bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactions Between Endothelial Mediators
Authors: Gryglewski Ryszard J.
Published: March 2009

AbstractProstacyclin, nitric oxide and tissue plasminogen activator constitute a prominent triad of endothelial mediators. Prostacyclin is responsible mainly for maintaining vascular thromboresistance against platelet clumps, inhibits proliferation of vascular smooth muscle and modulates cholesterol turnover, tissue plasminogen activator is a fibrinolytic agent and nitric oxide controls vascular tone and structure. Receptor agonists such as acetylcholine, kinins, endothelins or adenosine diphosphate evoke a coupled release of mediators from endothelial cells. Prostacyclin and nitric oxide synergize in their antiplatelet, fibrinolytic and cardioprotective, but not in their hypotensive actions. Prostacyclin, but not nitric oxide, prevents paradox thrombogenic effects of tissue plasminogen activator. Filogenetically, prostacyclin and tissue plasminogen activator are younger brothers of nitric oxide from which they take over and perfect regulatory properties in circulation. Further studies on interactions of endothelial mediators may lead to a better understanding of mechanisms of thrombosis, atherogenesis, diabetic angiopathies, endotoxic shock and arterial hypertension.
Effect of Long‐Term Sodium Selenite Supplementation on Levels and Distribution of Mercury in Blood, Brain and Kidneys of Methyl Mercury‐Exposed Female Mice
Authors: Glynn Anders Wicklund , Lind Ylva
Published: March 2009

Abstract Female Balb/c CA mice were supplemented for seven weeks with 0, 0.6 and 3 p.p.m. Se in tap water and were then exposed to a single oral dose of Me203Hg (2 μmol/kg). Se supplementation continued for 56 days after MeHg dosage. Supplemented animals showed enhanced activity of glutathione peroxidase in the blood. Twenty‐four hr after MeHg dosage, the level and distribution of Hg in blood, blood cells, and kidneys were not influenced by Se exposure. However, in the brain the Hg accumulation was increased and Hg distribution was altered by Se supplementation. Fifty‐six days after MeHg dosage, 70% to 80% of the dose had been eliminated from the body, and the brain of the 3 p.p.m. group still had a higher Hg level than the control group. Otherwise, there was no consistent effect of Se supplementation on retention of Hg in the animals. It is indicated that Se influences tissue accumulation and intracellular distribution of Hg through tissue‐specific mechanisms rather than through a more general effect on Hg sequestration and transport in the blood.
Effects of Enzyme Induction on the Distribution of the Food Carcinogen 2‐Amino‐3,8‐dimethyl‐imidazo[4,5‐f]‐quinoxaline (MeIQx) in Ah‐Receptor‐Responsive‐ and Ah‐Receptor‐non‐Responsive Mice
Authors: Vikse Rose , Ingebrigtsen Kristian , Klungsøyr Leiv , Alexander Jan
Published: March 2009

AbstractThe distribution of the food carcinogen 2‐amino‐3,8‐dimethyl‐imidazo[4,5‐f]quinoxaline (MeIQx) was studied in Ah‐responsive‐(C57BL/6J) and Ah‐non‐responsive mice (DBA/2N). The time dependent organ distribution of radioactivity after14C‐MeIQx (10 mg/kg) administration in C57BL/6J showed that at day 4 most of the radioactivity had been excreted and that the remaining radioactivity was found in liver, kidneys, lungs and spleen. C57BL/6J bound more radioactivity in the kidneys than the DBA/2N strain whereas approximately the same amount was left in the liver and lungs in both strains 4 days after MeIQx exposure. Liver microsomes of the two strains had approximately the same ability to activate MeIQx in the Ames Salmonella assay. β‐Naphthoflavone treatment of the animals greatly increased microsomal activating capacity, but only in the C57BL/6J strain. Isosafrole treatment of the animals only slightly increased the activating capacity, but particularly with microsomes from the DBA/2N strain, displacement of the putative inhibitory isosafrole metabolite greatly increased their activating capacity. In the whole animals pretreatment with β‐naphthoflavone, which induces P450IA only in the C57BL/6J strain, did not significantly change the amount of retained radioactivity in any of the strains. Isosafrole induces only P450IA2, the major N2‐hydroxylating enzyme of heterocyclic amines, in both strains. Such pretreatment reduced the amount retained in the kidney of both strains whereas it reduced the retained amount of radioactivity in the liver with about 60% only in the Ah‐non‐responsive strain (DBA/2N). The effect of isosafrole did not persist when MeIQx was given three days after the last injection. The results indicate that induction by β‐naphthaflavone in the C57BL/6J mice increases P450IA dependent N2‐hydroxylation. The lack of change in MeIQx binding may be due to enhancement also of detoxification, but more likely, the rate limiting step is the ultimate esterification of the N2‐hydroxylamine derivative. With isosafrole, which induces only P450IA2 in both strains, the results indicate that an isosafrole metabolic product inhibits P450IA2 activity alsoin vivo.Treatment with phenethyl isothiocyanate which has been claimed to block the action of certain carcinogens, caused an increased binding of MeIQx in the liver and kidneys of C57BL/6J mice.
Inhibition of ATP‐Sensitive Potassium Channels in Cardiac Myocytes by the Novel Class III Antiarrhythmic Agent MS‐551
Authors: Martin Donald K. , Nakaya Yutaka , Wyse Kenneth R. , Bursill Jane A. , West Paul D. , Campbell Terence J.
Published: March 2009

Abstract The novel class III antiarrhythmic agent, MS‐551, has recently been shown to attenuate the decrease in ventricular effective refractory period and to prevent the subsequent ventricular fibrillation induced by pinacidil and hypoxia in isolated perfused rabbit hearts (Friedrichs et al. 1994). We studied the effects of MS‐551 on single ATP‐sensitive potassium channels in isolated rabbit ventricular myocytes using standard patch‐clamp methods. MS‐551 in the range from 1 μM to 100 μM produced a concentration‐dependent reduction of the open probability of the ATP‐sensitive potassium channel, with an apparent ED50 of 30 μM. This reduced channel activity was due to a smaller number of channel openings per unit time, and the average duration of each opening of the channel was unaffected. This property of MS‐551 is likely to be of most significance in ischaemic tissue, where the ATP‐sensitive channels are thought to carry the predominant current that shortens the duration of the action potential.
Serotonergic Mechanisms Involved in the Exploratory Behaviour of Mice in a Fully Automated Two‐Compartment Black and White Test Box
Authors: Sánchez Connie
Published: March 2009

Abstract A fully automated version of the black and white two‐compartment box for mice is presented. The anxiolyticlike effects of the benzodiazepines, diazepam and chlordiazepoxide, were confirmed, and the involvement of serotonergic mechanisms was studied in this animal model of anxiety. The partial 5‐HT1A receptor agonists, buspirone and ipsapirone showed anxiolytic‐like effects in a limited dose interval. The full agonist hydroxy‐2‐(di‐n‐propylamino)tetraline (8‐OH‐DPAT) was inactive. The non‐selective 5‐HT1 receptor agonist, eltoprazine, induced marked increases of exploratory behaviour in the white compartment over a broad range of doses. Also pindolol a mixed 5‐HT1A/1B and β‐adrenergic receptor antagonist showed anxiolytic‐like effects, whereas another compound with a similar profile (‐)‐, penbutolol and the β‐adrenoceptor antagonist ICI 118,551, was inactive. The 5‐HT2A/2C receptor antagonist, ritanserin, showed anxiogenic‐like, and the 5‐HT3 receptor antagonists, zacopride and ondansetron, showed anixiolytic‐like effects. An overall increase of serotonergic activity by means of 5‐HT uptake inhibition (citalopram), 5‐HT release (fenfluramine) or administration of a 5‐HT precursor (1–5‐HTP) facilitated exploratory activity in the white compartment. Reduction of serotonergic activity by treatment with the 5‐HT depletor p‐chloro‐phenylalanine methyl ester (PCPA) did not change the exploratory behaviour, but attenuated the response to fenfluramine significantly.
Effects of Intermittent and Continuous Subchronic Administration of Raclopride on Motor Activity, Dopamine Turnover and Receptor Occupancy in the Rat
Authors: Ericson H. , Radesäter A.‐C. , Servin E. , Magnusson O. , Mohringe B.
Published: March 2009

Abstract:With the purpose of finding means to circumvent the marked pharmacokinetic differences of raclopride between rats and man, the effects of intermittent and continuous administration of raclopride were compared in rats. Intermittent administration of raclopride via subcutaneous injections resulted in a prompt increase of dopamine (DA) turnover and decrease of motor activity but these effects were of short duration, probably due to rapidly decreasing raclopride DA D2receptor occupancy. In contrast, but similar to schizophrenic patients on raclopride treatment, stable plasma raclopride levels and a steady DA D2receptor occupancy above 70% were produced in the caudate‐putamen and nucleus accumbens/olfactory tubercle, when raclopride was administered continuously via minipumps at daily doses above 2 mg/kg. Tolerance to the acute effects of raclopride on DA turnover and locomotion was found with both routes of administration but it was more marked with continuous administration. At continuous raclopride administration, tolerance to the effects of raclopride on DA turnover and spontaneous motor activity as well as supersensitivity to amphetamine‐induced motor activity occurred when 70% or more of DA D2receptor sites were occupied, i.e. the same degree of receptor occupancy as found in patients given therapeutic doses of raclopride.
α1‐ and β‐Adrenoceptor‐Mediated Increase in86Rb+‐Uptake in Isolated Cardiomyocytes from Adult Rat Heart: Evidence for Interaction between the Two Receptor Systems
Authors: Viko Håvard , Osnes Jan‐Bjørn , Skomedal Tor
Published: March 2009

Abstract:The aim of the present investigation was to study the effect of α1‐ and β‐adrenoceptor stimulation, alone and in combination, on potassium uptake in isolated ventricular cardiomyocytes from adult rat heart, using the potassium analogue86Rb+. The reliability of86Rb+as a potassium analogue was also investigated. α1‐, β‐, And combined adrenoceptor stimulation was achieved by using noradrenaline in the presence and absence of appropriate adrenoceptor antagonists. The uptake of86Rb+was found to increase linearly with time up to 20 min., both during basal and receptor‐stimulated conditions. The basal uptake rate was about 0.18 ml/g protein X min. At 15 min. both α1, β‐ and combined adrenoceptor stimulation dose‐dependently increased the86Rb+‐uptake with a ‐logEC50of 7.05, 6.68 and 6.73, respectively. The maximal increase in these series achieved by 5×10−5mol/l noradrenaline was 29%, 24% and 41% above basal level, respectively. Comparison of the maximal effects in the same cell preparations, with the observed value for combined adrenoceptor stimulation in each experiment as 100%, gave a relative maximal increase in86Rb+‐uptake after separate α1‐adrenoceptor stimulation of 67±8%, and of 68±6% after separate β‐adrenoceptor stimulation. The theoretically calculated value for combined adrenoceptor stimulation, if additivity, was 135±11%, which was significantly higher than the observed value (100%) (P=0.026). The effect of noradrenaline was not limited by the maximal86Rb+‐uptake capacity, as 10−5mol/l forskolin increased the86Rb+‐uptake more than noradrenaline. Examining the reliability of86Rb+as potassium‐analogue by combining42K+and86Rb+in the same experiments, showed that combined adrenoceptor stimulation dose‐dependently increased both the42K+‐ and86Rb+‐uptake with the same potency and to the same extent. Thus86Rb+is a reliable potassium‐analogue for these effects. In conclusion both α1and β‐adrenoceptor stimulation dose‐dependently increased the cellular86Rb+‐uptake to the same extent and with the same potency. The observed maximal86Rb+‐uptake after combined adrenoceptor stimulation was significantly higher than the maximal effect after either form of separate receptor stimulation, but significantly lower than expected if the effects were purely additive. The results thus show inhibitory interaction between the two receptor systems.
Effect of Arsenic (V) on the Antioxidant Defense System: In vitro Oxidation of Rat Plasma Lipoprotein
Authors: Schinella G. R. , Tournier H. A. , Buschiazzo H. O. , de Buschiazzo P. M.
Published: March 2009

Abstract: Adult male rats were treated orally with sodium arsenate (10 mg As/ kg/day) for 2 days, and an increase in hepatic glutathione level was seen. Ascorbic acid content increased in both liver and plasma of intoxicated animals. Hepatic activities of superoxide dismutase and glutathione peroxidase did not change with the treatment and there was no increase in the level of lipid peroxidation measured as thiobarbituric acid‐reacting substances (TBARS). Arsenic decreased the plasma level of uric acid and increased the plasma triglycerides content without modifying vitamin E levels. Both total lipoproteins and very low density lipoprotein plus low density lipoprotein (VLDL+LDL) fractions demonstrated greater propensity for in vitro oxidation than the corresponding untreated rats. The last finding might be a useful parameter for determining the degree of oxidative stress in the initial steps of intoxication with arsenic.
Uptake of Manganese and Cadmium from the Nasal Mucosa into the Central Nervous System via Olfactory Pathways in Rats *
Authors: Tjälve Hans , Henriksson Jörgen , Tallkvist Jonas , Larsson Bengt S. , Lindquist Nils Gunnar
Published: March 2009

Abstract: In the olfactory epithelium the primary olfactory neurones are in contact with the environment and via the axonal projections they are also connected to the olfactory bulbs of the brain. Therefore, the primary olfactory neurones provide a pathway by which foreign materials may gain access to the brain. In the present study we used autoradiography and gamma spectrometry to show that intranasal instillation of manganese (54Mn2+) in rats results in initial uptake of the metal in the olfactory bulbs. The metal was then seen to migrate via secondary and tertiary olfactory pathways and via further connections into most parts of the brain and also to the spinal cord. Intranasal instillation of cadmium (109Cd2+) resulted in uptake of the metal in the anterior parts of the olfactory bulbs but not in other areas of the brain. This indicates that this metal is unable to pass the synapses between the primary and secondary olfactory neurones in the bulbs. Intraperitoneal administration of 54Mn2+ or 109Cd2+ showed low uptake of the metals in the olfactory bulbs, an uptake not different from the rest of the brain. Manganese is a neurotoxic metal which in man can induce an extrapyramidal motor system dysfunction associated with occupational inhalation of manganese‐containing dusts or fumes. We propose that the neurotoxicity of inhaled manganese is related to an uptake of the metal into the brain via the olfactory pathways. In this way manganese can circumvent the blood‐brain barrier and gain direct access to the central nervous system.
Effects of Exposure to Lead on Selected Biochemical and Haematological Variables
Authors: Solliway Bernard M. , Schaffer Alex , Pratt Hillel , Yannai Shmuel
Published: March 2009

Abstract: Blood and urine samples were taken from 34 persons occupationally exposed to lead and from 56 non‐exposed control persons and blood lead and haemoglobin concentrations, red blood cell count, erythrocyte glutathione peroxidase (GSH‐peroxidase) and acetylcholinesterase (AChE), and urinary δ‐aminolevulinic acid were determined. Blood lead concentrations of the lead‐exposed subjects were within the range generally accepted as safe for occupationally‐exposed adults in many countries (i.e. below 50 μg Pb/dl blood). Yet, significant dose‐dependent elevations were found in erythrocyte GSH‐peroxidase and urinary δ‐aminolevulinic acid. The urinary δ‐aminolevulinic acid concentration of lead‐exposed smokers was significantly elevated over that of lead‐exposed non‐smokers. Smoking did not affect the urinary δ‐aminolevulinic acid concentration of control persons. In addition, a statistically significantly lower red blood cell count was observed in the lead‐exposed group. Our results indicate that the above described safety standard for blood lead concentrations in occupationally exposed adults, although generally accepted, needs revision.
The Toxicity of Repeated Exposures to Rolipram, a Type IV Phosphodiesterase Inhibitor, in Rats
Authors: Larson Jeffrey L. , Pino Michael V , Geiger Lee E. , Simeone Christopher R.
Published: March 2009

Abstract: Rolipram is a selective inhibitor of Type IV phosphodiesterase isozymes (PDE IV) which is often used as a baseline comparator for compounds in this class. To document the toxicological effects of rolipram, it was administered to female rats at 0, 10, 30 or 100 mg/kg/day orally for up to 2 weeks. One treatment‐related death in the 100 mg/kg/day dose group was observed on day 3, and all rats at this dose level were considered moribund and euthanatized on day 5. Several clinical signs were observed in treated rats, including increased salivation, slight distention of the abdomen, emaciated appearance, and ataxia. After 14 days of treatment, the rats were necropsied and tissues examined microscopically. A number of compound‐related histopathological changes were observed in rats receiving 30 or 100 mg/kg/day. Myocardial degeneration and necrosis, endocardial fibrosis, epicarditis, and arteritis/periarteritis of intramural and extramural coronary arteries were observed in the heart. A necrotizing vasculitis and inflammation were observed in the mesentery and interstitial areas of the liver, affecting medium‐sized portal arteries and veins. Focal necrosis was also observed in the glandular mucosa of the stomach at these 2 dose levels. Other treatment‐related effects included squamous hyperplasia and hyperkeratosis with or without ulceration in the nonglandular stomach of at least one animal from all treatment groups. Enlarged salivary glands were noted at necropsy in animals treated with 100 mg/kg/day, and this finding correlated microscopically with dilatation and degeneration of ducts and acini in the sublingual gland with secondary inflammation and edema. The results of this study demonstrate that rolipram, a selective inhibitor of the type IV class of PDE, can cause effects on the heart and vasculature of rats which heretofore have been ascribed only to selective inhibitors of the PDE III class of isozymes. Therefore, these organs should be closely examined in studies with other PDE IV inhibitors. In addition, the gastrointestinal tract and salivary glands were sites for rolipram‐induced toxicity and may be targets of other PDE IV inhibitors.
Selective Muscarinic Receptor Agonists and Antagonists
Authors: Eglen Richard M. , Watson Nikki
Published: March 2009

Abstract:Muscarinic receptors are composed of a family of four subtypes each of which can be distinguished pharmacologically and structurally. The physiological role of each subtype in the central and peripheral nervous systems remains to be clarified, due, in part, to a lack of agonists and antagonists with adequate subtype selectivity. Nonetheless, several agonists with functional selectivity for M1receptors are now in advanced clinical evaluation for Alzheimer's disease, while selective M1/M3antagonists may prove useful in the treatment of disorders of smooth muscle function. These novel compounds thus provide an advance over earlier therapeutics with which the clinical efficacy was compromised by the side effect profile. This review attempts to assess novel, selective agonists and antagonists, both in terms of their use in defining muscarinic receptor subtypes and their potential clinical utility.
The Pyridoindole Antioxidant Stobadine Prevents Alloxan‐Induced Lipid Peroxidation by Inhibiting its Propagation
Authors: Stefek Milan , Trnkova Zuzana
Published: March 2009

Abstract:Underin vitroconditions, the pyridoindole stobadine inhibited alloxan‐induced lipid peroxidation in a model biological membrane with the efficacy comparable with that of the standard Trolox. Intermediary alloxan radicals and hydroxyl radicals were not directly involved in the process of lipid peroxidation, however, the presence of iron chelate was a necessary prerequisite. Since stobadine did not affect the kinetics of alloxan redox‐cycling in the presence of GSH, we suggest that the protective action of stobadine against the alloxan‐induced lipid peroxidation was mediated predominantly by its ability to quench peroxyl radicals, inhibiting thus the propagation stage of the oxidative damage. The results also indicate that toxic effects of alloxan may well be mediated by mechanism(s) not involving hydroxyl radicals.
Relationship between Mephenytoin, Phenytoin and Tolbutamide Hydroxylations in Healthy African Subjects
Authors: Horsmans Y. , Kanyinda J. M. , Desager J. P.
Published: March 2009

Abstract:Mephenytoin, phenytoin and tolbutamide are metabolised by the cytochrome P‐450 (CYP) 2C family. Recently, it has been shown that phenytoin and tolbutamide are metabolised by CYP2C9/10 whereas mephenytoin is metabolised by CYP2C19. Until now,in vivostudies were only undertaken in Caucasian subjects and showed a strong relationship between phenytoin and tolbutamide metabolism but no significant relationship between the two drug metabolisms and that of mephenytoin. The metabolism of the three drugs was investigated in eight black Africans by urinary analysis. In this ethnic group, a strong relationship was found between phenytoin and tolbutamide oxidations (rs=‐0.83, P=0.01). On the other hand, no significant relationship was found between mephentoin oxidation and phenytoin or tolbutamide oxidations (rs=0.31 and rs=‐0.33, respectively). This study suggests that, in black Africans, phenytoin and tolbutamide but not mephenytoin are also hydroxylated by similar CYP enzyme(s).
Effect of the Class III Antiarrhythmic Agent E‐4031 on the ATP‐Sensitive Potassium Channel in Rabbit Ventricular Myocytes
Authors: West Paul D. , Bursill Jane A. , Wyse Kenneth R. , Martin Donald K. , Campbell Terence J.
Published: March 2009

Abstract: The class III antiarrhythymic drug E‐4031. a known blocker of the delayed rectifier potassium channel (IK), might also be capable of blocking the ATP‐sensitive potassium channel (IKATP)‐ We examined this possibility by studying the effect of E‐4031 on single IKATP channels in membrane patches excised from ventricular myocytes that were obtained by standard enzymatic dissociation techniques from New Zealand white rabbits. In inside‐out patches, E‐4031 caused a dose‐dependent block of IKATP with an EC50 of 31 ± 1 μM, Hill coefficient of 0.89±0.24 and no effect on channel conductance. Open dwell‐time kinetics were fitted by two exponential components, with E‐4031 causing reduction of the longer time constant. In outside‐out patches, the concentration of E‐4031 required to produce blockade was much higher. We conclude that E‐4031 blocks the ATP‐sensitive potassium channel and that it does so from within the cytoplasm, with one‐to‐one channel binding stoichiometry. Single channel conductance is unchanged, but the longer time constant for the open state is reduced, which suggests that E‐4031 may be an open channel blocker of intermediate to slow time course.
C‐Methylated Dihydrochalcones from Myrica gale L: Effects as Antioxidants and as Scavengers of 1,1‐Diphenyl‐2‐Picrylhydrazyl
Authors: Malterud Karl Egil , Diep Oanh Hong , Sund Reidar Bredo
Published: March 2009

Abstract: A number of isomeric or chemically closely related C‐methylated dihydrochalcones, which is a rare substance class, has been isolated from the fruit exudate of Myrica gale L. and subjected to the following tests: 1) inhibition of lipid peroxidation induced by tert‐butyl hydroperoxide or bromotrichloromethane in isolated rat hepatocytes, 2) inhibition of peroxidation induced by Fe2+ ions in a cell free system with linolenic acid as substrate, 3) scavenging activity against the diphenylpicrylhydrazyl radical, and 4) inhibition of enzymatic lipid peroxidation in linoleic acid by soybean 15‐lipoxygenase. One of the compounds (myrigalone B = MyB; 2′,6′‐dihydroxy‐4′‐methoxy‐3′,5′‐dimethyldihydrochalcone) showed good activity in all tests, whereas the others were inactive or slightly active, except that myrigalone A (MyA; 3‐(1‐oxo‐3‐phenylpropyl)‐1,1.5‐trimethylcyclohexane‐2.4.6‐trione)) like its synthetic analogue MyA* (the polar part of MyA) was nearly as active as MyB in 4). The antioxidant properties of MyB are probably due to its radical scavenging activity and may be related to its conformation, which differs from that of the other compounds.
Interaction between Erythromycin and the Benzodiazepines Diazepam and Flunitrazepam
Authors: Luurila Harri , Olkkola Klaus T. , Neuvonen Pertti J.
Published: March 2009

Abstract: The effect of erythromycin on the pharmacokinetics and pharmacodynamics of diazepam and flunitrazepam was investigated in two randomized, double‐blind, cross‐over studies. Healthy volunteers ingested erythromycin for one week 500 mg t.i.d. On the 4th day they ingested a single 5 mg dose of diazepam (6 subjects, Study 1) or 1 mg dose of flunitrazepam (5 subjects, Study 2), respectively. Plasma drug concentrations and psychomotor effects were measured during 42 hr after the ingestion of diazepam or flunitrazepam. In Study 1 erythromycin increased the area under the diazepam plasma concentration‐time curve [AUC (0‐42 hr)] by 15% (P<0.05) and the concentration of diazepam in plasma at 42 hr by 63% (P<0.05). The median peak concentration (Cmax) and the half‐life (t1/2) of diazepam were increased but they did not change significantly (P=0.17 and 0.12, respectively). Plasma N‐desmethyldiazepam concentrations were slightly reduced during erythromycin treatment up to 8 hr (P<0.05). In Study 2 the AUC (0‐42 hr) of flunitrazepam was increased by 25% (P<0.05) during the erythromycin treatment. The t1/2 of flunitrazepam increased significantly (P<0.05), but the Cmax remained unchanged. The psychomotor effects of diazepam or flunitrazepam were not changed significantly by erythromycin. These pharmacokinetic interactions can be explained by the reduced metabolic elimination of diazepam and flunitrazepam. The interactions of erythromycin with diazepam and flunitrazepam seem to be slight and of limited clinical significance only.
Effect of Aluminium Hydroxide Administration on Normal Mice: Tissue Distribution and Ultrastructural Localization of Aluminium in Liver
Authors: Fiejka Maria , Fiejka Elżbieta , Di̇ugaszek Maria
Published: March 2009

Abstract: In order to assess the risk of parenteral aluminium (Al) exposure, we evaluated the effects of intraperitoneal administration of aluminium hydroxide, a compound widely used in medicine. Mice (strain Pzh:SFIS) received intraperitoneally, every two weeks 1 mg Al or 0.1 mg Al for five days a week. Controls received injections of saline. Al concentrations in liver, bone and brain were evaluated by electrothermal atomic absorption spectrometry after exposure to 2 mg, 4 mg, and 6 mg Al. The concentration was the highest in liver and occurred after exposure to only 2 mg Al (265.1±27.7 mg/kg, 233.5±28.0 mg/kg). Generally further accumulation was not dose‐ and treatment‐dependent. The only exception was a significant Al increase in the liver after exposure to 6 mg Al. injected 0.1 mg Al five days/week. Development of resorption granulomas was observed in the liver, Al being revealed by Morin fluorescence in constituent macrophages and giant cells. By electron probe X‐ray microanalysis, Al was identified predominantly in lysosomes of macrophages and Kupffer cells. In tibia of mice, a dose‐dependent Al accumulation was observed. The highest level of Al concentration after the 6 mg treatment was 23.5±3.82 mg/kg and 25.06±2.3 mg/kg. The Al concentration in the brain of mice had not changed significantly during Al treatment.
Effects of Calcium Channel Modulators on the Regulation of Cytoplasmic Ca2+and Hormone Secretion of Parathyroid Cells
Authors: Ridefelt Peter , Hellman Per , Rastad Jonas , Larsson Rolf , Akersrröm Göran , Gylfe Erik
Published: March 2009

Abstract:Effects of Ca2+‐channel modulators were examined in human, bovine and murine parathyroid tissue. In 0.5 mM external Ca2+, 100 μM verapamil inhibited parathyroid hormone release, stimulated uptake and efflux of45Ca and raised cytoplasmic Ca2+concentration ([Ca2+]i). However, in 3.0 mM Ca2+the drug only affected efflux. Methoxyverapamil (50 μM) inhibited parathyroid hormone release in 0.5 mM but stimulated secretion in 3.0 mM Ca2+. BAY K. 8644 (10 μM) had similar actions as verapamil on parathyroid hormone release and [Ca2+]i, whereas nifedipine (1μM) and diltiazem (50‐100 μM) lacked effects. Despite the lack of voltage‐dependent Ca2+channels in parathyroid cells, drugs with established actions on such channels affect [Ca2+]iand parathyroid hormone release. However, these actions are not sufficiently pronounced and tissue specific to allow their use for correcting hyperparathyroidism.
Arsenic‐Copper Interaction in the Kidney of the Rat: Influence of Arsenic Metabolites *
Authors: Ademuyiwa O. , Elsenhans B. , Nguyen P.‐T. , Forth W
Published: March 2009

Abstract:The present study was an attempt to investigate whether the renal accumulation of Cu observed in the kidneys of rats and guinea‐pigs exposed to arsenite (As‐III) was an effect of arsenite alone or also shared by its metabolites‐arsenate (As‐V), dimethylarsinic acid and monomethylarsonic acid. The four arsenic compounds were administered subcutaneously and separately to rats for 12 days in increasing doses. Kidney, liver and blood were taken and analysed for As, Cu and other trace elements by atomic emission spectrometry. Results indicate that administration of As‐V leads to renal Cu accumulation similar to that observed on administration of As‐III and that the accumulation in both cases is dependent on the dose of arsenic, although higher doses of As‐V were required to achieve renal Cu levels comparable to that of As‐III. A constant molar As:Cu ratio independent of arsenic dose was obtained in the kidney. Dimethylarsinic acid did not affect renal Cu levels at all. Administration of monomethylarsonic acid led to a slight increase in renal Cu levels which did not increase further in spite of increased doses of monomethylarsonic acid. It is concluded from these studies that neither the metabolic transformation of inorganic arsenic to its methylated products nor its metabolites (dimethylarsinic acid and monomethylarsonic acid) caused the observed renal Cu accumulation, rather, the inorganic form of As, either in the trivalent or pentavalent form is responsible.
Effect of Dopexamine Hydrochloride on Sympathetic Neuroeffector Transmission in Rabbit Isolated Pulmonary Artery
Authors: Nedergaard Ove A.
Published: March 2009

Abstract:The effects of dopexamine hydrochloride on sympathetic neuroeffector transmission were studied in rabbit isolated pulmonary artery. Short‐term exposure of dopexamine (10‐8x10‐7M) and cocaine (10‐6‐3x10‐5M), but not desipramine (3x10‐9‐3x10‐7M), to the artery enhanced the contractions evoked by electrical‐field stimulation. Corticosterone (4x10‐5M), corticosterone (4x10‐5M) plus cocaine (3x10‐8M), but not cocaine (3x10‐5M), attenuated the enhancement seen with dopexamine. High concentrations of dopexamine (10‐5‐3x10‐5M), cocaine (10‐4M), and desipramine (10‐6‐10‐5M) decreased the stimulation‐evoked contractions. Dopexamine (10‐7‐3x10‐5M), but neither cocaine nor desipramine, caused an increase in resting tension that waned with time. Corticosterone (4x10‐5M), but not cocaine (3x10‐5M), attenuated the increase in resting tension. Propranolol (10‐6M) did not alter the enhancing and inhibitory effects of dopexamine. A single concentration (10‐7and 10‐6M) of either dopexamine or desipramine caused a time‐dependent biphasic response as regards the repetitive stimulation‐evoked contractions of pulmonary artery: initial enhancement followed by inhibition. The inhibitory effect of dopexamine (10‐6M) and desipramine (3x10‐6M) seen after prolonged exposure was almost irreversible and partially reversible, respectively, by washing the preparations with drug‐free salt solution. Cocaine caused a monophasic steady‐state response: either enhancement (10‐5M) or inhibition (2x10‐4M). In both cases, the onset was rapid. The reduction caused by cocaine (2x10‐4M) and by prazosin (10‐9M) was fully reversed. Dopexamine (10‐5M) antagonized competitively the contractions evoked by noradrenaline (3x10‐9‐10‐4M). It is concluded that (1) the dopexamine‐induced enhancement of neurogenic contractions is not due to either inhibition of neuronal and extraneuronal uptake of noradrenaline or an agonist action on prejunctional β2‐adrenoceptors; (2) that the dopexamine‐induced inhibition of stimulation‐evoked contraction is due to an inhibition of postjunctional α1‐adrenoceptors; and (3) that the dopexamine‐induced increase in resting tension is due to its metabolite methyldopexamine.
Nephroprotective Mechanism(s) of Pentoxifylline: Reduction of Erythrocyte‐Mediated Vascular Congestion and Inhibition of Nitric Oxide Release *
Authors: Vadiei Kiumars , Tucker Stanley D. , Lopcz‐Berestein Gabriel , Wasan Kishor M.
Published: March 2009

Abstract: The present study attempted to evaluate pentoxifylline's mechanism(s) of action in the prevention of acute renal failure by examining its vascular decongestant activity in a rat model for acute renal failure and inhibitory activity of nitric oxide release from activated macrophage‐like (RAW 264.7 cells) and murine mammary adenocarcinoma (EMT‐6 cells) cell lines. Radiolabeled chronium‐erythrocytes were injected intravenously into all rats. Following occlusion of the left kidney for 45 minutes, rats were treated with pentoxifylline or normal saline. The medulla of the left (ischaemic) kidney had significantly higher radioactive counts than the right (control kidney) following an intravenous dose of normal saline. The medulla to whole blood radioactivity ratio of the left kidney was significantly greater than for the right (control) kidney. Animals administered intravenous pentoxifylline (5 mg/kg) had significantly lower radioactive counts in the medulla of the left (ischaemic) kidney than animals administered intravenous normal saline. No differences in radioactivity counts in the medulla of the left (ischaemic) kidney were observed when animals received intraperitoneal pentoxifylline (45 mg/kg) versus normal saline. In a second set of experiments the nitrite synthesis and percent cytotoxicity of pentoxifylline‐ and dexamethasone‐treated cells were determined. Pentoxifylline at concentrations of 4 mM and 8 mM significantly decreased nitrite synthesis in RAW 264.7 cells, and at pentoxifylline concentrations of 2 mM, 4 mM, and 8 mM in EMT‐6 cells compared to untreated cells. Dexamethasone at a concentration of 1 μM decreased nitrite synthesis in RAW 264.7 and EMT‐6 cells compared to untreated cells. Pentoxifylline at concentrations of 0.5 mM through 8 mM significantly decreased cytotoxicity in RAW 264.7 and EMT‐6 cells compared to untreated cells. Dexamethasone at a concentration of 1 μM decreased cytotoxicity in RAW 264.7 and EMT‐6 cells compared to untreated cells. These finding suggest that pentoxifylline's ability to prevent acute renal failure may be a consequence of reduced vascular congestion and inhibition of nitric oxide release from activated macrophages.
Protective Effects of Ca2+ Channel Blockers against Methyl Mercury Toxicity
Authors: Sakamoto Mineshi , Ikegami Naohito , Nakano Atsuhiro
Published: March 2009

Abstract: The protective effects of Ca2+ channel blockers against the toxicity of methyl mercury were examined by both in vivo and in vitro experiments. In the in vivo study we first examined the effects of the Ca2+ channel blockers (20 mg/ kg/day), flunarizine, nifedipine, nicardipine, and verapamil against the toxic level of methyl mercury treatment (5 mg/kg/ day of methyl mercuric chloride for 12 consecutive days). However, there was a difference in potency of the effects among the reagents. All the Ca2+ channel blockers prevented a decrease in body weight and/or the appearance of the symptoms of neurological disorders in the rats treated with methyl mercury. In the next experiment, we examined flunarizine at different levels of supplementation (1,25 and 50 mg/kg/day). Flunarizine in a dose‐dependent manner prevented a decrease in body weight, appearance of the symptoms of neurological disorder and mortality in the rats treated with methyl mercury. Flunarizine treatment (25 mg/kg/day) for the first 5 days did not affect mercury distribution among the tissues, suggesting that the mechanism of protection against methyl mercury‐induced toxicity may be attributed to its own pharmacological effect. In the in vitro study we examined the effect of flunarizine (0, 0.5, 5 and 50 μM) using primary cultures of cerebellar granular cells in 96‐well culture plates. Viable cell numbers were estimated 1 and 3 days after treatment with methyl mercury. The estimated 50% lethal concentration (LC50) of methyl mercury was higher in plates treated with 5 and 50 uM of flunarizine both on days 1 and 3, indicating that flunarizine protected the primary cultured cerebellar granular cells against the toxicity of methyl mercury. As such, Ca2+ channel blockers protected against the toxicity of methyl mercury both in vivo and in vitro, suggesting that Ca2+ plays an important role in the mechanisms of methyl mercury toxicity.
Characteristics of the Protective Action of α‐Tocopherol in Vascular Hypoxia
Authors: Kelly M. J. , Richardson W
Published: March 2009

Abstract: The functioning of the guinea‐pig isolated portal vein was monitored by measuring spontaneous mechanical activity, responses to electrical stimulation and administered noradrenaline in normoxic conditions. The effect of hypoxia, induced by bubbling the physiological bathing solution with a 95% N2/5% CO2 gas mixture, on the mechanical performance of the vein was then assessed. Spontaneous activity declined in hypoxia, with mean contraction tension reduced by 55±8.8%. The responses to electrical field stimulation (2‐32 Hz, 0.7 msec. 70 V) were lowered by 14±4.6% but contractions produced by a range of noradrenaline concentrations (0.01‐160 μM) were unaffected by hypoxia. Substitution of glucose in the bathing solution with sucrose, a substrate unavailable to the cells for energy generation, produced a marked enhancement of the effect of hypoxia. Spontaneous activity was reduced by 76±8.3%, electrically‐induced activity by 80±14.4% and noradrenaline‐induced responses by 85±6.8%. Although in normoxia the activity and responses of the portal vein were unaffected by the presence of α‐tocopherol, it significantly protected the functioning of the vein in hypoxic conditions. This effect was concentration‐dependent within the range 10‐160 μM and was most marked when glucose was replaced by sucrose in the bathing solution.
Paracetamol‐Induced Spindle Disturbances in V79 Cells with and without Expression of Human CYP1A2
Authors: Jensen Klaus Gjervig , Poulsen Henrik Enghusen , Doehmer Johannes , Loft Steffen
Published: March 2009

Abstract: Spindle disturbing effects in terms of c‐mitosis and cytotoxicity of paracetamol were investigated in two Chinese hamster V79 cell lines, one of which (V79MZh1A2) was transfected with human CYP1A2. This enzyme catalyses the oxidative formation of the reactive paracetamol metabolite, NAPQI, believed to initiate hepatoxicity by covalent binding to proteins after overdose. In the native V79 cell line paracetamol increased c‐mitosis frequency in a concentration dependent manner from 8.7±3.5% (control) to 66±18% at 20 mM. A significant increase to 13.3±3.5% was first seen at 2.5 mM in the native cell line (P<0.05). In the V79MZh1A2 cells the concentration‐effect curve was slightly shifted to the left (P<0.05) with c‐mitosis frequency increased to 12.1±2.6% (P<0.05) at 1 mM paracetamol. At 5 mM paracetamol the c‐mitosis frequency was 14.4±5.0% and 19.0±3.8% in the native and CYP1A2 expressing cell lines, respectively (P<0.05). At 20 mM paracetamol the c‐mitosis frequency was 61±10% in the V79MZhlA2 cells. Cell survival was reduced to approximately 50% at 5‐10 mM paracetamol in both cell lines. At 20 mM paracetamol survival was further decreased to 39±9% in V79MZh1A2 cells only (P<0.05). The present study demonstrated that paracetamol may disturb the spindle of dividing cells conveying a risk of aneuploidy. The spindle disturbind effect was only slightly enhanced by expression of CYP1A2, suggesting that metabolic activation plays only a minor role in this genotoxic effect. The reduction of survival mirrored the increase in c‐mitosis frequency.
Arylamine N‐Acetyltransferase in Erythrocytes of Cystic Fibrosis Patients
Authors: Risch Angela , Smelt Valerie , Lane Donald , Stanley Lesley , Van Der Slot Wilma , Ward Alison , Sim Edith
Published: March 2009

Abstract:Sulphamethoxazole, a substrate of human arylamine N‐acetyltransferase, is used in the treatment of cystic fibrosis patients, who metabolise the drug rapidly. Increased metabolic clearance of sulphamethoxazole has been suggested to account for this rapid metabolism. Arylamine N‐acetyltransferase type 1 is expressed in erythrocytes and leucocytes and the activity in erythrocytes is shown to contribute approximately 99% of the activity of arylamine N‐acetyltransferase type 1 in blood cells. Arylamine N‐acetyltransferase type 1 activity in erythrocytes from 16 adult cystic fibrosis patients and 19 age‐matched controls were compared. Although there is a variation in erythrocyte arylamine N‐acetyltransferase type 1 activity within each group, no difference was found when the two groups were compared. All individuals from the cystic fibrosis and control groups were investigated for certain allelic variants of the arylamine N‐acetyltransferase type 1 gene (NAT1). Only one copy of a mutantNAT1allele (NATI*11) was found. The heterozygousNAT1individual is a cystic fibrosis patient with a low level of erythrocyte arylamine N‐acetyltransferase type 1 activity. A second distinct arylamine N‐acetyltransferase isozyme, arylamine N‐acetyltransferase type 2, is encoded at the multi‐allelicNAT2locus. There was no correlation between erythrocyte arylamine N‐acetyltransferase‐1 activity andNAT2alleles present in either the cystic fibrosis or control groups. The distribution ofNA T2alleles was very similar in the two groups. The increased clearance of sulphamethoxazole in cystic fibrosis patients appears unlikely to be due to erythrocyte arylamine N‐acetyltransferase type 1 activity or to inheritance of alleles at either theNA T1orNA T2loci.
The Involvement of Cytochrome P4502E1 in 2‐Bromoethanol‐Induced Hepatocyte Cytotoxicity
Authors: Khan Sumsullah , Sood Christian , O'Brien Peter J.
Published: March 2009

Abstract:The cytotoxicity of 2‐bromoethanol towards hepatocytes isolated from rats was concentration‐dependent (EC50‐100 μM, 2 hr). Bromoacetaldehyde was more toxic (EC50‐60 μM, 2 hr) and bromoacetic acid was less toxic (EC50‐150 μM, 2 hr). Glutathione (GSH) depletion occurred before cytotoxicity ensued and GSH depleted hepatocytes were more susceptible to 2‐bromoethanol. Lipid peroxidation increased steadily 1 hr after 2‐bromoethanol addition and antioxidants, iron chelators or hypoxia prevented 2‐bromoethanol induced lipid peroxidation and cell lysis. Alcohol de‐hydrogenase inhibitors, methyl pyrazole or dimethyl sulfoxide only partly prevented 2‐bromoethanol induced GSH depletion, lipid peroxidation and cytotoxicity. However, cytochrome P4502E1 (CYP2EI) inhibitors/substrates were more effective at preventing 2‐bromoethanol‐induced GSH depletion, lipid peroxidation and cytotoxicity suggesting that 2‐bromoethanol is mostly metabolically activated by CYP2E1. Also, hepatocytes isolated from CYP2E1 induced rats were more susceptible to 2‐bromoethanol and hepatocytes isolated from rats pretreated with carbon disulfide to inactivate CYP2E1 were more resistant to 2‐bromoethanol treatment. Formation of S‐(formylmethyl)glutathione during 2‐bromoethanol metabolism by microsomal mixed function oxidase in the presence of GSH was also prevented by cytochrome P4502E1 inhibitors/substrates or by Anti‐Rat CYP2E1. Furthermore, aldehyde dehydrogenase inhibitors‐cyanamide or chloral hydrate increased 2‐bromoethanol dependent hepatocyte susceptibility. This suggests that 2‐bromoethanol is preferably metabolised by CYP2E1 dependent monoxygenase to form 2‐bromoacetaldehyde which causes cell lysis as a result of GSH depletion and lipid peroxidation.
Agonist and Antagonist Properties of β3‐Adrenoceptors in Human Omental and Mouse 3T3‐L1 Adipocytes
Authors: Shimizu Manabu , Blaak Ellen E. , Lönnqvist Fredrik , Gåfvels Mats E. , Arner Peter
Published: March 2009

Abstract:The pharmacological properties of the native human β3‐adrenoceptor are poorly defined. In the present study, the agonist and antagonist properties of β3‐adrenoceptors in human omental and mouse 3T3‐L1 adipocytes were compared by measuring lipolysis in the absence or presence of adrenoceptor blockers. Methodological experiments revealed that all three β‐adrenoceptors were functionally expressed in both types of adipocytes. This makes the human and the mouse cells directly comparable in pharmacological studies. CGP 12177 was a selective partial p3‐adrenoceptor agonist in both cell types with a pD2of about 7.5. The order of potency of classical non‐selective adrenoceptor agonists, when determined during blockade of β1, β2‐ and α2‐adrenoceptors, was isoprenaline>noradrenaline>adrenaline in both human and 3T3‐L1 adipocytes. This is different from the order of potency of the same agonists at the β1or β2‐adrenoceptors. The sensitivity of the β3‐adrenoceptor to these catecholamines, expressed as pD2values, were virtually identical in both adipocyte types. Isoprenaline, noradrenaline, and adrenaline were almost full agonists in both cell types (intrinsic activity from 74% or 95%) during combined β1, β2‐ and α2‐adrenoceptor blockade. Antagonist potencies (expressed as pA2and using CGP 12177 as agonist) at the β3‐adrenoceptor were similar in both adipocyte types: bupranolol>propranolol>meto‐prolol. The corresponding pA2values for bupranolol, propanolol and metoprolol were about 7, 6 and 5, respectively in both species. In conclusion, the pharmacological properties of classical catecholamines, P‐adrenoceptor blockers and CGP 12177 are almost identical at the β3‐adrenoceptors of human omental adipocytes and 3T3‐L1 adipocytes.
Interaction of μ‐Opioid Antagonistic Drugs with Antiepileptics
Authors: Frey Hans‐Hasso , Schicht Sabine
Published: March 2009

Abstract:Interactions of the μ‐opioid receptor antagonists, naloxone (0.3 and 1 mg/kg), cyprodime and clocinnamox (3 and 10 mg/kg for both drugs) with phenytoin (7 mg/kg), phenobarbital (7 mg/kg), carbamazepine (10 mg/kg) and valproic acid (130 mg/kg) were investigated using the electroconvulsive threshold in mice as a model in order to elucidate a possible role of μ‐receptor mediated reactions in the mechanism of action of antiepileptic drugs. All 3 μ‐antagonists are devoid of an effect on the electroconvulsive threshold. Pretreatment with the μ‐antagonists resulted partly in an increase of anticonvulsant action, partly in a decrease, and partly the pretreatment had no effect on the electroconvulsive threshold. The anticonvulsant effect of phenytoin was antagonized dose‐dependently by naloxone, that of phenobarbital by the dose of 10 mg/kg of clocinnamox. A common denominator of the μ‐antagonistic interactions with anticonvulsants cannot be found and the effects observed are therefore considered as "unspecific".