems to cause an impairment in the passive avoidance test at dose 2.0 mg/kg.
Domoic Acid Toxicity in Rats and Mice after Intracerebroventricular Administration: Comparison with Excitatory Amino Acid Agonists
Authors: Chiamulera Christian , Costa Silvano , Valerio Enzo , Reggiani Angelo
Published: March 2009

Abstract:A behavioural study of the domoic acid (DOM)‐induced convulsive behaviour after intracerebroventricular administration was carried out in rats and mice. DOM‐induced behaviours were compared to those elicited by other excitatory amino acid (EAA) agonists N‐methyl‐D‐aspartate (NMDA), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) and kainic acid (KA), in such a way as to assess the possible similarities between DOM‐induced effects and EAA subtype receptor activationin vivo. In rat, DOM (0.03–3 nmol/rat) caused a complex pattern of convulsive behaviour, quantified by means of a 15‐point rating scale. DOM‐induced behavioural profile was characterized at the lower doses by “preconvulsive” behaviours as wet dog shakes, hypermotility, mild facial clonus. At higher doses, DOM caused clonic convulsions followed by the “status epilepticus” syndrome (wet dog shakes, forelimb clonus, rearing, salivation). Rats treated with KA (0.3–10 nmol/rat) showed an almost identical behavioural profile. AMPA (1–10 nmol/rat)‐induced convulsive behaviour was similar to DOM and KA only at the higher doses. NMDA (0.25–10 nmol/rat) caused clonic convulsions but not “status epilepticus”. In mice, similar results were obtained: all the tested drugs induced generalized seizures, but only animals treated with DOM, KA and AMPA showed a prolonged sequence of seizures with forelimb clonus. Our results confirm the findings reported in the literature and support the hypothesis that DOM and KA act at the same EAA receptor.
Serotonin Receptors in the Brain of Rats Treated Chronically with Imipramine or RU24969: Support for the 5‐HT1BReceptor Being a 5‐HT Autoreceptor
Authors: Johanning Helle , Plenge Per , Mellerup Erling
Published: March 2009

Abstract:Rats were treated by intraperitoneal injection for four weeks with either RU24969, a 5‐HT1Band 5‐HT1Aagonist or imipramine, a 5‐HT uptake inhibitor. Pre‐ and postsynaptic 5‐HT receptors were measured to compare the effect of direct or indirect stimulation of the 5‐HT autoreceptor (5‐HT1Breceptor). The 5‐HT transport protein (5‐HT uptake site), labelled with [3H]paroxetine, was unaffected after treatment with either one of the drugs. The density of 5‐HT2 receptors, labelled with [3H]ketanserin, we found increased after treatment with RU24969 (Bmax=161 fmol/mg protein) and decreased after treatment with imipramine (Bmax=109 fmol/mg protein) as compared with control rats (Bmax=134 fmol/mg protein). The 5‐HT1Breceptor was found decreased both by the imipramine treatment (Bmax=106 fmol/mg protein) and the treatment with RU24969 (Bmax=105 fmol/mg protein), compared with control rats (Bmax=130 fmol/mg protein). The 5‐HT1Areceptor was found to be decreased after treatment with RU24969 (control: Bmax=62 fmol/mg protein; RU24969‐treated: 49 fmol/mg protein), but unchanged after treatment with imipramine (Bmax=58 fmol/mg protein). These results correspond to what could be expected, if the 5‐HT1Breceptor is the 5‐HT autoreceptor.
Effects of Acute Lethal Cyanide Intoxication on Central Dopaminergic Pathways
Authors: Cassel Gudrun , Persson Sven‐Åke
Published: March 2009

Abstract:In rats treated with sodium cyanide (NaCN), 20 mg/kg intraperitoneally, the striatal dopamine (DA) level was decreased within 60 sec. compared to controls injected with NaCl 0.9%. Treatment with NaCN also increased the naturally occuring L‐DOPA in the striatum, but not in the other brain regions studied. Decreased DA levels but increased L‐DOPA accumulation were also seen in cyanide‐treated animals after inhibition of neuronal L‐aromatic amino decarboxylase. In rats given a non‐lethal dose of NaCN, 2.5 mg/kg intraperitoneally, 30 min. before sacrifice and L‐DOPA, 100 mg/kg intraperitoneally, 25 min. before sacrifice, regional L‐DOPA levels were not significantly changed, but the striatal DA levels were diminished compared to controls. Decreased DA levels might indicate that cyanide inhibits the synthesis of brain DA. However, both increased L‐DOPA and increased accumulation of L‐DOPA after neuronal decarboxylase were observed after cyanide. Furthermore, we have earlier reported that lethal doses of NaCN decreased the DA metabolite HVA in the striatum but did not significantly change the oxidatively deaminated metabolite of DA, DOPAC. Inhibition of L‐aromatic amino acid decarboxylase appears to play a minor role in causing decreased striatal DA levels. However, our findings might be compatible with cyanide‐produced inhibition of the energy‐demanding granular uptake and/or release of DA.
Comparison of the Effects of Thapsigargin and BAY K 8644 on Spontaneous Mechanical Activity in Rat Portal Vein and Contractile Responses of Rat Cardiac Muscle
Authors: Mikkelsen E. O. , Poulsen S. H. , Christensen S. Brøgger
Published: March 2009

Abstract:The effect of thapsigargin, 10–9–10–6M, and Bay K 8644, 10–9–10–7M, was studied on isolated portal veins and cardiac muscles from rats. In rat portal veins thapsigargin induced a concentration dependent increase in the amplitude of the spontaneous mechanical activity without increasing the frequency of spontaneous activity. Thapsigargin was less effective than Bay K 8644 in increasing the amplitude of the mechanical activity. In contrast to thapsigargin Bay K 8644, 10–6M increases the frequency of the mechanical activity. Atropine, 10–6M, and phentolamine, 10–6M, had no effect on the thapsigargin and Bay K 8644 induced increase in mechanical activity. Nitrendipine, 10–6M, totally abolished the mechanical response in preparations stimulated by thapsigargin and Bay K 8644. In rat atrial and papillary muscles Bay K 8644 increases the frequency in right atrium and tension in both atrial and papillary muscles. Thapsigargin was without effect on the frequency and tension in the cardial preparations. In conclusion, thapsigargin increases the amplitude of spontaneous activity in rat portal veins. In contrast to Bay K 8644 thapsigargin was less effective in increasing the amplitude and had no effect on the frequency of spontaneous activity; furthermore, thapsigargin was without effect on cardiac muscles. The results support the view that an endoplasmatic Ca2+‐pump sensitive to thapsigargin is of importance for spontaneous activity in portal veins while such pump is of minor importance for contractile activity in cardiac muscles.
Anxiolytic Potential of 5‐HT3 Receptor Antagonists
Authors: Costall Brenda , Naylor Robert J.
Published: March 2009

Abstract: The 5‐HT3 receptor antagonists such as ondansetron have been shown to have anxiolytic‐like activity in a wide range of preclinical tests: in the mouse black: white test, the rat social interaction test, the rat elevated X‐maze and the marmoset human threat test. Ondansetron, like other 5‐HT3 receptor antagonists appears to have important advantages over existing anxiolytic therapies. Thus, the 5‐HT3 receptor antagonists are not sedative, they do not have addictive liabilities, there are no problems of withdrawing from chronic treatment and they can be used following benzodiazepine withdrawal. Such compounds even inhibit the behavioural syndrome associated with withdrawal from drugs of abuse, nicotine, alcohol, cocaine, opiates. The preclinical data, therefore, indicates the 5‐HT3 receptor antagonists as novel anxiolytics of the future, and there is new clinical work in support of this suggestion.