bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Temperature and Extracellular pH on Contractile Responses in Isolated Human Hand Veins
Authors: Arner Marianne , Högestätt Edward D.
Published: March 2009

The effects of moderate cooling and extracellular pH changes on concentration‐response relationships for noradrenaline (NA), 5‐hydroxytryptamine (5‐HT) and prostaglandin F2α(PGF2α) were investigated in isolated human hand veins. pH changes were achieved by altering the NaHCO3content of the Krebs solution. Cooling to 24° reduced the maximum contractile responses to K+(124 mM), NA and PGF2αby 20–30%, whereas that to 5‐HT was unchanged. The NA and 5‐HT potencies were increased 8–10 times, whereas the PGF2αpotency was unaffected. A shift from alkalotic (pH 7.6) to acidotic (pH 6.9) conditions did not influence the contractile response to 124 mM K+, whereas the responses to NA, 5‐HT and PGF2αwere inhibited with regard to both potency and maximum contraction. When related to neutral pH, acidosis significantly reduced only the 5‐HT potency (4 times), whereas alkalosis selectively increased the NA and PGF2αpotencies (3 times). In the presence of prazosin (10‐7M), cooling to 24° significantly increased the NA potency, whereas no such increase was seen in the presence of rauwolscine (10‐7M). Alkalosis significantly increased the NA potency in the presence of either antagonist. In conclusion, temperature and extracellular pH influenced the contractile responses to NA, 5‐HT and PGF2αin a differentiated manner. Alkalosis appeared to increase the response to both α1‐ and α2‐adrenoceptor stimulation, whereas cooling preferentially increased that to α2‐adrenoceptor stimulation.
Effect of Cyclosporin A and Different Vehicles on ATP Production in Mitochondria Isolated from the Rat Kidney Cortex
Authors: Nässberger Lennart
Published: March 2009

Isolated rat kidney mitochondria were exposed in vitro to cyclosporin A and three different vehicles, ethanol, DMSO and cremophor. Spontaneous ATP production and oxidative phosphorylation were measured with a bioluminometric method. Both ethanol and cremophor caused a slight (4–7%) decrease in spontaneous ATP production, and also cyclosporin A itself had a minimal effect. On the other hand DMSO had an opposite effect, causing an increase of about 20%. Cyclosporin A showed a dose dependent inhibition of oxidative phosphorylation, being most pronounced when dissolved in ethanol. Cremophor, the castor oil used in commercial preparations caused per se almost a 40% inhibition of the oxidative phosphorylation.
Lack of Effect of Pinacidil on Theophylline Pharmacokinetics and Metabolism in Man
Authors: Nielsen‐Kudsk Jens Erik , Nielsen Claus Brøckner , Mellemkjær Søren , Siggaard Charlotte
Published: March 2009

Pinacidil, a pyridyl cyanoguanidine derivative, is a new antihypertensive vasodilator drug. It shares structural similarities with the histamine H2‐receptor blocker cimetidine, an imidazole cyanoguanidine derivative, which is a potent inhibitor of cytochrome P‐450 and of theophylline metabolism. In the present study the pharmacokinetics and metabolism of theophylline were determined in six healthy volunteers before and on the last day of oral pinacidil administration for two weeks. The dosage of pinacidil was 12.5 mg twice a day in the first week and 25 mg in the second. There were no significant changes in theophylline plasma clearance, terminal half‐life or volume of distribution during pinacidil administration. Also the renal and metabolic clearance of theophylline and the formation clearances of the major theophylline metabolites in the urine (DMU, 1MU, 3MX) did not change significantly during administration of therapeutic doses of pinacidil.
Hydroxyurea: Relationship between Toxicity and Centrally‐Induced Adrenal Activation
Authors: Navarra P. , Carmine R. Del , Ciabattoni G. , D'Amato M. , Ragazzoni E. , Vacca M. , Volpe A. R. , Preziosi P.
Published: March 2009

The anticancer drug hydroxyurea (HU) at doses of 300–800 mg/kg/day causes a dramatic lethality (up to 100% after a 5‐day treatment) in hypophysectomized as well as in adrenalectomized rats drinking physiological saline+ 5% glucose. Mortality in controls was less than 10% over a 5‐day period. Adrenal stimulatory or replacement therapies protect pituitary‐ or adrenal‐ablated rats against HU toxicity. They also counteract white blood cell changes induced by the drug. HU (30‐800 mg/kg) induces a dose‐dependent increase of plasma corticosterone in normal rats after single or repeated treatments that is not observed in hypophysectomized animals. HU also increases plasma levels of epinephrine, although this finding cannot account for the rise in plasma corticosterone; indeed, it is secondary to a strong rise in plasma corticosterone. The stimulation of the hypothalamic‐hypophyseal‐adrenal axis induced by HU is responsible for the drug‐induced adrenocortical activation. This activation appears to be a valuable defence mechanism protecting intact rats against HU lethality, and its failure causes the dramatic HU lethality in pituitary‐ or adrenal‐ablated animals.
Foetal and Maternal Distribution of Inhaled Mercury Vapour in Pregnant Mice: Influence of Selenite and Dithiocarbamates
Authors: Danielsson Beugt R. G. , Khayat Amir , Dencker Lennart
Published: March 2009

The distribution of mercury after inhalation of metallic mercury vapour (6‐8 μmol 203Hg0/kg b.wt.) was studied in pregnant mice (day 17 of gestation) after pretreatment with selenite (10 μmol Se/kg b.wt. intraperitoneally 1 hr before inhalation), thiram, disulfiram or diethyldithiocarbamate (1 mmol/kg orally 2 hr before inhalation of Hg0). For comparison, the effects of thiram, disulfiram and diethyldithiocarbamate on the distribution of mercury after administration of ionic mercury (7 μmol 203HgCl2/kg b.wt. intravenously) were also studied. Selenite pretreatment caused a longer retention of mercury in maternal tissues but decreased the foetal concentrations after 203Hg0 inhalation, similarly to what has been shown previously after administration of ionic mercury (Hg2+). Pretreatment with the three dithiocarbamates markedly increased the uptake in maternal brain and fat and decreased the foetal concentrations after intravenous injection of 203HgCl2. In contrast, no change in foetal uptake and only slight changes in maternal tissue concentration of mercury were observed after treatment with the dithiocarbamates followed by inhalation of 203Hg0, compared with 203Hg0 inhalation alone. The results are in favour of a firmer binding of mercury after Hg0 inhalation, when oxidation of Hg0 to Hg2+ occurs intracellularly, than after Hg2+ injection. Further studies, using repeatedly low dose administration of selenium, are needed to draw any conclusions concerning the protective effects of selenium after exposure to metallic mercury vapour.
Comparison of the Effects of Auranofin, Heavy Metals and Retinoids on Protein Kinase Cin Vitroand on a Protein Kinase C Mediated Response in Macrophages
Authors: Lison D. , Raguzzi F. , Lauwerys R.
Published: March 2009

The effect of auranofin (AF), retinoic acid (RA), and three heavy metals reacting with thiol groups (Hg, Cd, Pb) has been compared on a PKC mediated response of intact macrophages (i.e. plasminogen activator (PA) induction) and on purified PKC activity. AF, cadmium chloride, and lead nitrate directly inhibit PKC and hence prevent the induction of PA activity in macrophages stimulated with PMA.In vitro, and in absence of chelators, mercuric chloride is also a potent inhibitor of PKC. However, at the cellular level, the PKC mediated response (PA induction) was not inhibited by non‐cytotoxic concentrations of mercury possibly due to interference of the metal with additional cellular mechanisms such as calcium mobilisation. Direct inhibition of PKC is probably not the mechanism by which retinoids block the activation of macrophages.
Genetic Polymorphism of Sparteine/Debrisoquine Oxidation: A Reappraisal
Authors: Lennard M. S.
Published: March 2009

Polymorphic oxidation of the sparteine/debrisoquine‐type has been shown to account for much of the interindividual variation in the metabolism, pharmacokinetics and pharmacodynamics of an increasing number of drugs, including some antiarrhythmic, antidepressant and beta‐adrenoceptor antagonist agents. Impaired hydroxylation of these drugs results from the absence of the enzyme cytochrome P450IID6 in the livers of poor metabolisers, who constitute 6% to 10% of Caucasian populations. The clinical importance of the phenomenon has to be explored further and for most sparteine/debrisoquine‐related substrates there is a need for controlled prospective studies to define the consequences to the patient of impaired or enhanced drug oxidation.
MPTP‐Induced Hypoactivity in Mice: Reversal by L‐Dopa
Authors: Fredriksson Anders , Plaznik Adam , Sundström Erik , Jonsson Gosta , Archer Trevor
Published: March 2009

Three experiments were performed to study the subchronic effects of treatment with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 2 × 40 mg/kg subcutaneously two weeks before testing) in C57 BL/6 mice upon spontaneous motor activity and the reversal of the long‐term behavioural changes by acute treatment with L‐Dopa. Mice treated with MPTP showed a drastic reduction of striatal dopamine levels (‐88%) associated with reductions of all three parameters of spontaneous motor activity, i.e. locomotion, rearing and total activity, during both the initial, exploratory, stage (first 90 min), and later stages of the 3‐ or 4‐hr test periods. L‐Dopa (5–80 mg/kg subcutaneously) injected 60 min. after the start of testing dose‐dependently improved all three parameters studied in MPTP treated mice with 10 mg/kg being the lowest dose causing a significant effect, while doses above 20 mg/kg caused hyperactivity. During the initial period, rearing activity in MPTP mice was to a variable degree suppressed by the L‐Dopa treatment (20–80 mg/kg); these reductions were followed by enormous increases in motor activity by the 40 mg/kg (locomotion) and 80 mg/kg (total activity) L‐Dopa groups. Both the degree and duration of the L‐Dopa‐induced hypoactivity for locomotor behaviour increased dose‐dependently in control mice. No suppressive effects of L‐Dopa were obtained for total activity in control mice, although the 80 mg/kg L‐Dopa doses evoked hyperactivity for up to 90 min. following treatment for both locomotion and total activity. At the 20–80 mg/kg doses, significant reductions were even obtained in MPTP mice during the initial period after administration, for locomotor activity; In saline‐treated control mice, the higher doses of L‐Dopa (20–80 mg/kg) by which caused considerable reductions in locomotor activity followed again by large increases in activity may have been caused an initial dopamine autoreceptor action, which appears also for the MPTP treated mice as reflected by the locomotion data of the 20–80 mg/kg L‐Dopa groups. The results indicate that the MPTP‐treated mouse model may provide an important drug screen of compounds of potential therapeutic importance for at least some symptoms of Parkinson's illness.
Effect of Toluene on Ethanol Preference in Rats
Authors: Ladefoged Ole , Kjær Vibeke , Larsen Jens‐Jørgen
Published: March 2009

The effect of toluene on the preference of ethanol was studied in rats. Toluene was administered orally by stomac tube in doses of 200, 400 or 800 mg/kg daily for 5 weeks or by inhalation at a concentration of 2000 p.p.m. 6 or 8 hr daily for 5 or 6 days per week for 2 weeks in rats of different age. During toluene inhalation exposure the rats had access to either tap water or ethanol‐containing water (6 or 10%). After the exposure and during oral administration the rats had access to both ethanol‐free and ethanol‐containing water. Toluene inhibited the body weight gain in the highest oral dose group and in rats exposed to toluene and forced to drink ethanol in the inhalation experiments. In these experiments, the intake of fluid was reduced in the exposure period in rats forced to drink ethanol‐containing water and further reduced in rats exposed to both ethanol and toluene. Exposure to toluene alone increased the fluid consumption. The preference of ethanol defined as consumed ethanol‐containing water in per cent of the total water intake was not influenced by oral administration of toluene. It was, however, reduced by toluene given by inhalation to rats forced to drink ethanol‐containing water during the exposure period. Toluene exposure alone or forced ethanol intake alone caused in these experiments a short‐lasting reduction of the ethanol preference. It is concluded that toluene decreases the preference of ethanol in rats forced to drink ethanol during exposure to toluene.
The Disposition of Ivermectin in Atlantic Salmon (Salmo salar)
Authors: Høy Tonje , Horsberg Tor Einar , Nafstad Inger
Published: March 2009

The disposition of tritium‐labelled ivermectin (22, 23 di‐3H‐avermectin, B1a) in Atlantic salmon was studied by whole‐body autoradiography, liquid scintillation counting, and thin‐layer chromatography. Ivermectin was slowly absorbed, the highest concentrations being found in lipid‐containing organs. High concentrations were also found in the central nervous system, indicating that the blood‐brain barrier in salmon is poorly developed compared to mammals. The excretion of the drug was very slow. The total amount of radioactivity in blood, muscle, liver and kidney diminished by only 35% from day 4 to day 28 after administration. Excretion was mainly by the biliary route, and enterohepatic circulation of the drug was apparent. The drug was mainly excreted in the unchanged form. Distribution to the central nervous system, and the prolonged excretion period, makes the drug unsuitable for the control of parasitic infestations in salmon.
The Actions of Some β‐Receptor Agonists and Xanthines on Isolated Muscle Strips from the Human Oesophago‐Gastric Junction
Authors: Tøttrup Anders , Forman Axel , Madsen Gunnar , Andersson Karl‐Erik
Published: March 2009

Isolated preparations from the circular muscle layer of the human oesophago‐gastric junction were mounted in organ baths and isometric tension recorded. During an equilibration period, active resting tension developed suggesting that the preparations were representing the lower oesophageal sphincter. Active tension was abolished by exposing the preparations to Ca++‐free medium. The two xanthines theophylline and enprofylline almost equipotently relaxed the preparations in a concentration‐dependent manner (10‐7‐10‐3M). Within therapeutic concentrations, theophylline inhibited active resting tension by 30–60%, while enprofylline lowered tension by less than 20%. Inhibitory actions of adenosine were demonstrated, and this suggests that adenosine antagonism is not the mechanism of action for xanthines in the oesophagus. Non‐selective β‐receptor stimulation with isoprenaline inhibited active tension by 70% (10‐7M), while β2‐receptor stimulation with terbutaline inhibited tension by 47% (10‐5M). Dobutamine, believed to preferentially stimulate β1‐receptors, inhibited active tension in a concentration‐dependent manner (10‐7‐10‐4M). Metoprolol (10‐6M), a selective β1‐receptor antagonist, shifted the concentration‐response curve for isoprenaline to the right, but left the maximal response unchanged. It is concluded that xanthines and β‐receptor agonists have inhibitory actions on circular muscle from the human oesophagogastric junction. The experimental data suggest the presence of β1‐ as well as β2‐receptors, both mediating inhibition of active resting tension.
5‐Hydroxytryptamine Receptor Subtypes
Authors: Peroutka Stephen J.
Published: March 2009

Significant advances in the molecular pharmacological analysis of 5‐hydroxytryptamine (5‐HT) receptor subtypes occurred in the 1980's. To a significant degree, this progress resulted from 2 independent approaches: molecular biology and molecular pharmacology. This review focuses on the pharmacological data derived from radioligand binding studies. At the present time, 5‐HT receptor subtypes are often categorized into at least 3 major “families” as well as a few “orphan” receptors that cannot yet be placed into the major categories. Each “family” consists of multiple receptor subtypes which share similarities in their molecular biological, pharmacological, biochemical and physiological properties. In order to provide a comparative pharmacological analysis of the 7 most extensively characterized 5‐HT receptor subtypes, potency information is presented on the 30 pharmacological agents that have been, to date, studied most extensively in the published literature.
Verapamil Potentiates 4′‐Epidoxorubicin Cytotoxicity in a Rat Hepatoma Cell Line and in a Substrain Resistant to 4′‐Epidoxorubicin
Authors: Hall Kirsten Sundby , Endresen Liv , Rugstad Hans Erik
Published: March 2009

We have examined the influence of verapamil (VP) on the in vitro effect of 4′‐epidoxorubicin (Epi‐A) in a rat hepatocarcinoma cell line (MH1C1) and in an Epi‐A resistant substrain. A VP concentration of 500 ng/ml (1.1 μmol/l) markedly potentiated the cytotoxic effect of Epi‐A in the parent line. The resistant cells grow at an Epi‐A concentration of 7500 ng/ml (12.9 μmol/l). This is approximately 15‐fold higher than the concentration tolerated by parental cells. In these cells VP reversed the acquired resistance to Epi‐A in a concentration dependent manner; thus, a concentration in the range of 500–750 ng/ml (1.1–1.7 μmol/l) of VP restored the sensitivity to Epi‐A in the resistant cells. Our results demonstrate that VP increases the sensitivity to Epi‐A in hepatocarcinoma cells never exposed to this drug, as well as in hepatocarcinoma cells with acquired Epi‐A resistance.
Mechanisms behind the Relaxing Effect of Furosemide on the Isolated Rabbit Ear Artery
Authors: Tian Rong , Aalkjær Christian , Andreasen Frederik
Published: March 2009

The effect of furosemide on isometric contraction and 26Rb uptake were studied in the isolated rabbit central ear artery (CEA). A concentration‐dependent relaxing effect of furosemide (0.06 mM–1.0 mM) was found in vessel segments with intact endothelium. The maximal relaxation was 28.6 ± 3.9% (10). The effect was not diminished in segments deprived of endothelium, and removal of endothelium itself caused no change of the force development to electrical field stimulation. The relaxing effect was time‐dependent and stimulation‐dependent and was not significantly affected by membrane depolarization induced by increasing external [K+] from 10 to 120 mM. The 86Rb uptake was inhibited by both furosemide and ouabain (8.0 ± 0.5(8) and 5.3 ± 0.5(8) versus 12.8 ± 0.9(16) nmol (K+) · mm‐1 · (10 min.)‐1 in the furosemide (1.0 mM), ouabain (1.0 mM) and control groups, respectively) without interaction between the two drugs. The 86Rb uptake was not further inhibited by increasing the furosemide concentration from 0.12 mM to 1.0 mM. Our results suggest: firstly, the direct relaxing effect of furosemide on isolated vessel segments is endothelium‐independent and secondly, the inhibition of the Na+‐K+‐Cl‐ cotransport and a possible consequent hyperpolarization of the membrane is unlikely to be the sole mechanism responsible for the vasorelaxant effect of furosemide. The demonstrated direct effect on vascular tone may be of clinical importance in situations with very high plasma concentrations of the drug or very low concentrations of serum albumin.
Effect of Sodium Fluoride on Growth of Human Diploid Cells in Culture
Authors: Oguro Akira , Cervenka Jaroslav , Horii Kin‐ichi
Published: March 2009

Cytotoxicity of sodium fluoride (NaF) on human diploid cells in exponential growth was investigated using a) Flow 1000 cells, passage No. 13, obtained from skin and muscle tissues of male black foetus, b) IMR‐90 cells, passage No. 22, derived from lung tissue of female Caucasian foetus and c) primary fibroblast‐like cell cultures from 5 Japanese whole foetuses. Diploid cells did not survive at 20 p.p.m. of ionic fluoride (F‐) concentration. However, the cells were capable of proliferation with no significant impairment of growth up to 0.2 p.p.m. F‐, a level which is much higher than the plasma concentration in human subjects from areas with highly fluoridated water. The growth of the cells was markedly affected by F‐ concentrations greater than 2 p.p.m.
Mechanism of Pharmacodynamic and Pharmacokinetic Interactions between Acetohexamide and Phenylbutazone in Rabbits
Authors: Imamura* Yorishige , Nomura Tadayuki , Katsuki Yuriko , Kojima Yuichiro , Otagiri Masaki
Published: March 2009

The interaction of acetohexamide (AH) with phenylbutazone (PBZ) was investigated in rabbits. Orally administered PBZ caused a potentiation of hypoglycaemic action after oral administration of AH. This can be explained by the fact that the co‐administration of PBZ significantly increased both the serum concentrations of AH and its pharmacologically active metabolite, (—)‐hydroxyhexamide [(—)‐HH], after AH administration. The co‐administration of PBZ decreased the renal clearance (Clr) and non‐renal clearance (Clnr) of AH. PBZ inhibited thein vitroreduction of AH to (—)‐HH and decreased the accumulation of (—)‐HH by the kidney cortical slices. These results indicate that the mechanism ofin vivointeraction of AH with PBZ is complicated.
Plasma Concentrations and Haemodynamic Effects of d‐Sotalol after β‐Blockade in Dogs
Authors: Mortensen Elin , Tande Pål M. , Kløw Nils‐Einar , Refsum Helge
Published: March 2009

This study was designed to investigate the haemodynamic effects of d‐sotalol at plasma concentrations producing class III antiarrhythmic effects. d‐Sotalol 1, 4 and 10 mg/kg intravenously was given after β‐blockade (propranolol 0.25 mg/kg intravenously) to seven pentobarbital anaesthetized dogs. Left ventricular (LV) systolic and end‐diastolic pressures, LV dP/dtmax, mean aortic pressure, stroke volume, cardiac output and total peripheral resistance were not significantly changed by d‐sotalol. There was a linear correlation between the dose of d‐sotalol infused and the plasma concentration of d‐sotalol obtained. Heart rate decreased and QT‐time increased with increasing plasma concentrations of d‐sotalol, whereas the QRS‐width did not change. There was a linear correlation between the decrease in heart rate and the increase in QT‐time, and between the plasma concentration of d‐sotalol and increase in QT‐time. In conclusion, the study indicates that after β‐blockade, d‐sotalol has no cardiodepressive effects at concentrations that prolong repolarization.
Receptor binding properties of amperozide
Authors: Svartengren J. , Simonsson P.
Published: March 2009

The receptor pharmacology of amperozide was investigated with in vitro radioligand binding technique. Amperozide possessed a high affinity to the 5‐HT2receptors (Ki= 16.5±2.1 nM) and a moderate affinity to α1‐adrenergic receptors of rat cerebral cortical membranes (Ki=172±14 nM). The affinity of amperozide for striatal and limbic dopamine D2receptors was low and not significantly different (Ki±S.E.M. = 540 ± 59 nM vs 403±42 nM; p<0.11, n = 4). The affinity for striatal and limbic 5‐HT2receptors was measured as well and found to be very close to the affinity to the cerebral cortical 5‐HT2receptor. The drug affinity for D2and 5‐HT2receptors seems thus not to be influenced by the location of the receptor moiety. The affinity for several other rat brain receptors such as 5‐HT1A, α2‐adrenergic, dopamine D1muscarinic M1 and M2, opiate sigma and β2‐adrenergic was low.

The pseudo‐Hill coefficient of the amperozide competition binding curve was consistently higher than one indicating antagonistic and complex interactions with the 5‐HT2receptor or with α1‐adrenergic and dopamine D2receptors.

The antagonistic properties of amperozide were investigated by its ability to antagonize the serotonin‐induced formation of inositol‐1‐phosphate in human blood platelets. Amperozide inhibited this 5‐HT2receptor‐mediated intracellular response with similar potency as ketanserin.

These results suggest that amperozide is a selective 5‐HT2receptor antagonist.
Amperozide and conditioned behaviour in rats: potentiation by classical neuroleptics and α‐methylparatyrosine
Authors: Egbe Patrik , Engel Jörgen , Gustafsson Bo , Christensson Erik
Published: March 2009

Amperozide, a new putatively antipsychotic compound, has been evaluated for its effect on conditioned avoidance response and food‐reinforced lever‐pressing. Given alone, amperozide was almost equipotent to clozapine, but less potent than haloperidol in both test models. It was found that there was a statistically significant synergism, in these two models, between amperozide and classical neuroleptics. Since amperozide is inactive in behavioural tests reflecting striatal dopaminergic mechanisms, the synergistic effect could be of great therapeutic value in the treatment of psychotic disorders.
Effects of amperozide on induced turning behaviour in 6‐OHDA lesioned rats
Authors: Christensson Erik G.
Published: March 2009

The effect of amperozide on DA synapses was studied in 6‐OHDA lesioned rats exhibiting a specific turning behaviour in response to the DA agonists apomorphine and pergolide or indirectly acting stimulating agents like amphetamine. Amperozide, unlike classical neuroleptics, failed to antagonize apomorphine induced turning behaviour in a regular fashion, but showed pergolide antagonism within the D2 receptor selective dose range, suggesting a type of selective interference with dopaminergic nerve transmission which differs from that caused by classical neuroleptics. Furthermore, amperozide antagonized the turning behaviour induced by amphetamine, presumably by interfering with the availability of newly synthesized DA and NA suggesting a similar influence also on other DA releasing agents. Although amperozide potentiated the effects of α‐MPT, the drug seemed not to influence the reserpine sensitive pool of DA.
The effect of amperozide on uptake and release of [3H]‐dopamine in vitro from perfused rat striatal and limbic brain areas
Authors: Eriksson Eva , Christensson Erik
Published: March 2009

Amperozide, a putatively antipsychotic drug, was studied for its effects on uptake and release of [3H]‐dopamine in rat brainin vitro.Amperozide inhibited uptake of [3H]‐dopamine in striatal chopped tissuein vitrowith an IC50of 18 μM. It also increased basal release of [3H]‐dopamine from perfused rat striatal and limbic tissuein vitroat concentrations above 5 μM. Release of [3H]‐dopamine from perfused rat striatal and limbic tissue stimulated with 5 μM amphetamine, was inhibited by 1 μM amperozide to 46%. No significant difference was found for the effect of amperozide onin vitrorelease of [3H]‐dopamine from corpus striatum compared to tissue from limbic brain regions; neither on basal release nor on amphetamine‐stimulated release of dopamine.
ROLE OF INOSITOL‐1‐PHOSPHATASE INHIBITION IN THE MECHANISM OF ACTION OF LITHIUM
Authors: RH Belmaker , A Livne , G Agam , DG Moscovich , N Grisaru , G Schreiber , S Avissar , A Danon , O Kofman
Published: March 2009

Abstract: Li inhibition of noradrenergic adenylate cyclase may be due to inhibition by Li of agonist‐induced increases in GTP binding to G‐protein. Such inhibition by Li of G‐protein function could have effects on phosphatidyl‐ inositol‐mediated second messenger systems as well as on cyclic AMP‐mediated systems. However, Sherman, Berridge and others have proposed that Li affects phosphatidylinositol metabolism by inhibiting inositol‐1‐phosphatase. We recently have been able to measure inositol‐1‐phosphatase in human red blood cells. Preliminary data on patients treated with Li compared with, controls suggests that the enzyme is indeed inhibited in vivo in patients undergoing Li treatment. However, a series of experiments in rats on addition of inositol to Li treatment did not find that inositol could reverse Li effects. Chronic oral high dose inositol does not reverse Li‐induced polyuria (measured by polydipsia), Li‐induced weight loss or Li‐induced depression of exploratory behavior. These results suggest that Li inhibition of inositol‐1‐phosphatase indeed occurs in vivo. However, the physiological significance of inosltol‐1‐phosphatase inhibition is not yet established.
Tissue‐Specificity of Hydroxylation and N‐Methylation of Arylalkylimidazoles
Authors: Salonen Jarmo S.
Published: March 2009

Abstract: Hydroxylation and N‐methylation of three potent α2‐adrenoceptor agonists detomidine, medetomidine and dexmedetomidine by rat brain, kidney, liver and lung were studied in vitro. NADPH‐dependent hydroxylation of the 3′‐methyl group was catalyzed mainly by the microsomal fraction of liver. Monooxygenation by the other tissues was negligible. The hepatic monooxygenase reaction was characterized by high affinity (Km 5.5‐9.8 μM) and low capacity (Vmax 29‐66 pmol/min. per mg protein). Statistically significant (P < 0.05) differences between the Km and Vmax values of medetomidine and dexmedetomidine were observed suggesting stereoselective oxidation of the drug molecule. N‐Methylation of the arylalkylimidazoles occurred mainly in the cytosolic fraction of the kidney. With S‐adenosylmethionine as the methyl donor, the transferase activities in other tissues were less than 10% of the specific activity of the renal enzyme (about 7 pmol/min. per mg protein for medetomidine). Even the renal enzyme showed a relatively low capacity (Km 250‐300 μM and Vmax 15‐33 pmol/min. per mg protein). Different tissue distributions of the arylalkylimidazole N‐methyltransferase and histamine N‐methyltransferase suggest that they are two distinct enzyme species. Based on these results, aliphatic hydroxylation is the major (metabolic) elimination mechanism of the arylalkylimidazole drugs, and liver is the principal eliminating organ. The importance of N‐methylation is diminished by its low capacity and probable regeneration of the parent drug by demethylation.
Heterogeneous Effects of Ethylenebisdithiocarbamate (EBDC) Pesticides on Oxidative Metabolism of Xenobiotics
Authors: Siddiqui Abrar , Ali Basheer , Srivastava Satya P.
Published: March 2009

Abstract:Comparative evaluation of the acute effects of ethylenebisdithiocarbamate (EBDC) fungicides, mancozeb and zineb on microsomal mixed function oxidases (MFO) revealed marked substrate‐dependent inhibition of oxidative metabolism of aminopyrine, p‐nitroanisole and aniline in rats sacrificed 4 hr after oral administration of 100 mg mancozeb or zineb/kg body weight. Mancozeb inhibited p‐nitroanisole O‐dealkylase and aniline hydroxylase to a greater degree than zineb, whereas the inhibition of aminopyrine N‐demethylase by the two fungicides was quantitatively comparable. Interestingly, aryl hydrocarbon hydroxylase (AHH) which exhibited maximum inhibition with mancozeb, remained unaffected following zineb administration. The time‐course and dose‐dependence of MFO inhibition examined 1 and 4 hr after a single oral dose of 100 mg or 250 mg zineb/kg was expressed as a dose‐dependent decline in the rate of xenobiotic biotransformation at 4 hr.In vitrointeraction of zineb with MFO resulted in slightly greater inhibition of aminopyrine, p‐nitroanisole and aniline while AHH exhibited more pronounced decrease with mancozeb. The magnitude of inhibition of aminopyrine N‐demethylase and AHH was independent of the time of preincubation of fungicides with the enzyme. Kinetic studies indicated the non‐competitive nature of AHH inhibition. Chronic oral treatment with mancozeb and zineb at a dose of 250 mg/kg for 4 weeks did not modify xenobiotic biotransformations except for a slight induction of aminopyrine N‐demethylase by mancozeb.
Dual Effect of Magnesium on Compound 48/80‐Induced Histamine Secretion from Rat Peritoneal Mast Cells
Authors: Bertelsen Henrik , Johansen Torben
Published: March 2009

Abstract:The effect of magnesium on the secretory response to compound 48/80 from rat peritoneal mast cells was studied. The decrease in secretion caused by calcium deprivation was enlarged by magnesium. Glucose partially counteracted the decrease caused by calcium deprivation but not the one caused by magnesium. The addition of calcium to the cells simultaneously with compound 48/80 completely restored the secretory response if magnesium was present. The response was only partially restored in a magnesium‐ and glucose‐free medium, whereas it was almost completely restored if glucose was present. Magnesium had a considerable effect on the restoration of the secretory response of EGTA‐treated cells, whereas the effect of glucose was minimal indicating that an effect on the energy metabolism was of minor importance. The secretory response could also be restored by an exposure of the cells to calcium prior to stimulation with compound 48/80. This was, however, only observed if magnesium was present and glucose had no effect. The influence of magnesium on the restoration of the secretory response may partly occur by an effect on the energy metabolism, partly by an effect on the stimulus‐secretion coupling. We propose that insufficient supply of Mg2+to the G‐protein during activation by compound 48/80 might cause a suboptimal signal transduction.
Tissue Distribution and Urinary Excretion of14C‐Ethion in Goats
Authors: Mosha Resto D.
Published: March 2009

Abstract:Tissue concentration and elimination and urinary excretion were followed after intravenous injection of14C‐ethion in 12 goats. Tissue levels were determined in two goats after 8 hr and on each of days 1, 3, 7, 14 and 28 after exposure. During the four‐week period plasma and all tissues examined (liver, kidney, fat, muscle, lung, heart and brain) had detectable14C‐residues, the highest values being found in liver, kidney and fat. Elimination of14C‐residues was faster in the first 3 days than in the later part of the experiment, where the elimination half‐life for most tissues was approximately 2 weeks. During the first two weeks after exposure, 77% of the administered dose was eliminated in urine (55%) and faeces (22%). TLC of urine collected over the first 15 hr after exposure showed at least 8 bands of metabolites, five of which accounted for about two thirds of the dose excreted in urine.
A Comparative Study of the Effects of δ‐Aminolaevulinic Acid and the G ABAA Agonist, Muscimol, in Rat Jejunal Preparations
Authors: Cutler Margaret G. , Turner John M. , Moore Michael R.
Published: March 2009

Abstract: Preparations of rat jejunum were tested for their responsiveness to the GABAA receptor agonist, muscimol, and to the haem precursor, δ‐aminolaevulinic acid (ALA). Both muscimol (1.0–3. μM) and ALA (1.0 μM‐3.0 mM) elicited a concentration‐dependent increase in tone. Pretreatment with the GABAA antagonist, bicuculline (10‐5 M), blocked effects of muscimol at all concentrations tested and attenuated effects of 0.3 mM ALA. However, bicuculline enhanced responsiveness of the preparations to ALA at low concentrations (0.01‐0.05 μM), as also did picrotoxin (10‐5 M), eliciting a significant increase of tone. The significance of these findings is discussed. This finding of pharmacological activity by ALA at concentrations comparable with its blood levels during acute attacks of intermittent porphyria provides support for the proposal that is may play a role in the aetiology of the gastrointestinal manifestations of this disease.
Acute Toxicity of Three New Selective COMT Inhibitors in Mice with Special Emphasis on Interactions with Drugs Increasing Catecholaminergic Neurotransmission
Authors: Törnwall M. , Männistö P. T.
Published: March 2009

Abstract:3‐Nitropyrocatechols are very potent and selective inhibitors of catechol‐O‐methyltransferase (COMT). LD50 values of three of these compounds were assessed after intraperitoneal administration with a special emphasis on interactions with drugs increasing catecholaminergic neurotransmission. LD50 values of the inhibitors varied from 137 mg/kg (Ro 41–0960. to 507 mg/kg (OR‐462) and 544 mg/kg (OR‐611). The LD50 value of Ro 41–096. was significantly lower than that of OR‐462 and OR‐611 (P<0.05). At toxic dose levels all inhibitors caused convulsions and hypomotility. OR‐462 and OR‐611 had statistically significant mortality increasing interaction with 20 mg/kg of nomifensine (P<0.05) and the former also with 10 mg/kg of amphetamine (P<0.05). Owing to their high therapeutic indexes these compounds can be considered useful new tools in pharmacological research.
Interaction of Zinc, Methionine or Their Combination with Lead at Gastrointestinal or Post‐Absorptive Level in Rats
Authors: Flora S. J. S. , Kumar Deo , Gupta S. Das
Published: March 2009

Abstract: The ability of zinc, methionine or their combination given by gavage to prevent or treat experimental oral lead intoxication in rats was investigated. Simultaneous oral supplementation with zinc plus methionine was found to be most effective in reducing lead induced inhibition of δ‐aminolevulinic acid dehydratase (ALAD) activity in blood, elevation of urinary δ‐aminolevulinic acid (ALA) excretion and in enhancing the hepatic glutathione (GSH) contents. The combination was also most effective in reducing the accumulation of lead in blood, liver and kidney compared to zinc or methionine alone. Prevention was more effective than treatment after lead exposure which may be caused by a decrease in the absorption of lead in the gastrointestinal tract in the presence of zinc and/or methionine.
5‐Hydroxytryptamine Antagonistic Effects of ICI 169,369, ICI 170,809 and Methysergide in Human Temporal and Cerebral Arteries
Authors: Jansen I. , Blackburn T. , Eriksen K. , Edvinsson L.
Published: March 2009

Abstract: ICI 169,369 and ICI 170,809 are two chemically novel 5‐HT antagonists that have high affinity for the 5‐HT2 binding site in rat cortex (Ki 1.79 × 10−8M and 6.6 × 10−10M, respectively). In human temporal artery preparations ICI 169,369 was shown to cause a progressive rightward shift of the 5‐HT‐response curve over the range 10−7‐10−5M, while ICI 170,809 in these concentrations shifted the curve to the same degree (no dose dependency). In human cerebral vessels no effect was observed until a high concentration (10−5M) was used for either compounds. The mixed 5‐HT1/5‐HT2 antagonist, methysergide, induced a non parallel rightward shift of the 5‐HT‐induced concentration‐effect curve with a depression of the maximum achievable response in both the temporal and cerebral artery. The mode of effect of ICI 169,369 and ICI 170,809 to block the 5‐HT‐induced contractions in human temporal vessels resembles that of the pure 5‐HT2 antagonist ketanserin, thus suggesting that the two ICI compounds are mainly 5‐HT2 antagonists. In high concentrations both ICI 169,369 and ICI 170,809 have vasorelaxant properties, explaining the reduction in maximum 5‐HT‐induced contraction seen at high antagonist concentrations.
Effect of Human Growth Hormone on the Reproduction of Female Rats
Authors: Jørgensen Karin Damm , Svendsen O. , Agergaard N. , Skydsgaard K.
Published: March 2009

Abstract: Female rats were treated with human growth hormone (hGH) 0.3, 1.0 and 3.3 IU/kg daily for two weeks before mating, throughout mating and during the first seven days of pregnancy. Treatment with 1.0 and 3.3 IU/kg hGH caused a significant prolongation of the oestrous cycle. As a consequence the number of mating days was more than doubled compared to placebo treatment. The number of implantation sites and corpora lutea was significantly higher in hGH treated rats than in placebo treated rats. The number of early resorptions was increased in the rats given 3.3 IU/kg. The number of foetuses in rats sacrificed on day 20 of pregnancy and the number of viable offspring from the rats allowed to give birth were significantly increased by treatment with 1.0 IU/kg hGH. In a study of 4‐day cyclic rats, treatment with 3.3 IU/kg hGH caused a prolongation of the cycle length to an average of 10.1 days, and the plasma progesterone levels tended to be higher in those rats in which the cyclic patterns had been most deranged. Foetal body weights were increased in the hGH groups, and a study with 125I‐hGH indicated that hGH administered to pregnant rats will to some extent pass the placenta.
Motor Effects of Loperamide on Rat Urinary Bladder: An in Vitro Study
Authors: Berggren A. , Sillén U. , Rubenson A.
Published: March 2009

Abstract:Motility recordings in muscle strips from rat urinary bladder were performed and the effect of the opiate agonist loperamide on motor activity was studied. Loperamide induced a concentration‐dependent (10−7‐10−3M) inhibition of the contractile response of the detrusor strip of the same order of magnitude after activation of intramural nerves, stimulation of cholinergic receptors with acetylcholine and after direct depolarisation of the cell with potassium. Pretreatment with the opiate‐antagonist naloxone (10−5M) did not antagonise the inhibitory action of loperamide on bladder motility regardless of the type of activation. Naloxoneper se, however, facilitated the nerve‐mediated motor response. The inhibitory action of loperamide on the potassium‐induced contraction could partly be counteracted by elevation of the calcium concentration in the medium. It is suggested that the demonstrated inhibitory effect of loperamide on bladder motility is a calcium‐dependent direct smooth muscle action, without any significant opiate‐receptor‐mediated action in the presentin vitropreparation.
Changes of Isolated Cardiac Muscle Function in Response to Extracellular Sodium Reduction
Authors: Lüllmann H. , Ravens U. , Stöckel P.
Published: March 2009

Abstract: The effects of low extracellular sodium concentration ([Na+]0, 76 mmol/l) on force of contraction, transmembrane action potentials and on calcium, sodium and potassium contents were studied in guinea‐pig heart muscle using sucrose or lithium as substitutes for sodium. In papillary muscle, the positive inotropic response to low [Na+]0 was accompanied by shortening in action potential duration, in atrial muscle, prolongation at 90% of repolarization was observed. After 30 min. in low [Na+]0 solution (Ca2+ 1.8 mmol/l), the net uptake of calcium in left atria was larger in sucrose‐ than in lithium‐substituted solution, i.e. 0.45 and 0.2 mmol Ca2+/kg wet weight, respectively. The net sodium content decreased monophasically; but the potassium content did not change consistently. The uptake of lithium by the atria was at least partially compensated for by a loss in potassium and by a transient decrease in sodium content. Increase in stimulation frequency from 0.1 to 1 Hz accelerated the time course of change by a factor of 2. In low [Na+]0, post‐rest adaptation of twitch tension appeared abolished in atria because of high amplitude contractions. The recovery pattern of post‐rest twitch amplitude was greatly accelerated in papillary muscle. In conclusion, low [Na+]0 elevates the cellular calcium content; this extra calcium is probably located in cellular stores that are involved in the regulation of twitch amplitude.
A New Approach to the Determination of Ethanol Elimination RateIn Vivo:An Extension of Widmark's Equation
Authors: Thieden Herluf I. D. , Hunding Axel
Published: March 2009

Abstract:In order to provide more experimental data about a single ethanol elimination sequence, tracer amounts of14C‐labelled ethanol were given intravenously in fed and fasted rats into a preexisting pool of unlabelled ethanol. The profiles of the elimination curves of14C‐labelled ethanol were distinctly different from those of unlabelled ethanol. This necessitated the elaboration of a mathematical model based on a two‐compartment system, which by using the early distribution phase of the14C‐labelled ethanol and the linear part of the elimination curve of unlabelled ethanol enables the determination of the time‐rate constants for distribution of ethanol, K12and K21and ethanol elimination rate Q. It is shown that the ratio K21'/(K21' + K12') is “r”, the distribution volume of ethanol in the sense of Widmark, K12' is K12divided with Va (initial distribution space of ethanol) and K21' is K21divided with Vb (the peripheral compartment). The mean value ±S.E.M. is 0.57±0.05 for fed rats and 0.49±0.03 for fasted. The slope of the time‐concentration curve of ethanol, Widmark's β, is shown to be K12'/(K12'xK21')xQ where Q is ethanol elimination rate. The mean elimination rate is 0.303±0.036 mmol × l−1× min−1in fed rats and 0.219±0.015 mmol × l−1× min.−1in fasted (P<0.05). It is concluded that we are now able to extend Widmark's equation by an independent determination of the distribution factor “r”.
Exogenous GTP Enhances the Effects of Sodium Nitrite on Cyclic GMP Accumulation, Vascular Smooth Muscle Relaxation and Platelet Aggregation
Authors: Laustiola Kai E. , Vuorinen Pauli , Pörsti Ilkka , Metsä‐Ketelä Timo , Manninen Vesa , Vapaatalo Heikki
Published: March 2009

Abstract:Exogenous guanosine triphosphate (GTP) (1‐2 × 10−4M) resulted in increased concentrations of cyclic GMP both in endothelium denuded rat mesenteric artery (RMA) and in human ADP‐stimulated platelets. Sodium nitrite (3.3 × 10−4M) relaxed precontracted RMA by 34%. When the arteries were preincubated with GTP (2 × 10−4M) sodium nitrite administration resulted in a significantly greater relaxation (58%) of the RMA with concomitant 2‐fold increase in cGMP. Sodium nitrite (1 × 10−4M) had an inhibitory effect on ADP‐induced platelet aggregation. Preincubation with GTP enhanced significantly the sodium nitrite‐induced inhibition of ADP‐induced platelet aggregation with a simultaneous 5‐fold increase in cGMP. These results indicate that exogenous GTP enhances the sodium nitrite‐induced stimulation of guanylate cyclase and thus enhances the effects of sodium nitrite on arterial smooth muscle and platelets.
Affinity of Nortriptyline and its E‐10‐Hydroxy Metabolite for Muscarinic Receptors
Authors: Nilvebrant Lisbeth , Nordin Conny
Published: March 2009

Abstract: In the present investigation, the binding of nortriptyline and its active metabolite 10‐hydroxynortriptyline (E‐10‐OH‐NT) to muscarinic receptors was studied in the heart, parotid gland, cerebral cortex, urinary bladder and ileum from guinea pig. The affinity of E‐10‐OH‐NT, as determined by competition with 1‐quinuclidinyl (phenyl 4‐3H)benzilate (‐)3H‐QNB), was about 10‐12 times lower than that of nortriptyline in each tissue and none of the compounds seemed to exhibit any tissue selectivity. It is concluded that the increased heart rate induced by E‐10‐OH‐NT, but not by nortriptyline, cannot be attributed to a selective blockade of cardiac muscarinic receptors.
Perturbation of Metabolism and Disposition of Cyclophosphamide by Interferon and Poly I:C, an Interferon Inducer, in Mice
Authors: Ishikawa Masaaki , Sasaki Kenroh , Takayanagi Yoshio , Sasaki Ken‐ichi
Published: March 2009

Abstract:The effects of interferon and poly I:C on the metabolism and disposition of cyclophosphamide were investigated in mice. Elimination of cyclophosphamide from the blood was decreased in mice treated 24 hr previously with interferon (2.5 × 106U/kg, intraperitoneally) or poly I:C (10 mg/kg, intraperitoneally). The blood half‐life of cyclophosphamide in interferon or poly I:C‐pretreated mice was prolonged to a first order of disappearance of 29.3 and 41.6 min., respectively, compared to 19.0 min. in control mice. Also, the rate of formation of activated cyclophosphamide was delayed and the peak blood level of activated cyclophosphamide was not as high in poly I:C‐pretreated and interferon‐pretreated mice as in control mice. The decreased elimination and elevated blood levels of activated cyclophosphamide were reflected by changes in its antitumour activity and toxicity in the mice. In 9,000 × g supernatants prepared from the liver homogenate of mice treated with interferon or poly I:C, the oxidation of cyclophosphamide in vitro has decreased by 29 and 37%, respectively. However, the addition of these agents to normal 9,000 × g supernatant suspensions had no effect on cyclophosphamide oxidation. Modulation of the metabolism and disposition resulted from depressed levels of cytochrome P‐450 in the hepatic microsomes of the mice administered interferon or poly I:C.