bluuebunny/crossref_metadata_2025 huggingface dataset:
Both α1‐ and β‐Adrenoceptor Stimulation Determine the Time Course of the Inotropic Effect of Noradrenaline in Rabbit Heart
Authors: Skomedal Tor , Aass Halfdan , Osnes Jan‐Bjørn
Published: March 2009

It has been a matter of controversy whether α1‐adrenoceptor stimulation contributes to the final inotropic and lusitropic responses in mammalian myocardium to noradrenaline duringconcomitantandunopposedβ‐adrenoceptor stimulation. In the present paper we report studies that compare time courses of the inotropic and lusitropic responses to separate and combined α‐ and β‐adrenoceptor stimulation, respectively, in electrically driven rabbit papillary muscles by a submaximal concentration of noradrenaline. Separate α1‐ or β‐adrenoceptor stimulation (presence of appropriate receptor blocker) showed the characteristic slow and fast development, respectively, of the inotropic responses. Qualitatively, the respective characteristic changes were also observed: α1‐adrenoceptor stimulation caused a negative lusitropic effect giving a prolongation of the time to peak tension (TPT), while β‐adrenoceptor stimulation caused a pronounced positive lusitropic effect giving a shortening of TPT. The time course of the inotropic response to combined adrenoceptor stimulation had characteristics that deviated from the respective time courses to separate α1‐ or β‐adrenoceptor stimulation thus indicating a contribution from both adrenoceptor populations to the final inotropic response. Combined α1‐ and β‐adrenoceptor stimulation gave a pronounced positive lusitropic response as might be expected due to the obviously dominating role of the β‐adrenergic component. However, the maximal lusitropic effect and the shortening of TPT were both slightly less during combined adrenoceptor stimulation compared to separate β‐stimulation thus indicating an influence of the α1‐adrenoceptor mediated negative lusitropic effect. Quantitatively, the separate α1‐ and the separate β‐adrenoceptor mediated inotropic effects were not additive. In accordance with other recent studies, this indicated an inhibitory interaction between the two adrenergic receptor populations in myocardium.
Toxicological Aspects of Vanadyl Sulphate on Diabetic Rats: Effects on Vanadium Levels and Pancreatic B‐Cell Morphology
Authors: Mongold J. J. , Cros G. H. , Vian L. , Tep A. , Ramanadham S. , Siou G. , Diaz J. , McNeill J. H. , Serrano J. J.
Published: March 2009

This study explored some toxicological aspects of vanadyl sulphate (VOSO4) treatment of rats made diabetic with a single intravenous injection of streptozotocin (60 mg/kg). Administered in drinking water (0.25, 0.5, 0.75 or 1 mg of VOSO4, 5H2O ml) VOSO4treatment partially or totally corrected some of the alterations associated with the diabetic state (hyperglycaemia, polydipsia, polyphagia, high cholesterol and triglycerides levels) and did not produce any changes in various plasma or blood cell paramenters which were not previously altered by diabetes. Measurement of vanadium levels indicated that tissues accumulated vanadium in the following order of concentrations: bone > kidney > spleen > liver > lung > heart ≥ muscle > blood. Histopathological studies did not reveal any difference in liver, stomach, ileum, spleen, heart and lung from control, non‐treated diabetic or VOSO4‐treated diabetic animals. Kidneys of all non‐treated diabetic animals showed an epithelial cellular swelling of distal tubules while only 2 of 6 VOSO4‐treated diabetic animals showed this alteration. Cellular degeneration of pancreas B‐cells was less marked in VOSO4‐treated that in non‐treated diabetic animals. The study indicates that VOSO4may be a potential antidiabetic agent.
Cardiovascular Effects of Irindalone, a New S2‐Serotonergic Antagonist, in the Rat
Authors: Gradin Kathryn , Carlsson Stefan , Hedner Thomas , Persson Bengt
Published: March 2009

Irindalone is a new antihypertensive agent with affinity to serotonin (5‐HT2) receptors and at higher concentrations also to α1‐adrenoceptors. The present study was designed to evaluate the relative importance of the antagonism of central and peripheral α1‐ and 5‐HT2‐receptors in the blood pressure lowering properties or irindalone after acute administration. In conscious Sprague‐Dawley rats intravenous irindalone (0.05–1.5 mg/kg) dose‐dependently reduced the blood pressure. In the same dose‐range irindalone antagonized pressor responses to phenylephrine and electrical stimulation of the spinal sympathetic outflow (SNS) in the pithed rats, indicating that the acute blood pressure lowering effect is primarily related to the blockade of α1‐adrenoceptors. However, the concomitant 5‐HT2‐receptor blockade may contribute since irindalone in a dose (0.15 mg/kg) where it had no α‐adrenoceptor blocking properties enhanced the hypotensive response to selective a α1‐adrenoceptor blockade by prazosin (1 μg/kg). We found no evidence that central mechanisms contributed to the blood pressure lowering effect of irindalone. In anaesthetized rats irindalone (1 mg/kg) did not reduce the directly recorded sympathetic nerve activity. Intracerebroventricular administration of irindalone in conscious rats (10–100 μg) had no consistent effects on the blood pressure and did not enhance the hypotensive response to intracerebroventricularly administered prazosin (10 μg). Finally, the hypotensive response to irindalone was not influenced by depletion of central serotonin stores (by PCPA). It is concluded that the blood pressure lowering effect of irindalone following acute administration is related primarily to blockade of peripheral α‐adrenoceptors but that the concomitant blockade of 5‐HT2‐receptors may contribute.
Effect of Chlordecone (Kepone®) on Calcium Transport Mechanisms in Rat Heart Sarcoplasmic Reticulum*
Authors: Kodavanti Prasada Rao S. , Cameron Joseph A. , Yallapragada Prabhakara R. , Desaiah Durisala
Published: March 2009

Previous studies from our laboratory have indicated that chlordecone (Kepone®, CD), an organochlorine insecticide, inhibited cardiac sodium pump activity and catecholamine uptake suggesting that CD may interfere with cardiac function. Sarcoplasmic reticulum (SR) calcium pump has an important role in myocardial contraction and relaxation, besides Na+ transport. Since CD interferes with cardiac Na+ ion translocases, we have studied CD effects on cardiac SR calcium pump activity. Experiments were carried out both in vitro and in vivo. SR was isolated from heart ventricles of male Sprague‐Dawley rats. Cardiac SR Ca2+‐ATPase, 45Ca‐uptake and cAMP as well as calmodulin (CaM) dependent protein phosphorylation were measured. Ca2+‐ATPase was differentiated into low affinity and high affinity forms by measuring the activity using 50 and 0.7 μM free Ca2+ respectively. CD in vitro inhibited 45Ca‐uptake by SR in a concentration dependent manner with an IC50 value of 7 μM and SR 45Ca‐uptake was totally inhibited at 20–30 μM CD. In agreement with this, both high affinity and low affinity Ca2+‐ATPases, which are involved in Ca2+ transport across membranes, were also inhibited by CD in a concentration dependent manner with IC50 values of 0.7 and 3.2 μM respectively. Both Ca2+‐ATPase and 45Ca‐uptake by cardiac SR were significantly lower in rats treated with CD (25, 50 or 75 mg/kg) when compared to control rats. cAMP as well as CaM significantly elevated the 32P‐binding to SR proteins in vitro to about 70–80%. In the presence of CD, this 32P‐binding was reduced, however, not concentration dependent. In agreement with in vitro studies, 32P‐bound to proteins was significantly lowered in rats treated with CD. SDS‐polyacrylamide gel electrophoresis of the cardiac SR revealed the presence of at least 30 comassie blue‐stainable bands with mobilities corresponding to molecular weights ranging from 9 to 120 kDa using 15% acrylamide gels. Autoradiographs from samples incubated in the presence of cAMP or CaM indicated 32P‐incorporation in 7 bands. Of these, bands corresponding to about 24 kDa and adjacent lower molecular weights decreased in their intensity by CD in vitro as well as in vivo. These results indicate that CD treatment may be reducing SR calcium transport mechanisms by altering phosphorylation of a number of proteins including phospholamban in rat cardiac SR.
Effects of Pinacidil upon Penile Erectile Tissue, in Vitro and in Vivo
Authors: Giraldi Annamaria , Wagner Gorm
Published: March 2009

The effect of pinacidil, a new antihypertensive vasodilator, was studied in vitro upon human and porcine Corpus cavernosum and in vivo upon simian Corpus cavernosum. In vitro, pinacidil incubation (10‐5‐10‐3M) was found to induce a concentration‐dependent inhibition of the tissue response to norepinephrine (NE) and high potassium (K+). Likewise a concentration‐related relaxation of the tissue, precontracted with either NE or K+, was seen using pinacidil 10‐5‐10‐3M. Depending on the concentration applied, spontaneous activity as well as tone and amplitude of the contractions were reduced until total relaxation of the tissue was obtained with a pinacidil incubation of 10‐3M. In vivo, 5 mg pinacidil in 0.3 ml solution was injected intracavernosally in 17 monkeys. Sixteen monkeys developed tumescence and 10, rigidity of the penis as well. Only one of 5 showed a decrease in the systemic blood pressure. Pinacidil might be of clinical interest as an agent facilitating erection when given intravernosally.
Pharmacokinetics of Trimeprazine in Children
Authors: Sponheim S. , Aune H. , Gulliksen M. , Mørland J.
Published: March 2009

The pharmacokinetics of trimeprazine (alimemazine) were studied over 24 hr in six children after a recommended preanaesthetic oral dose of 3 mg · kg‐1. The degree of sedation before anaesthesia was evaluated. Median maximal venous blood drug concentration was 0.357 μmol · 1‐1, 1–2 hr after oral ingestion, half‐life 6.8 hr and AUC0‐∞h 2.758 μmol · 1‐1 hr. Assuming 100 per cent bioavailability, blood clearance was estimated to median 3.7 1 · kg‐1 · hr‐1. Trimeprazine concentrations in cerebrospinal fluid (CSF) and in venous blood were compared in three other children, measured by gas chromatography. No trimeprazine was detected in the cerebrospinal fluid. We found a rough correlation between preanaesthetic sedation and blood trimeprazine concentrations. The kinetic parameters showed substantial interindividual differences, and accordingly, major interindividual variations in drug response might be anticipated even on standardized dosage regimens.
Differential Relaxant Responses to Pinacidil of Smooth Muscle Preparations Contracted by a High Concentration of Potassium in Isoosmolar and Hyperosmolar Solutions
Authors: Nielsen‐Kudsk Jens Erik , Mellemkjær Søren , Nielsen Claus Brøckner , Siggaard Charlotte
Published: March 2009

Contractions were produced in guinea‐pig trachealis, aorta and pulmonary artery by depolarization with 124 mM K+ using two commonly applied techniques. Addition of KCl to the organ bath solution making it hyperosmolar induced slowly developing contractions, which were only weakly inhibited by pinacidil. Hyperosmolar mannitol‐induced contractions showed similar characteristics. In contrast, contractions elicited by isoosmolar K+ Krebs solution developed more rapidly and could be completely suppressed by pinacidil (10‐6‐10‐3 M) in a concentration‐dependent manner. The findings explain previously published discrepant results on the relaxant response to pinacidil of smooth muscle preparations contracted by high concentrations of K+, and indicate other mechanisms of action for pinacidil in addition to K+ channel opening, in the concentration range 10‐6‐10‐3 M.
Release of3H‐Noradrenaline from Rabbit Isolated Ear Artery
Authors: Abrahamsen Jan , Nedergaard Ove A.
Published: March 2009

The stimulation‐evoked3H‐overflow from rabbit isolated ear arteries preincubated with3H‐noradrenaline was studied. Three strips were derived from each central artery. The strips were incubated (30 min.) with3H‐noradrenaline (10‐7M) and the spontaneous3H‐outflow and stimulation‐evoked3H‐overflow were followed by fractional collection. After a wash‐out period (75 min.), the strips were stimulated (225 mA; 150 monophasic pulses; 3 Hz; 0.5 msec.) several times. The initial stimulation‐evoked3H‐overflow (S1) was about 5‐fold higher than the subsequent five3H‐overflows (S2‐S6) which remained almost constant. Bretylium (10‐5M), tetrodotoxin (10‐6M), and omission of Ca2+from the physiological salt solution reduced the stimulation‐evoked3H‐overflow by maximally 52%, 77% and 62%, respectively. An increase in stimulation current from 50 to 225 mA caused a continuous rise in stimulation‐evoked3H‐overflow, which tended to be Ca2+‐sensitive. The stimulation‐evoked3H‐overflow was frequency‐dependent: at 1–4 Hz, the3H‐overflows were the same; at 8 and 16 Hz, they increased. Cocaine (3 × 10‐5M) plus corticosterone (4 ×10‐5M) enhanced the stimulation‐evoked3H‐overflow at 1–8 Hz, while it had no effect at 16 Hz. Propranolol (3 × 10‐7M) did not antagonize this enhancement. An increase in number of pulses from 10 to 1000 in the stimulus caused a corresponding rise in the evoked3H‐overflow. This was also the case when cocaine plus corticosterone were present. Cocaine at low concentrations increased the stimulation‐evoked3H‐overflow at two frequencies (3 and 16 Hz), while a high concentration of cocaine decreased the3H‐overflow at 16 Hz. The results suggest that the strip preparation of rabbit central ear artery is suitable for studying the release of3H‐noradrenaline evoked by electrical‐field stimulation, and that this release is in part of extraneuronal origin.
Interaction of the Hexamethonium Derivative W84, an Allosteric Effector at Muscarinic Cholinoceptors, with Rat Brain Nicotinic Binding Sites
Authors: Leithäuser F. , Mohr K. , Staschen C.‐M.
Published: March 2009

The hexamethonium derivative W84 (hexamethylene‐bis‐[dimethyl‐(3‐phthalimidopropyl)‐ammonium bromide]) combined with atropine has an overadditive protective action against organophosphorus intoxications. It affects allosterically the binding of (—)[3H]N‐methylscopolamine ([3H]NMS) to muscarinic cholinoceptors. Because nicotinic receptors are involved in organophosphorus intoxications, the interaction of W84 with nicotinic cholinoceptors was investigated. (—)[3H]nicotine (2.5 nM) was used to label nicotinic binding sites in rat brain membranes in 50 mM Tris, pH 7.3, at 23°. Under control conditions, (—)[3H]nicotine‐binding revealed a KDof 4×10‐9M and a Bmaxof 53 fmol/mg membrane protein. W84 inhibited (—)[3H]nicotine‐binding with an IC50 of 3 × 10‐5M by reducing the binding affinity. The IC50 of hexamethonium was 20 × 10‐5M. At 10‐4M, W84 did not affect the dissociation rate of (—)[3H]nicotine, suggesting a lack of allosteric activity. For sake of comparison, the action of W84 was checked on [3H]NMS‐binding (control: KD∼ 1 × 10‐9M, Bmax∼ 500 fmol/mg prot.). W84 inhibited the binding of [3H]NMS (0.5 nM) with an IC50 of 1.5 × 10‐5M. At 10‐4M, W84 prevented [3H]NMS‐dissociation almost completely, thus displaying the allosteric action at muscarinic cholinoceptors. In conclusion, the results of the (—)[3H]nicotine‐binding experiments point to a pure competitive action of W84 at nicotine cholinoceptors, lacking any allosteric effect. This competitive action may contribute to the protective effect of W84 in organophosphorus poisoning.
Morphine and Oxycodone in the Management of Cancer Pain: Plasma Levels Determined by Chemical and Radioreceptor Assays
Authors: Kalso Eija , Vainio Anneli , Mattila Maori J. , Rosenberg Per H. , Seppαlä Timo
Published: March 2009

Morphine and oxycodone were administered to ten patients suffering from severe cancer pain in a double‐blind cross‐over study. The patients titrated themselves pain‐free, first intravenously, using a patient‐controlled analgesia device, and then orally. Each titration phase lasted for 48 hours. Blood samples were drawn after 36 hr of each administration phase. The plasma levels of morphine, morphine‐6‐ and morphine‐3 glucuronides were determined with high performance liquid chromatography (HPLC), whereas the oxycodone samples were assayed with gas chromatography (GC). Twin samples were analyzed for plasma opioid activity with a radioreceptor assay (RRA) using3H‐dihydromorphine and3H‐naloxone as radioligands. Adequate analgesia was achieved with both morphine and oxycodone. About 30% more oxycodone was needed intravenously, whereas 25% less oxycodone than morphine was consumed orally. There was a good linear correlation between the morphine concentrations measured with HPLC and RRA. The mean morphine‐6‐glucuronide to morphine concentration ratio was 2.3 after intravenous and 4.6 after oral administration. Results from RRA indicate that oxycodonein vivois a potent μ‐agonist and that at least part of its analgesic action is mediated by active metabolites.In vitromorphine glucuronides enhanced morphine in displacing radioligands from the opioid receptors, thus suggesting their complex interactionsin vivo.
Influence of Enzyme Induction and Exposure Profile on Liver Injury Due to Chlorinated Hydrocarbon Inhalation
Authors: Plummer John L. , de la M. Hall Pauline , Ilsley Anthony H. , Jenner Mark A. , Cousins Michael J.
Published: March 2009

Rats were exposed for four weeks either to air or to vapours of chloroform, carbon tetrachloride or 1,1‐dichloroethylene given either as a constant concentration (continuous profile) or as repeated exposures for 6 hr per day, 5 days per week (fluctuating profile). Vapour concentrations were used such that the total exposure (concentration × time) was the same for the two profiles. Within each group, some animals received the enzyme‐inducing agents, phenobarbitone or 1,3‐butanediol, in their drinking water. Separate experiments were conducted to determine the influence of enzyme inducers and vapour concentration on chlorocarbon uptake and metabolism. In the case of chloroform, hepatic injury was more severe in animals exposed to constant vapour concentration, while dichloroethylene was more toxic when given as a fluctuating profile, especially in butanediol‐treated rats. Carbon tetrachloride hepatotoxicity was similar in the two exposure profiles but was exacerbated by butanediol treatment. Butanediol‐treated animals in the fluctuating profile group showed evidence of developing cirrhosis. These results could not be fully explained on the basis of the effect of enzyme inducers and exposure profile on amount of agent metabolized. Both the amount of toxic metabolites and the temporal pattern of their formation appear to be important determinants of liver injury.
Biochemical Changes and Morphological Alterations of the Liver in Guinea‐Pigs after Administration of Simvastatin (HMG CoA Reductase‐Inhibitor)
Authors: Horsmans Yves , Desager Jean‐P. , Harvengt Carl
Published: March 2009

Simvastatin is a potent competitive inhibitor of the 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMG‐CoA reductase) which is the rate‐limiting enzyme of cholesterol synthesis. In guinea‐pigs, administration of a high oral dose of simvastatin (125 mg/kg/day at the beginning of the study) during 18 days had a major hepatotoxic effect whereas a lower oral dose (30 mg/kg/day) did not seem to cause any liver damage. A significant reduction in microsomal Cyt P 450 content was only observed on a high dose of simvastatin whereas HMG CoA reductase activity was reduced in the group with the low simvastatin dose. The hepatic microsomal aminopyrine N‐demethylase activity remained unchanged in all groups. The liver lesion was hepatocellular necrosis accompanied in some animals by a biliary duct proliferation. It was associated with a 10‐fold elevation in serum aspartate and alanine aminotransferase activities, as well as a great reduction in daily food intake and body weight (28%). The hepatotoxicity of simvastatin could result from the low basal content of HMG‐CoA reductase in guinea‐pig liver, the prolonged inhibition of mevalonate synthesis and probably, from the absence of HMG‐CoA reductase enzymede novosynthesis.
Exposure of Rats to High Concentrations of 1,1,1‐Trichloroethane and its Effects on Brain Lipid and Fatty Acid Composition
Authors: Kyrklund Titus , Haglid Kenneth G.
Published: March 2009

Exposure of rats to 1,1,1‐trichloroethane (TRI) (1200 p.p.m.) for 30 days resulted in changes in the fatty acid pattern of the brain ethanolamine phosphoglyceride. A decrease was observed in stearic acid (18:0) and arachidonic acid (20:4), while the 22‐carbon (n‐3) fatty acids were increased. These changes in the fatty acid pattern were similar to that observed previously in the rat for another solvent, perchloroethylene, at a lower exposure concentration (320 p.p.m). Both these solvents are little metabolised and it seems that a common mechanism exists whereby these solvents alter the fatty acid pattern of brain phospholipid upon exposure. The relatively low uptake of TRI makes a high exposure level (1200 p.p.m.) necessary to attain a blood concentration high enough for the changes to appear.
Antidotal Effect of Lipopolysaccharide Against Acetaminophen‐Induced Mortality in Mice
Authors: Ishikawa Masaaki , Tanno Kouichi , Sasaki Minoru , Takayanagi Yoshio , Sasaki Ken‐ichi
Published: March 2009

The possibility that pretreatment with LPS (lipopolysaccharide obtained fromEscherichia coli), an immune system stimulant and interferon inducer, could prevent the hepatotoxic effects of acetaminophen (NAPAP) was investigated in mice. When mice were pretreated with LPS (4 mg/kg), intraperitoneally for 24 hr the mortality caused by NAPAP was considerably reduced. Histological examination of the livers and leakage of the enzymes into the blood demonstrated that NAPAP‐induced necrosis was decreased in LPS‐treated mice compared to that induced by NAPAP alone. Pretreatment with 400 mg/kg or 800 mg/kg of NAPAP decreased the amount of covalently‐bound acetaminophen metabolites. Since the level of hepatic glutathione and microsomal cytochrome P‐450 were depressed in these experiments, it is concluded that LPS depresses the cytochrome P‐450 species responsible for the formation of the toxic metabolites and that less reactive species are available for binding to cell macromolecules.
Effects of Prolonged Treatment with Phthalate Ester on Rat Liver
Authors: Ganning A. E. , Olsson M. J. , Brunk U. , Dallner G.
Published: March 2009

Rats were fed a diet containing 2%, 0.2% or 0.02% di(2‐ethylhexyl)phthalate (DEHP) for a period of 102 weeks. Only the 2% diet caused a substantial decrease in body weight. Both peroxisomal palmitoyl‐CoA dehydrogenase and mitochondrial carnitine acetyltransferase activities were greatly induced by exposure to the highest dose of phthalate ester, reaching maximal plateau values after about 20 weeks of treatment. The diet containing 0.2% DEHP increased both activities slowly, but continuously, and at the end of the two‐year period these increases were almost comparable to those obtained with the highest dose. Even the lowest dose gave a slowly increase in these activities. Both microsomal NADPH‐cytochromecreductase activity and the level of cytochrome P‐450 were increased initially by exposure to 2% DEHP, but returned almost or completely to the control level after about 30 weeks of exposure. Depending on the dose of DEHP in the diet, peroxisomal catalase activity was elevated above the control level during the first year of treatment but was about the same as in the control animals during the second year. A substantial decrease in peroxisomal urate oxidase activity was observed throughout the entire experimental period. When treatment was ceased after one year, all activities returned to the control values within 2–3 weeks. These results demonstrate the complex nature of the effects caused by prolonged treatment with DEHP with cumulative increases at low doses.
Amperozide – a new putatively antipsychotic drug with a limbic mode of action on dopamine mediated behaviour
Authors: Gustafsson B. , Christensson E.
Published: March 2009

Amperozide, a new putatively antipsychotic drug, was found to exert a functional selectivity for the limbic system of the brain. Thus, amperozide was as active as both classical and atypical neuroleptics on hypermotility induced by a low dose of amphetamine. On the other hand, amperozide did not produce catalepsy, nor did it reverse amphetamine‐induced stereotypies. Moreover, amperozide inhibited exploratory behaviour in mice. The present results indicate an antipsychotic effect of amperozide, with a minimal risk for EPS when used in the clinic.
Effects of amperozide, a putative antipsychotic drug, on rat midbrain dopamine neurons recordedin vivo
Authors: Grenhoff Johan , Tung Che‐Se , Ugedo Luisa , Svensson Torgny H.
Published: March 2009

The effect of the putative antipsychotic compound amperozide on the electrical activity of single identified midbrain dopamine (DA) neurons was investigated in the chloral hydrate anesthetized male rat. While the activity of DA cells in the substantia nigra was unaffected, DA neurons of the ventral tegmental area (VTA), the origin of the mesolimbocortical DA system, were affected in either of two ways: 1) increased firing rate and burst firing, i.e. an excitation, or 2) regularization of the firing pattern. Reversible cold inactivation of the medial prefrontal cortex (PFC) induced a pacemaker‐like firing of VTA‐DA cells, an effect blocked by amperozide in the cells excited by the drug. Cells responding with a regularization were not protected against the effect of PFC inactivation. These different effects of amperozide, which may in part be mediated by 5‐HT2receptor blockade, suggest an antipsychotic activity of amperozide, particularly in schizophrenia with negative symptoms.
Amperozide and emotional behaviour
Authors: Gustafsson B. , Christensson E.
Published: March 2009

The new putatively antipsychotic drug amperozide is characterized pharmacologically by a specific limbic mode of action. Thus amperozide is a potent antagonist of muricidal behaviour (ED50=0.16 mg/kg) as well as aggression between isolated male mice. Although amperozide displays anxiolytic properties in Vogel's conflict test as well as an antidepressive effect in the despair test, the drug does not interfere with motor coordination or cause sedation (ED50> 50 mg/kg). These results could make amperozide very interesting as an antipsychotic drug in the clinic, with effect on both postive and negative symptoms.
Effect of amperozide on the synthesis and turnover of monoamines in rat brain
Authors: Pettersson G. , Johannessen K. , Hulthe P. , Engel J. A.
Published: March 2009

The effects of amperozide on the synthesis and the turnover of monoamines in different brain regions of the rat were determined using bothex vivoandin vivobiochemical techniques (i.e.post‐mortem measurements of the tissue levels by HPLC‐EC, and direct measurements with thein vivovoltammetry technique). It was found that amperozide slightly increased the DOPA accumulation and the DOPAC content in limbic brain areas but not in the striatum. The DOPA accumulation was also slightly increased in the noradrenaline rich cortical region indicating increased synthesis of noradrenaline. Furthermore, amperozide increased the utilization of noradrenaline after tyrosine hydroxylase inhibition by α‐methyl‐p‐tyrosine. The synthesis of 5‐HT was not significantly altered by amperozide. In conclusion, the biochemical data obtained in this study suggest that amperozide produces preferential effects on the mesolimbic dopaminergic system. In addition, amperozide also interacts with the noradrenergic system.
Amperozide – effect on prolactin release in the rat
Authors: Albinsson A. , Eriksson E. , Andersson G.
Published: March 2009

Amperozide, a new putatively antipsychotic drug was investigated for its effect on prolactin release in the rat. A significant decrease in the plasma concentration of prolactin was found at 30 minutes after treatment with amperozide. However, there was no effect of amperozide on prolactin release from isolated pituitary cells. These results suggest that there is no direct effect of amperozide on the pituitary lactotrophs and that the attenuation of prolactin secretion in vivo is mediated at a higher level.
Structure‐Related Inhibitory Effect of Quinolones on Alky1‐Xanthine Elimination in Rats
Authors: Hasegawa Takaaki , Kuzuya Takafumi , Apichartpichean Ruttikorn , Nadai Masayuki , Nitta Atsumi , Takagi Kenzo , Nabeshima Toshitaka
Published: March 2009

Abstract:To investigate the relationship between the chemical structures of quinolones, enoxacin (ENX) and its analogues, and their metabolic inhibitory effects on theophylline, a xanthine derivative closely related to theophylline, 1‐methyl‐3‐propylxanthine (MPX), was used as a model of theophylline in rats. The disappearance of MPX from plasma was significantly delayed by treatment with ENX and analogue A (derivatives without substituent group at both 3′‐ and 5′‐carbon atom in the piperazinyl ring): total body clearance of MPX was significantly decreased by approximately 50%. However, analogue A was converted into ENX in the rat body (about 14% of dose). Analogues B and C (derivatives with substituent group at 3′‐ or 5′‐carbon atom in the piperazinyl ring) had little or no effect on MPX disposition. No significant change in the volume of distribution of MPX was observed after coadministration with these quinolones. The results of this study indicate that the substitutions on 3′ and 5′‐carbon atoms of piperazinyl ring at 7‐position of the quinolone molecule may play important role in the inhibition of theophylline metabolism.
Acetaminophen Does Not Induce Oxidative Stress in Isolated Rat Hepatocytes: Its Probable Antioxidant Effect is Potentiated by the Flavonoid Silybin
Authors: Garrido Argelia , Arancibia Claudio , Campos Rolando , Valenzuela Alfonso
Published: March 2009

Abstract:Acetaminophen hepatotoxicity is characterized by glutathione depletion and the formation of the reactive electrophilic metabolite N‐acetyl‐p‐benzoquinone imine. The induction of oxidative stress, expressed as lipid peroxidation, is controversial in acute acetaminophen intoxication. Isolated rat hepatocytes develop spontaneously or when incubated with buthionine sulfoximide, a progressive lipid peroxidation which may be inhibited by the antioxidant flavonoid silybin. When cells are incubated with acetaminophen, lipid peroxidation is not observed, this antilipoperoxidative effect being potentiated by silybin. It is proposed that when hepatocytes are incubated with a high concentration of acetaminophen, the drug may accumulate in the cells due to saturation and/or inhibition of detoxification pathways (as in the case of silybin). Under these conditions the development of hepatocyte oxidative stress may be inhibited due to the antioxidant behaviour of acetaminophen.
Cerebral Lithium, Inositol and Inositol Monophosphates
Authors: Hirvonen Maija‐Riitta
Published: March 2009

Abstract:Cerebral regional inositol, inositol‐1‐phosphate (InslP), and inositol‐4‐phosphate (Ins4P), intermediates in phosphoinositide (PI) cycle, and brain lithium levels were studied in male HamWistar rats 24 hr after an intraperitoneal injection of a single dose (2, 5–1. mEq./kg) of LiCl. A dose of LiCl higher than 5 mEq/kg caused a remarkable accumulation of Li+in the brain. Basal brain regional inositol levels (17–2. mmol/kg) were reduced by 6‐8 mmol/kg dry brain tissue at doses exceeding 5 mEq/kg of LiCl in all brain regions except the piriform cortex. However, higher doses of LiCl did not cause any further decrease in brain inositol. LiCl increased basal brain regional InslP levels (170–24. μmol/kg) by 0.8 mmol/kg dry brain tissue at most, and there were no consistent additional increases of InslP at LiCl doses exceeding 5 mEq./kg. Moreover, lithium slightly decreased regional cerebral concentrations of Ins4P. Thus, lithium‐induced accumulation of InslP or changes of Ins4P levels do not explain lithium‐induced decrease in cerebral inositol. Effects of lithium on brain PI turnover are likely to be multifocal and to differ markedly at different concentrations of Li+in the brain.
Infertility in Rats Induced by 2,5‐Hexanedione in Combination with Acetone
Authors: Larsen Jens‐Jargen , Lykkegaard Merete , Ladefoged Ole
Published: March 2009

Abstract: The morphological changes as well as the functional consequences for the reproduction of the testis‐injuring effect of 2,5‐hexanedione (2,5‐HD) were evaluated in rats. The potentiation by acetone and the reversibility of the effects was also studied. Male rats were dosed for 6 weeks with 0, 0.13%, 0.25% or 0.50% 2,5‐HD alone or in combination with 0.50% acetone in the drinking water. During the last week of treatment the fertility of half of the treated males was studied by introducing each of them to a non‐treated female rat, after which the number of matings, pregnancies and foetuses was examined. In order to evaluate the degree of reversibility of the effect on testis the same examination was made in the other half of the males after a 10 weeks dose‐free period. The weight and morphology of testis from all the males was studied. The weight of testis, testis tubuli diameter and fertility was reduced by 2,5‐HD and further reduced in groups dosed with 2,5‐HD, 0.25% and 0.50% plus acetone 0.50%. Combined administration of acetone and 2,5‐HD caused a potentiation comparable to the effect of the double dose of 2,5‐HD. Minor changes were reversible within the 10 weeks dose‐free period, whereas infertility and other severe changes in the highest combined group were non‐reversible within this period. The number of matings was unaffected. It is concluded that 2,5‐HD has a testis‐injuring effect, which in high doses and combined with acetone causes non‐reversible infertility and that testis is more sensitive than the nerve tissue to 2,5‐HD. In addition to the wellknown potentiation of the neurotoxic effect, acetone also potentiates the testis‐injuring effect of 2,5‐HD in rats.
Effect of Nitrogen Dioxide on Sulfhydryl Groups in the Central Nervous System of Guinea Pigs
Authors: Farahani Hyder , Hasan Mahdi
Published: March 2009

Abstract: Two groups of male guinea pigs were exposed to 5 and 10 p.p.m. nitrogen dioxide, 2 hr daily for 35 consecutive days, respectively. The third group, exposed to clean room air, was used as control. Total, free and protein bound sulfhydryl groups were estimated in the cerebral hemisphere cerebellum, midbrain and spinal cord. Significant decrement in total and protein bound sulfhydryl groups and increment in free sulfhydryl groups have been observed. Interestingly, dose‐related statistically significant alterations in various CNS regions have been detected.
Inability of Thiol Compounds to Restore CNS Arylsulfatases Inhibited by Methyl Mercury
Authors: Vinay S. D. , Sood P. P.
Published: March 2009

Abstract: Arylsulfatase A and B activities have been analysed in different areas of the CNS (olfactory bulbs, cerebral hemispheres, cerebellum, medulla oblongata and spinal cord) during methyl mercuric chloride (MMC), N‐acetyl‐DL‐homocysteine thiolactone (NAHT) and glutathione (GSH) treatment. Male albino rats were administered with two different doses of MMC (1 mg/kg and 10 mg/kg), NAHT (40 mg/kg and 80 mg/kg) and GSH (100 mg/kg and 150 mg/ kg) for 2, 7 and 15 days, and sacrificed on the 3rd, 8th and 16th day, respectively. Likewise, eight groups of animals, after treatment for 7 days with MMC, were kept for another 7 days and sacrificed on the 15th day (normal withdrawal). Sixteen groups of 7 days MMC pretreated animals were given either NAHT or GSH for another seven days before sacrifice on the 15th day. The study revealed 1) a dose and duration dependent inhibition of the enzymes in all CNS areas, 2) a maximum inhibition of the enzymes among various hydrolases reported so far, and 3) none of the antagonists restored the enzymes significantly except for one group with NAHT. It is, therefore, concluded that arylsulfatases are more sensitive to MMC than other lysosomal enzymes, and the antagonists used here have not helped their restoration.
Antioxidant Action of Propofol on Liver Microsomes, Mitochondria and Brain Synaptosomes in the Rat*
Authors: Musacchio E. , Rizzoli V. , Bianchi M. , Bindoli A. , Galzigna L.
Published: March 2009

Abstract: 2,6‐Diisopropylphenol (propofol), a new intravenous anaesthetic, has a structure similar to that of butylated hydroxytoluene (BHT). Both compounds inhibit the production of malondialdehyde (MDA) in rat liver mitochondria and microsomes as well as in rat brain synaptosomes treated with lipid peroxidation inducers.
Drug Interaction Effects on Antitumour Drugs (VIII): Prevention of Ifosfamide‐Induced Urotoxicity by Disulfiram and its Effect on Antitumour Activity and Acute Toxicity of Alkylating Agents in Mice
Authors: Ishikawa Masaaki , Takayanagi Yoshio , Sasaki Ken‐ichi
Published: March 2009

Abstract:To reduce the side‐effects and to enhance the antitumour activities of antitumour agents, we have been investigating their combined use with routine drugs. In the present study, we examined the effects of disulfiram (DSF) in combination with ifosfamide (IFX). DSF prevented IFX‐induced bladder damage in a dose‐dependent manner in tumour‐free ddY mice when orally administered simultaneously with antitumour agent, but failed to diminish the acute lethal toxicity or leukocytotoxicity of IFX. Diethyldithiocarbamate (DDTC) prevented IFX‐induced bladder damage when administered simultaneously with IFX or 1 to 5 hr afterwards. The antitumour activity of IFX in ddY‐mice inoculated with Sarcoma 180 or in C57BL/6J mice inoculated with EL‐4 leukaemia was not impaired when it was given simultaneously with DSF or 3 hr before DDTC. Thus, neither DSF nor DDTC impaired the antitumour effect of IFX and both diminished its adverse effects. The bladder protection of DSF and DDTC appeared resulted from adduct formation with acrolein and not from inhibition of the metabolic activation of IFX.
Modulation of Calmodulin Properties by Amiodarone and its Major Metabolite Desethylamiodarone*
Authors: Vig P. J. S. , Yallapragada P. R. , Kodavanti P. R. S. , Desaiah D.
Published: March 2009

Abstract:Long‐term amiodarone therapy is invariably associated with some side effects. Although its mechanism of action, as an antiarrhythmic drug is well understood, the side effect profile of amiodarone is not yet established. To determine possible mechanisms, the interaction of amiodarone and its major metabolite desethylamiodarone with calmodulin was investigated, since calmodulin is known to regulate Ca2+transport, cell proliferation and the enzymes involved in signal transduction and nucleotide metabolism. The interaction between the drugs and calmodulin was studied by monitoring intrinsic tyrosine fluorescence of calmodulin and by using a fluorescent probe, N‐phenyl‐1‐naphthylamine (NPN).14C‐Chlorpromazine displacement studies were conducted to differentiate the specific binding sites. The effect on the biological activity of calmodulin was determined with calmodulin dependent phosphodiesterase and Ca2+‐ATPase. The dansyl calmodulin was used as fluorescent probe to study the effect of these drugs on complex formation between calmodulin and phosphodiesterase. Both amiodarone and desethylamiodarone decreased tyrosine fluorescence of calmodulin with IC50 of 4.9 and 4.4 μM respectively and these interactions were Ca2+‐dependent. NPN fluorescence was also affected in a concentration dependent manner. These drugs also displaced bound14C‐chlorpromazine from calmodulin and the effect was biphasic. However, desethylamiodarone was more potent than amiodarone. The binding of3H‐amiodarone to calmodulin was modified by a variety of compounds, one class of compounds decreased and the other increased3H‐amiodarone binding to calmodulin. Only, desethylamiodarone inhibited the phosphodiesterase activation by calmodulin with IC50 of 13.2 μM without changing the basal enzyme. Desethylamiodarone was more potent in altering calmodulin‐dependent synaptic membrane Ca2+‐ATPase activity than amiodarone. Desethylamiodarone also inhibited Ca2+‐dependent complex formation between dansyl calmodulin and phosphodiesterase more effectively than amiodarone. These data suggest that amiodarone and desethylamiodarone interact with calmodulin at specific sites altering its active conformation and some of the side effects associated with amiodarone therapy may be due to this interaction with calmodulin.
A Comparison of Bromopride and Domperidone Effects on Rat Conditioned Avoidance and Motor Activity
Authors: Nasello Antonia Gladys , Vanzeler Maria Luzinete Alves , Felicio Luciano Freitas
Published: March 2009

Abstract: Acute intraperitoneal administration of bromopride (BRO) and domperidone (DOMP), two dopamine D2 blockers used as antiemetics in gastroenterology, were tested in male rats for effects on motor activity and on active and inhibitory conditioned behaviour. BRO dose‐dependently depressed ambulation and rearing, impairing the performance of active conditioned avoidance (CAR) even when injected prior to the retention session. It also impaired inhibitory avoidance responses (IAR). All these effects were dose‐dependent. DOMP was ineffective at modifying any of the above described parameters. These results suggest that BRO exerts neuroleptic effects which are neither mediated by actions on peripheral dopamine receptors nor by increased prolactin levels. These data also suggest that DOMP is a more appropriate drug for gastroenterology.
Dose‐Effect Relationship of Disulfiram in Human Volunteers. I: Clinical Studies
Authors: Christensen Jens Knud , Møller Ib W. , Rønsted Per , Angelo Helle R. , Johansson Benny
Published: March 2009

Abstract: The aim of this study was to investigate the relation between Antabus® dosage and the disulfiram‐alcohol reaction (DAR) after ethanol challenge. Fifty‐two healthy volunteers, 29 men and 23 women, aged 20‐61 years, were treated with increasing doses of Antabuse (1, 100, 200, 300 mg) for 14 days each. At the end of each 14 days the volunteers were challenged with 0.15 g ethanol/kg body weight. Blood pressure, pulse rate, respiration rate, and symptoms such as flushing, heat sensation, nausea, vomiting, palpitations, breathlessness, and headache were monitored for the next 50 min. The volunteers left the study when they had experienced a valid DAR. A valid DAR, which was principally defined on the basis of the patients' feeling of discomfort, but for safety reasons also on the basis of unacceptable circulatory changes, was reached in 21 out of 52 volunteers after 100 mg Antabuse, in 27 after 200 mg, and in 4 after 300 mg. Most of them left the study after flushing and circulatory changes, but did not feel ill enough to be convinced that they should abstain from drinking. Ten volunteers with weak subjective symptoms, but with a valid DAR, were therefore rechallenged after the next increased dose and experienced a somewhat stronger reaction. We conclude that a daily dose of 200 mg Antabuse brings about a substantial reaction in volunteers in the presence of alcohol. The possible need for a 300 mg dose of Antabuse to prevent a patient from drinking was discussed.
Mechanisms of Hydroperoxide‐Induced Broncho‐ and Vasoconstriction in Isolated and Perfused Rat Lung
Authors: Olafsdóttir K. , Atzori L. , Ryrfeldt Å. , Berggren M. , Kumlin M. , Moldéus P.
Published: March 2009

Abstract: The mechanisms of hydroperoxide‐induced broncho‐ and vasoconstriction were investigated in the perfused and ventilated rat lung. Hydrogen peroxide (500 μM), tertiary butylhydroperoxide (500 μM) and arachidonic acid (100 μM) induced similar profiles of broncho‐ and vasoconstriction which could be prevented by the inhibitor of cyclooxygenase, diclofenac (100 μM) but not by nordihydroguaiaretic acid (5 and 25 μM), an inhibitor of lipoxygenase. The hydroperoxides also caused a time‐dependent increase in the levels of thromboxane and prostacycline, products of cyclooxygenase. Furthermore, the thromboxane agonist, U44069 (100 pmoles), caused a very rapid broncho‐ and vasoconstriction that was preventable by the thromboxane antagonist L655.240 (1 μM). L655.240 also inhibited hydrogen peroxide‐induced broncho‐ and vasoconstriction. The phospholipase A2 inhibitors, quinacrine (100 μM) and dibucaine (100 μM), did not prevent hydroperoxide‐induced broncho‐ and vasoconstriction. The Ca2+ chelator, EGTA, prevented hydroperoxide and arachidonic acid‐induced lung constriction, although it did not inhibit the release of thromboxane. The infusion of arachidonic acid and hydroperoxides resulted in edema in the lung which was prevented by prior administration of diclofenac, indomethacin or L655.240. These results indicate that hydroperoxide‐induced broncho‐ and vasoconstriction and lung edema are mediated by thromboxane, a product of cyclooxygenase. The mechanism of hydroperoxide‐induced release of arachidonic acid is not clear but does not seem to involve Ca2+ nor the activation of phospholipase A2.
Role of Selenium‐Dependent Glutathione Peroxidase in Protecting againstt‐Butyl Hydroperoxide‐Induced Damage in Hepatocytes
Authors: Yuan Cai , Penttilä Kai E. , Alfthan Georg , Lindros Kai O.
Published: March 2009

Abstract:The role of the selenoenzyme glutathione peroxidase (Se‐GSHPx) in protecting against oxidative injury was studied in hepatocytes isolated from rats fed either a low‐selenium (Se−) or a selenium‐adequate (Se+, control) diet. In rats fed Se−diet for eight weeks the selenium content of plasma and liver was lowered to 15 and 8%, respectively. No Se‐GSHPx and only 5% of total GSHPx activity was detected in Se−hepatocytes. However, the Se−hepatocytes were as resistant as the Se+cells to oxidative injury by 0.8 mMtert‐butyl hydroperoxide (t‐BuOOH), or 0.2 mMt‐BuOOH plus 1,3‐bis(2‐chloroethyl)‐1‐nitrosourea (BCNU), an inhibitor of oxidized glutathione (GSSG) reductase. Only at 1.5 mMt‐BuOOH or at 0.5 mMt‐BuOOH with BCNU were cell damage and lipid peroxidation more evident in Se−cells. At allt‐BuOOH concentrations used the depletion of cellular glutathione (GSH) was similar in magnitude in Se−and Se+cells, but Se+cells released more glutathione (mainly GSSG), obviously due to their higher Se‐GSHPx activity. These results suggest that hepatocytes devoid of Se‐GSHPx activity maintain a high capacity to resist peroxidative attack, either via residual (non‐Se)GSHPx activity or other compensatory GSH‐associated detoxication mechanisms.
Methyl Mercuric Chloride Toxicokinetics in Mice. I: Effects of Strain, Sex, Route of Administration and Dose
Authors: Nielsen Jesper Bo , Andersen Ole
Published: March 2009

Abstract:The toxicokinetics of methyl mercury is studied most intensively in the rat. However, the toxicokinetics of methyl mercury in man is closer to the toxicokinetics in the mouse. This study describes the effects of dose, route of administration, and strain and sex on the toxicokinetics of methyl mercuric chloride in mice. Half‐time values, fractional whole‐body retentions and relative organ distributions of mercury were compared after a single oral or intraperitoneal administration of methyl mercuric chloride. The intestinal absorption was almost complete in accordance with earlier published results. The route of methyl mercury administration did not affect the whole‐body retention of mercury significantly, but male mice retained lower amounts of mercury than did female mice. The elimination of mercury was demonstrated to follow first order kinetics during the two week study period independently of administration route, strain or sex. An inverse relationship between administered dose and whole‐body retention was observed and by indirect evidence demonstrated not to be caused by an effect on the intestinal uptake mechanism. Absorbed and retained mercury at day 14 was primarily deposited in the carcass, but major deposits were also found in liver, kidneys and intestinal tract. Dose and route of administration did not affect the relative organ distribution of mercury significantly. However, the relative kidney deposition in male mice was about twice that in females. A significant difference in whole‐body retention of mercury was observed between different strains of inbred mice at day 14 after administration. The relative organ distribution of mercury also varied significantly between different strains of mice.