bluuebunny/crossref_metadata_2025 huggingface dataset:
Lead Alters Inositol Polyphosphate Receptor Activities: Protection by ATP
Authors: Vig P. J. S. , Pentyala S. N. , Chetty C. S. , Rajanna B. , Desaiah D.
Published: March 2009

Abstract:Receptor‐mediated phosphoinositide signaling pathway which generates a variety of second messengers is regulated by intracellular free Ca2+concentrations. Since toxic metal cations like Pb2+are known to alter Ca2+‐dependent processes, the present study was initiated to study the effects of Pb2+on inositol 1,4,5‐trisphosphate (InsP3) and inositol 1,3,4,5‐tetrakisphosphate (InsP3) receptor binding and InsP3‐mediated Ca2+‐release. Rat cerebellar membrane and microsomal fractions were incubated with various concentrations of Pb2+(0.01‐100 μM). Pb2+significantly stimulated [3H]‐InsP3, and [3H]‐InsP4receptor binding (EC5022.7 and 13.5 μM respectively) as a function of metal concentrations. However, InsP3‐mediated Ca2+release, determined by measuring the changes in fluorescence intensity of Fura‐2, was significantly inhibited by varying concentrations of Pb2+. Re‐uptake of Ca2+into the microsomes was also inhibited by Pb2+. A significant inhibition of microsomal Ca2+‐pump by micromolar concentration of Pb2+was also observed. ATP at 5‐1000 μM concentration range inhibited [3H]‐InsP3, and [3H]‐InsP4binding to the specific receptors. [3H]‐InsP4receptor binding was more sensitive to ATP inhibition as compared to [3H]‐InsP3, receptor binding. Furthermore, varying concentrations of ATP also inhibited Pb2+‐mediated increase in [3H]‐InsP3and [3H]‐InsP4receptor binding. The kinetic analysis of ATP effect on Pb2+‐stimulated [3H]‐InsP4receptor binding revealed non‐competitive type of interaction. The results of the present study suggest that Pb2+may be increasing the binding of [3H]‐InsP3and [3H]‐InsP4to the specific receptors by modulating the conformation of the receptor sites. ATP may be playing a protective role in Pb2+induced alteration of the receptor sites.
Effects of D1 and D2 Agonists on Spontaneous Motor Activity in MPTP Treated Mice
Authors: Fredriksson Anders , Plaznik Adam , Sundström Erik , Archer Trevor
Published: March 2009

Abstract:Two experiments were performed to study the effect of combining bromocriptine with SKF 38393 (SKF), or vice/versa, upon parameters of spontaneous motor activity in MPTP treated and saline (control) treated mice. Treatment with MPTP (2 × 40 mg/kg, subcutaneously) induced a hypoactive condition compared with saline treated mice. Bromocriptine (10 mg/kg, subcutaneously), administered to MPTP mice 2 hr, but not 1 or 4 hr, after SKF (6 mg/kg, subcutaneously) caused a marked increase in locomotion and rearing behaviour. The administration of bromocriptine (10 mg/kg, subcutaneously) 4 hr before SKF (6 mg/kg, subcutaneously) elevated all three parameters of spontaneous activity in the MPTP treated mice, independent of the injection of SKF. Bromocriptine injection 1 or 2 hr before SKF decreased locomotion in both MPTP and control mice. Neurochemical analysis confirmed the dopamine depletion in the MPTP treated mice. These results are discussed in terms of the reliability of the MPTP model of parkinsonism in mice and the dopamine D1/D2 receptor hypersensitivity following denervation with the neurotoxin.
Effects of CAMP and cGMP Elevating Agents on HL‐60 Cell Differentiation
Authors: Bang Berit E. , Ericsen Christel , Aarhakke Jarle
Published: March 2009

Abstract:Previous studies have demonstrated low percentage of HL‐60 cell differentiation with theophylline. The present study demonstrate that millimolar concentrations of the non‐selective phosphodiesterase inhibitors theophylline, caffeine and isobutyl‐methylxanthine all inhibit growth, induce substantial differentiation and elevation of both cAMP and cGMP in HL‐60 cells. Selective inhibition of CAMP hydrolysis by Ro20‐1724 was without effect. The guanylate cyclase stimulator sodium nitroprusside, which increased cGMP only poorly and also increased CAMP, produced growth inhibition but no differentiation. We put forward the hypothesis that elevation of both cAMP and cGMP above a critical level is necessary for significant cyclic nucleotide induced HL‐60 cell differentiation.
Effect of Toluene Inhalation on Extracellular Striatal Acetylcholine Release Studied with Microdialysis
Authors: Stengård Karl
Published: March 2009

Abstract: Intracerebral microdialysis was performed on awake, freely moving rats in order to record effect of toluene exposure on acetylcholine release in striatum. Acetylcholine release decreased during (about 20%) and after (about 60%) toluene exposure (2 hr, 2000 p.p.m.) Striatal acetylcholine release is thought to be mediated by dopamine. In a previous work we found that extracellular dopamine levels increase during toluene exposure. A dopamine uptake inhibitor (LU 19‐005, 2 mg/kg) was therefore injected subcutaneously and the effect of increased extracellular dopamine on acetylcholine release within the striatum was monitored in the abscence of toluene exposure. LU 19‐005 increased striatal dopamine levels six times and the acetylcholine levels increased to about 14% of basal value. The present study shows that toluene exposure decrease acetylcholine release while an injection of a dopamine uptake inhibitor fails to decrease acetylcholine release. Indicating that acute exposure of toluene decreases striatal acetylcholine release by a mechanism that is not mediated by increased extracellular dopamine levels. Our data suggest that toluene decrease acetylcholine release within the striatum and that this effect not is mediated by increased extracellular dopamine levels.
Changes in the Contractile Responses to Carbachol and in the Inhibitory Effects of Verapamil and Nitrendipine on Isolated Smooth Muscle Preparations from Rats Subchronically Exposed to Pb2+and Zn2+
Authors: Vassilev Peter P. , Venkova Kalina , Pencheva Nevena , Radomirov Radomir , Staneva‐Stoytcheva Dushka
Published: March 2009

Abstract:Male Wistar rats were exposed to Pb2+or Zn2+and to Pb2++Zn2+, receiving Pb(CH3COO)2or/and ZnSO4with drinking water for 30 days. Cumulative concentration‐effect curves for carbachol were obtained in ileum and trachea isolated from control and heavy metal‐treated rats. The effect of the Ca2+channel blockers on the carbachol‐induced contractions was studied by addition of increasing concentrations of verapamil or nitrendipine to the bath solution 20 min. prior to carbachol. The results showed that exposure of rats to heavy metals in doses which did not change the body weight and behaviour, altered the contractile responses to carbachol. The sensitivity to carbachol was higher in preparations from the ileum of Zn2+‐exposed rats as compared to controls, while a tendency towards decreasing this sensitivity was observed in ileal preparations from Pb2+‐treated animals. The concentration‐effect curves for carbachol in ileal preparations from Pb2++ Zn2+‐treated rats did not differ from those in the preparations from untreated rats. The inhibitory effect of the Ca2+channel blockers on the contractility of ileal and tracheal preparations from treated rats was weaker as compared to that in controls.
Age Related Effects of Di(2‐ethylhexyl)phthalate on Hepatic Cytochrome P450 Monooxygenases in Wistar Rats
Authors: Parmar Devendra , Srivastava Satya P. , Seth Prahlad K.
Published: March 2009

Abstract:Age related response of di(2‐ethylhexyl)phthalate (DEHP) was studied by administering the plasticizer (2000 mg/kg, orally) to 3, 6 and 10 week old wistar rats for 1, 7 or 15 days and determining the activity of hepatic P450 monooxygenases. Single administration of DEHP decreased the cytochrome P450 contents and activity of arylhydrocarbon hydroxylase, aniline hydroxylase and ethylmorphine N‐demethylase at all the age groups while repeated exposure induced them with maximum alterations occuring in 3 week old rats. Repeated administration for 15 days, on the other hand, caused a decrease in the cytochrome P450 content and the activity of arylhydrocarbon hydroxylase, aniline hydroxylase and ethylmorphine N‐demethylase only in the 3 week old rats. The 6 and 10 week old rats exposed to the same schedule of DEHP showed an inhibition in the activity of arylhydrocarbon hydroxylase and an increase in the activity of aniline hydroxylase and ethylmorphine N‐demethylase, which was however lower than that seen after 7 days of exposure to DEHP in the respective age group of animals. Our data have indicated the differences in the sensitivity of the P450 monooxygenases towards DEHP and its metabolites amongst 3. 6 and 10 week old animals.
Short Chain Fatty Acids Relax Isolated Resistance Arteries from the Human Ileum by a Mechanism Dependent on Anion‐Exchange
Authors: Mortensen F. V. , Nielsen H. , Aalkjær C. , Mulvany M. J. , Hessov I.
Published: March 2009

Abstract: Ileal resistance arteries (internal diameter 184‐337 μm) were dissected out under microscope and mounted in a microvascular myograph for isometric tension recording. Experiments were designed to test compounds trophic to the small intestine, namely, epidermal growth factor, glutamine and the three short chain fatty acids, acetic, propionic and butyric acid, for effects on vascular tone. Glutamine in concentrations up to 30 mM and epidermal growth factor in concentrations up to 1μM had no contractile or relaxant effects on the resistance arteries. The three short chain fatty acids alone and in combination, however, caused a concentration‐dependent (range 0.1‐30 mM) relaxation of resistance arteries precontracted with 50 mM KCl. This relaxant effect was significantly inhibited by the presence of the anion‐exhange inhibitor 4,4′‐diisothiocyanatostilbene‐2,2′‐disulphonic acid whereas it was unaffected by removal of the endothelium, presence of indomethacin, propranolol or phentolamine. These data suggest that the trophic effects of glutamine and epidermal growth factor on the small intestinal mucosa cannot be explained through actions on the resistance vasculature. In contrast, the relaxant effect of short chain fatty acid on resistance arteries in vitro suggests that these compounds may be able to improve the microcirculation in vivo. An improved microcirculation will, all things considered, facilitate the growth of the small intestinal mucosa.
Diabetes‐Induced Changes in the Gi‐Modulated Muscarinic Receptor‐Adenylyl Cyclase System in Rat Myocardium*
Authors: Fu Liang‐Xiong , Bergh Claes‐Håkan , Liang Qi‐Ming , Sjögren Klas‐Göran , Xu Xuefan , Eriksson Peter , Hoebeke Johan , Hjalmarson Åke
Published: March 2009

Abstract: The inhibitory guanine nucleotide binding regulatory protein (Gi)‐mediated muscarinic receptor‐adenylyl cyclase system was studied in myocardium from adult male Wistar rats with 10 weeks of diabetes induced by a single intravenous injection of streptozotocin (60 mg/kg). Neither the messenger ribonucleic acid level nor the amount of Gi was changed in the streptozotocin diabetic group as compared to the control group. The activity of the adenylyl cyclase stimulated by guanyliminodiphosphate was decreased by 48% in the streptozotocin diabetic group whereas stimulated activities of adenylyl cyclase by sodium fluoride and forskolin remained unchanged. The inhibition of forskolin‐stimulated adenylyl cyclase activity by carbachol was more potent in membranes from the streptozotocin diabetic group than that in membranes from the control group. The competition binding curve between (3H)‐quinuclidinyl benzilate and carbachol obtained from the streptozotocin diabetic group was shifted to the left as compared to the control group. These results suggest that the myocardium of streptozotocin‐induced diabetic rats exhibited an increase in Gi function as demonstrated by the increased inhibition of guanyliminodiphosphate‐mediated adenylyl cyclase and the superhigh affinity for carbachol of the muscarinic receptors. As there were signs, similar to those seen in clinical heart failure, in the streptozotocin diabetic group, these results demonstrate that functional alteration of Gi might underlie, at least in part, the cardiac dysfunction that is associated with diabetes.
Enhanced Levels of Lipid Peroxidation and Xanthine Oxidase Activity in the Lung of Male Sprague‐Dawley Rats Following Treatment with O,O,S‐Trimethyl Phosphorothioate
Authors: Ohtaka Kosei , Koizumi Akio
Published: March 2009

Abstract: The purpose of this study was to investigate the roles of lipid peroxidation and a prototypical radical generating enzyme, xanthine oxidase, in lung injury caused by O,O,S‐trimethyl phosphorothioate (OOS‐TMP). Animals (five per group) were dosed with OOS‐TMP at 40 mg/kg and sacrificed on the 1st, 3rd or 7th day after treatment. OOS‐TMP increased lipid peroxidation (Mean ± S.E.) to 139 ± 9.6% of the control values in the lung and to 623 ± 203% in the liver on the 1st day. When rats were dosed with OOS‐TMP at 20, 40 and 60 mg/kg, lipid peroxidation in the lung and the liver were increased in a dose‐dependent manner. In the lung, the total activity of xanthine oxidase was coincidentally increased. In contrast, the activities of superoxide dismutase and catalase were not affected. Effects of OOS‐TMP on lipid peroxidation and the total activity of xanthine oxidase were completely abolished by coadministration with O,O,O‐trimethyl phosphorothionate of a non‐toxic dose (1 mg/kg), which antagonizes the lung injury after treatment with OOS‐TMP. The present results indicate that free radical formation may be involved in lung injury after OOS‐TMP treatment through activation of radical producing enzymes such as xanthine oxidase.
Morphological Effects of Sodium Fusidate (Fusidin) on Pancreatic Islet Cells: An Electron Microscopic study
Authors: Horn T. , Bendtzen K. , Hageman I. , Buschard K.
Published: March 2009

Abstract: Fusidic acid has been shown to prevent the lymphocyte co‐stimulatory activities of cytokines and seems ‐ in preliminary trials ‐ clinically effective as an immunoregulatory drug e.g. in insulin‐dependent diabetes mellitus. A toxic effect of fusidic acid may however be suspected since a previous study showed a significant dilatation of rough endoplasmic reticulum in cultured pancreatic islet cells from normal rats. In this study we examined the ultrastructural effects of the sodium salt of fusidic acid (fusidin) on cultured rat islet cells (treatment period 3‐5 days), and of islet cells from rats receiving fusidin for 6 days. Electron microscopically, fusidin treatment in vitro (3 to 30 μg/ml) showed a significant dilatation of the rough endoplasmic reticulum of islet cells. No dose dependent changes were found. In the in vivo model no changes were demonstrated in concentrations of fusidin up to 9.64 μg/ml of homogenated pancreatic tissue. It is concluded that treatment with fusidin gives no detectable ultrastructural changes in vivo.
Methyl Mercury during Late Gestation Affects Temporarily the Development of Cortical Muscarinic Receptors in Rat Offspring
Authors: Zanoli Paola , Truzzi Cristina , Veneri Cristina , Braghiroli Daniela , Baraldi Mario
Published: March 2009

Abstract:Pregnant Sprague‐Dawley rats were treated by gavage with a single dose of 8 mg/kg of methyl mercury on gestational day 15. Offspring of control and treated rats were killed at 14, 21 and 60 days of age. The binding characteristics of muscarinic receptors labelled in cortical membrane preparation by3H‐L‐quinuclidinyl benzilate were studied together with the assessment of mercury level in the same brain area. Furthermore, the performance in passive avoidance tasks was evaluated in 8 weeks old rats. Perinatal exposure to methyl mercury significantly reduced the maximum number of muscarinic receptors (Bmax) in the brain of 14 (53%) and 21 day old rats (21%), while this change was no more present in 60 day old rats. This phenomenon seems to be strictly related to the presence of mercury in the cortex since it disappeared with the normalization of mercury levels in the brain. Despite the recovery of muscarinic receptor densities in methyl mercury exposed rats at 8 weeks of age, the avoidance latency was reduced in passive avoidance test as an indication of learning and memory deficits in these animals. Results from this study indicate that prenatal methyl mercury exposure induces latent cognitive dysfunction which does not seem to be related to transient muscarinic receptor alteration found in the early period of postnatal life.
Toxicity Studies on One‐Year Treatment of Non‐Diabetic and Streptozotocin‐Diabetic Rats with Vanadyl Sulphate
Authors: Dai S. , Thompson K. H. , Vera E. , McNeill J. H.
Published: March 2009

Abstract:Streptozotocin‐diabetic and non‐diabetic rats were given vanadyl sulphate in drinking water at concentrations of 0.5‐1.5 mg/ml for one year. It was found that vanadyl treatment did not produce persistent changes in plasma aspartate aminotransferase, alanine aminotransferase, and urea, specific morphological abnormalities in the brain, thymus, heart, lung, liver, spleen, pancreas, kidney, adrenal, or testis, or abnormal organ weight/body weight ratio for these organs in either non‐diabetic or diabetic animals. Treatment significantly reduced the incidence of the occurrence of urinary stones in non‐diabetic rats. In diabetic animals vanadyl treatment significantly reduced the mortality rate and prevented the elevation of plasma levels of alanine aminotransferase and urea, the increases in organ size, and the occurrence of megacolon but did not affect the development of renal and testicular tumours. Plasma and tissue concentrations of vanadium were determined and found to have the following order of distribution: bone>kidney>testis>liver>pancreas>plasma>brain. Vanadium was retained in these organs at 16 weeks following vanadyl withdrawal while the plasma levels were beneath detection limits. It is concluded that vanadyl sulphate at antidiabetic doses is not significantly toxic to rats following a one‐year administration in drinking water, but vanadium may be retained in various organs for months after cessation of treatment.
Protection by Albumin against Ischaemia‐ and Hypoxia‐Induced Hepatic Injury
Authors: Strubelt O. , Younes M. , Li Y.
Published: March 2009

Abstract: In previous studies using isolated perfused rat livers, we have shown that reactive oxygen species are involved in hypoxic and ischaemic liver damage. Since albumin was shown to possess strong antioxidant properties we now investigated the capacity of albumin to prevent ischaemic and hypoxic damage in isolated perfused rat livers. Both, partial ischaemia and hypoxia/reoxygenation, resulted in marked hepatic injury as evidenced by an increased release of hepatic enzymes (GPT, LDH), by a strong decline of bile flow and by a decrease in hepatic GSH levels. With partial ischaemia, hepatic ATP depletion and calcium accumulation were also observed. Bovine serum albumin, added to the perfusate at concentrations of 0.1 or 1%, provided nearly complete protection against both types of liver injury. The same level of protection was also afforded by sulfhydryl‐blocked and fatty acid‐free bovine albumin preparations and by human albumin. In conclusion, the protective effect of albumin in our models of oxidative liver injury is neither due to the thiol moiety nor to the presence of oxidizable fatty acids in the albumin fraction. More likely, albumin provides protection by an unspecific binding of redox‐active transition metal ions capable of catalyzing reactions which yield hydroxyl or hydroxyl‐like radicals. Besides, unspecific sacrifice reactions of albumin with highly reactive oxygen species or other endogenous compounds may also be implicated.
Increased Intracellular Potassium and Water Contents in Rat Heart after α‐1‐Adrenoceptor Stimulation
Authors: Hanem Sigrid , Enger Mette , Skomedal Tor , Osnes Jan‐Bjørn
Published: March 2009

Abstract:Potassium accumulation in rat heart after α‐1‐adrenoceptor stimulation has previously been reported from indirect measurements. Here we present data on intracellular potassium content measured directly in the heart. Isolated rat hearts perfused in a non‐recirculating system were exposed to α‐1‐adrenoceptor stimulation (5 × 10‐5mol/1 phenylephrine in the presence of 10−6mol/1 timolol).14C‐Sucrose was used to estimate the extracellular space. From heart homogenates intracellular potassium, magnesium and cellular water contents were determined and the ion concentrations calculated accordingly. The intracellular magnesium content remained unchanged during all experimental conditions. α‐1‐Adreno‐ceptor stimulation evoked an increase in potassium content by 9% (4, 14; 95% confidence interval (CI), P=0.0006). Due to an observed increase in intracellular water by 17% (9, 26; 95% CI, P=0.0006), the potassium concentration apparently decreased by 8% (0.3, 15; 95% CI, P=0.04). During partial inhibition of the Na+/K+‐ATPase by 10−5mol/1 ouabain, there was an increase in potassium content by 5% (1, 9; 95% CI, P=0.008). There was, however, no significant increase in intracellular water in this situation. Calculated intracellular potassium concentration showed accordingly a slight increase. The effects upon potassium and water both in the absence and presence of ouabain were eliminated by the α‐1‐adrenocep‐tor blocker prazosin (10−6 mol/1). α‐1‐Adrenoceptor stimulation apparently increased cellular dry weight by 10% (2, 18; 95% CI, P=0.02). Changes in translocation of potassium and water must be considered as part of the α‐1‐adrenergic heart effects.
Derivatives of 2‐Nitrofluorene Cause Changes of Human Sperm Motility
Authors: Leijonhufvud Pär K. G. , Pousette Åke , Möller Lennart , Fredricsson Bengt
Published: March 2009

Abstract: The effects on human sperm motility characteristics of 2‐nitrofluorene and selected derivatives were studied in vitro, using computer aided sperm analysis (Cellsoft®). Substances to be tested were dissolved in acetone and added to separated spermatozoa in culture media to final concentrations of 100 and 1000 μM. Aliquots were removed immediately (<5 min.) and 24 hr after the addition and tested for sperm motility characteristics. Four of the substances tested; 2,4,7‐trinitrofluoren‐9‐one (2,4,7‐tNFO), 2,s‐diaminofluorene (2,5‐dAF), 7‐hydroxy‐2‐nitrofluorene (7‐OH‐NF) and 2,7‐diaminofluorene (2,7‐dAF) showed strong detrimental effects on the sperm motility. Slight detrimental effects were also recorded using 2‐nitrofluorene and 2,5‐dinitrofluorene (2,5‐dNF). Weak stimulatory effects were obtained using 2‐acetoamidofluorene (AAF) and 2,7‐dinitrofluorene (2,7‐dNF). No significant effects were seen with 5‐hydroxy‐2‐nitrofluorene (5‐OH‐NF), 2‐aminofluorene (AF), 2‐aminofluoren‐9‐one (AFO), 2‐amino‐9‐hydroxyfluorene (9‐OH‐AF) or 9‐hydroxy‐2‐nitrofluorene (9‐OH‐NF). The mechanism behind this effect is not known but it could be speculated that these lipophilic substances interact with the membranes or the cellular respiration.
Liver Enzyme Activities after Multiple Administration of Nifedipine in Mice
Authors: Dimova Svetlana , Koleva Milena , Rangelova Daniela , Stoytchev Tsanco
Published: March 2009

Abstract: The effect of multiple nifedipine administration on hexobarbital sleeping time, liver monooxygenase and synthetase activities, lipid peroxidation and microsomal membrane fluidity were studied in male albino mice. The drug was administered orally at a dose of 25 mg/kg daily for 14 and 21 days. Nifedipine caused enzyme induction, demonstrated by shortened hexobarbital sleeping time, enhanced ethylmorphine N‐demethylase, aniline 4‐hydroxylase, ethoxycoumarine O‐deethylase, UDP‐glucuronyl transferase, glutathione S‐transferase and NADPH‐cytochrome c reductase activities and increased content of cytochrome P450 and cytochrome b5. This effect persisted until the 7th day after the last dose of nifedipine. There were no changes in lipid peroxidation and fluidity of the microsomal membranes after 14‐day nifedipine administration. The increased cytochrome P450 content and drug metabolizing enzyme activities could be not associated with changes in these liver microsomal membrane properties.
Cerebral Vascular Smooth Muscle Potassium Channels and their Possible Role in the Management of Vasospasm
Authors: Zhang He , Cook David
Published: March 2009

Abstract:One of the promising therapeutic uses of the potassium channel openers is in the management of cerebral vasospasm, a prolonged vasoconstriction of major cerebral arteries which follows aneurysmal subarachnoid haemorrhage. In this review, we first summarize the properties of potassium channels in cerebral vascular smooth muscle. Calcium‐activated and ATP‐dependent potassium channels are the major potassium channels identified in the cerebrovascular smooth muscle and both are believed to play a role in the regulation of cerebrovascular smooth muscle tone. The calcium‐activated potassium channels can be activated by depolarization, by elevation of internal calcium and by some vasodilators. Some neuropeptides and potassium channel openers open the ATP‐dependent potassium channels and produce vasodilation. We then review the effects of both synthetic and endogenous potassium channel openers in the cerebrovascular system, discuss their efficacy in the management of models of cerebrovascular spasm, and outline the clinical promise of these agents.
Effect of Oral Glutathione Monoethyl Ester and Glutathione on Circulating and Hepatic Sulfhydrils in the Rat
Authors: Grattagliano Ignazio , Wieland Peter , Schranz Christian , Lauterburg Bernhard H.
Published: March 2009

Abstract:Glutathione (GSH) plays an important role in the detoxification of reactive metabolites of oxygen and xenobiotics and as a source of cysteine. Since several clinical situations characterized by low circulating and intracellular GSH have been identified, there is a growing interest in pharmacological interventions to correct a deranged sulfhydril status. Therefore, the systemic bioavailability of orally administered GSH and glutathione monoethyl ester (GSHE) was examined in the rat. Following the intraduodenal administration of 0.5 mmol/kg of GSH and GSHE there was no significant increase in the concentrations of cysteine and GSH in plasma, but hepatic cysteine and GSH increased significantly, albeit transiently. Five mmol/kg of GSH and GSHE significantly increased circulating and hepatic cysteine and GSH. Following the administration of 0.5 and 5 mmolikg of GSHE low concentrations of the ester were found in plasma and the liver, indicating that GSHE is not readily absorbed from the gastrointestinal tract, although it is not a substrate for γ‐glutamyl transferase. GSHE resulted in a delayed release of cysteine and GSH compared to GSH, such that the concentrations of GSH and cysteine in liver and plasma were significantly higher 2 h after administration of GSHE than after GSH. The data indicate that the bioavailability of GSH and GSHE is low in the rat. Orally administered GSH and GSHE do not affect the circulating concentrations of GSH and cysteine unless very high doses are administered, but increase hepatic cysteine and GSH at lower doses because of the efficient extraction by the liver of cysteine originating from the breakdown of GSH and GSHE in the gut.
Infusion of Nicotine in the Ventral Tegmental Area or the Nucleus Accumbens of the Rat Differentially Affects Accumbal Dopamine Release
Authors: Nisell Magnus , Nomikos George G. , Svensson Torgny H.
Published: March 2009

Abstract:The present study examined the effects of acute, continuous infusion of nicotine in either the ventral tegmental area or the nucleus accumbens on extracellular concentrations of dopamine in the nucleus accumbens by applyingin vivomicrodialysis in freely moving rats. Nicotine (1000 μM) infusion for 80 min. in the ventral tegmental area produced a long‐lasting increase in accumbal dopamine, whereas similar nicotine infusion in the nucleus accumbens increased dopamine levels only within the first 20 min. of administration. This effect was blocked by systemic pretreatment with the nicotinic receptor antagonist mecamylamine (1 mg/kg, subcutaneously). In contrast to the effects of nicotine, N‐methyl‐D‐aspartate infusion in the ventral tegmental area as well as in the nucleus accumbens produced a long‐lasting increase in accumbal dopamine levels. The more procounced effect of infusion of nicotine in the ventral tegmental area as compared to the nucleus accumbens on accumbal dopamine release may be due to a lower rate or even lack of tolerance to nicotine's stimulatory action in the ventral tegmental area. These results support the notion that nicotinic receptors in the ventral tegmental area may be of greater importance than those located in the nucleus accumbens for mediating some of the stimulatory effects of nicotine on the reward‐related mesoaccumbens dopamine system.
Gender Differences in Diazepam Withdrawal Syndrome in Mice
Authors: Pesce Maria Ester , Acevedo Ximena , Pinardi G. , Miranda H. F.
Published: March 2009

Abstract:Abstract The present work was designed to study the influence of testosterone and oestrogens on the benzodiazepine withdrawal syndrome in mice. Several withdrawal signs were induced by 15 mg/kg intraperitoneally of flumazenil in diazepam‐treated mice. The most noticeable were jerks, usually accompanied by tail lifts, and seizures. The intensity of the diazepam withdrawal syndrome was significantly lower in male than in female mice, especially in relation to the incidence of seizures. Castrated male mice showed a significant increase in the intensity of withdrawal syndrome. In addition, diazepam produced a significant increase of body weight in males but not in females. The principal finding of the present work is that the incidence of seizures produced by the administration of flumazenil was significantly lower in male than in female diazepam‐treated mice. This fact suggests that the mechanism of action of benzodiazepines is modulated by the action of sexual hormones, and that testosterone plays a relevant role.
Effects of theAnemonia sulcataToxin (ATX II) on Intracellular Sodium and Contractility in Rat and Guinea‐Pig Myocardium
Authors: Hoey Andrew , Harrison Simon M. , Boyett Mark R. , Ravens Ursula
Published: March 2009

Abstract:The effects of theAnemonia sulcatatoxin ATX II on action potentials and contractility of isolated papillary muscles and single myocytes from rat and guinea‐pig hearts have been studied. ATX II prolonged the action potential in both rat and guinea‐pig papillary muscle. Although it produced a positive inotropic effect in guinea‐pig papillary muscle, it failed to do so in rat papillary muscle. However, in single rat and guinea‐pig ventricular cells, it both prolonged the action potential and had a positive inotropic effect. We suggest that ATX II does not cause a positive inotropic effect in rat papillary muscle, because it induces Ca2+overload. In single cells the positive inotropic effect was reduced by −50% when the contractions were triggered by voltage clamp pulses of constant duration rather than by action potentials. This suggests that the inotropic effect of ATX II is in part the result of the prolongation of the action potential. The intracellular Na+activity (aiNa) in single ventricular cells was measured with the Na+‐sensitive fluorescent dye SBFI. After exposure of the cells to ATX II, aiNawas increased by a maximum of 1.9 ± 0.3 and 2.2 ± 0.3 mM in rat and guinea‐pig cells, respectively. It is suggested that the positive inotropic effect of ATX II is also in part the result of the rise in aiNa.
In Vivo and In Vitro Sevoflurane‐Induced Lipid Peroxidation in Guinea‐pig Liver Microsomes
Authors: Sato Nobuyoshi , Fujii Kohyu , Yuge Osafumi
Published: March 2009

Abstract: Sevoflurane is a recently introduced volatile inhalation anaesthetic and is already used commonly in Japan. We investigated the potential of sevoflurane to cause lipid peroxidation in vivo and in vitro. For the in vitro study, pentane formation in a mixture of guinea pig liver microsomes and sevoflurane in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) was analyzed by gas chromatography. Under anaerobic conditions, pentane formed without sevoflurane, but sevoflurane potentiated this anaerobic pentane formation. Two antioxidant agents, vitamine E and glutathione, reduced the pentane formation induced by sevoflurane. In the in vivo study, 18 guinea pigs were exposed to air (control), 0.5% halothane, or 1.2% sevoflurane. The extent of lipid peroxidation and liver damage was investigated by measuring the level of thiobarbituric acid reactive products and serum transaminase (alanine‐aminotransferase: ALAT and aspartate‐aminotransferase: ASAT) activity 12 hr after exposure. Both halothane and sevoflurane significantly increased thiobarbituric acid‐reactive products. The increase in thiobarbituric acid‐reactive products seen with sevoflurane administration was half that seen with halothane. Sevoflurane increased the ALAT activity to the same extent as did halothane but did not increase the ASAT activity. We conclude that sevoflurane potentiates lipid peroxidation in guinea pig liver microsomes in vivo and in vitro. However, because the degree of liver damage as measured by transaminase activity was minimal and the mechanism of sevoflurane‐induced lipid peroxidation is still unknown, we must be cautious in applying these results to humans.
Histamine‐Independent Modulation of the Neuropeptide Y‐Induced Pressor Response by α‐Trinositol in the Pithed Rat
Authors: Sun Xiangying , Edvinsson Lars , Hedner Thomas
Published: March 2009

Abstract:The modulatory effects of α‐trinositol (D‐myo‐inositol‐1.2.6‐trisphosphate; PP 56) on the systemic arterial blood pressor responses induced by neuropeptide Y, preganglionic nerve stimulation, phenylephrine and vasopressin were studied in pithed rats. Intravenous administration (within 2 min.) of α‐trinositol reduced the neuropeptide Y‐induced increase in mean arterial pressure within a defined dose range without altering the heart rate. The influence of α‐trinositol on the neuropeptide Y‐induced pressor response in the presence of non‐selective as well as H1‐ and H2‐selective histamine antagonists (diphenhydramine, mepyramine and cimetidine respectively) were investigated. The maximal increase in mean arterial pressure induced by neuropeptide Y as well as the duration of the pressor response was enhanced after non‐selective (diphenhydramine) or H1‐selective (mepyramine) histamine blockade. The enhancement of the neuropeptide Y‐induced pressor response by the H1specific antagonist mepyramine was significantly more pronounced compared to the H2‐selective agent. The exaggerated increase in mean arterial pressure in response to neuropeptide Y after histamine blockade was inhibited by α‐trinositol to a similar extent as without such pretreatment. We conclude that neuropeptide Y interacts with histamine in the pithed rat and that this action may partially offset the pressor actions of the peptide. The neuropeptide Y‐induced pressor responses may be inhibited by α‐trinositol within a defined dose range indicating that this non‐peptide agent may act as a functional inhibitor to neuropeptide Y in vascular tissue.
Allosteric Effects of the Alkane‐bis‐ammonium Compound W84 and of Tacrine on [3H]Pirenzepine Binding at M1‐Receptors in Rat Cerebral Cortex
Authors: Mohr Klaus , Tränkle Christian
Published: March 2009

Abstract:The bis‐quaternary W84, hexamethylene‐bis‐[dimethyl‐(3‐phthalimidopropyl)‐ammonium bromide], is a potent allosteric modulator of M2‐cholinoceptors. In this study we aimed at quantifying its allosteric effect on the dissociation of [3H]pirenzepine from M1‐cholinoceptors in rat cerebral cortex and to measure the effects on association and equilibrium binding of [3H]pirenzepine. For sake of comparison tacrine was included which is known to be a potent allosteric modulator of [3H]pirenzepine binding to M1‐receptors. Under control conditions (3 mM MgHPO4, 50 mM Tris‐HCl, pH 7.4, 23°) [3H]pirenzepine binding was characterized by KD=5 nM and Bmax=965 fmol/mg membrane protein, the rate constants amounting to k+1= 5.0 μM−1xmin−1and k‐1=0.031 min−1. W84 and tacrine reduced [3H]pirenzepine binding concentration‐dependently with IC50‐values of 1.9 μM and 2.6 μM, respectively. [3H]pirenzepine association was inhibited by the compounds with EC50,ass=1.8 μM for W84 and EC50,ass=2.4 μM for tacrine. The concentrations reducing the dissociation rate by 50% amounted to EC50,diss=21 μM for W84 and to EC50,diss=54 μM for tacrine. Compared with W84, the dose‐response curves of tacrine for the investigated effects were significantly steeper. In conclusion, W84 affected [3H]pirenzepine binding to M1‐receptors allosterically with a higher potency than tacrine but probably by a different mechanism.
Effects of Chlorhexidine on the Isolated Rat Phrenic Nerve‐Diaphragm Preparation
Authors: Røed Asbjørn
Published: March 2009

Dose‐dependent inhibitory effect of chlorhexidine (2.5 × 10−5–5.0 × 10−4) g/ml on neuromuscular transmission were localized by tension and electromyogram recording during indirect stimulation. Subsequent direct stimulation showed an additional inhibition which might be located to the sarcolemma. In addition, contracture was observed at the highest concentrations. Microelectrode experiments showed a miniature endplate potential frequency increase (at 1.0 × 10−6g/ ml), suggesting a presynaptic action. Increasing the dose to 5.0 × 10−6g/ml disclosed a decrease of the miniature endplate potential amplitude, indicating a reduction of the postsynaptic receptor sensitivity, which might cause neuromuscular inhibition. This was confirmed by endplate potential recording in cut preparations. The endplate potential showed a moderate degree of use‐dependent inhibition which did not usually cause a tetanic fade. Experiments with curare, decamethonium and neostigmine indicated that chlorhexidine probably caused a decamethonium‐like inhibition. A small depolarization of the sarcolemma was probably not the cause of the directly elicited inhibition or contracture. The contracture was potentiated in preparations made myotonic by pretreatment with para‐hydroxy‐mercuribenzoate. It could not be inhibited by the excitation‐contraction uncoupler dantrolene, but it was dependent on extracellular Ca2+. Chlorhexidine‐induced influx of Car2+might thus cause the contracture.
Pentamidine Accumulates in Rat Liver Lysosomes and Inhibits Phospholipid Degradation
Authors: Glaumann H. , Bronner U. , Ericsson Ö. , Gustafsson L. L. , Rombo L.
Published: March 2009

The subcellular distribution and the effects of pentamidine on the ultrastructure of the rat liver were studied. Rats were given single or repeated daily intraperitoneal injections of 10, 25 or 50 mg pentamidine isethionate/kg b. wt. for 1, 4, 6, 9 or 16 days. The livers were removed for ultrastructural and biochemical analyses on the day after termination of each series of injections and in addition 7 and 35 days after the 16th injection. Electron microscopy of liver tissues showed that the general cellular architecture of the hepatocytes was preserved. The subcellular organelles were normal, except for the secondary lysosomes, which were severely altered and laden with multilamellar, myelin structures (myelin bodies) that gradually increased with dose and time course following repeated injections. These altered lysosomes were enriched in phospholipids. The alteration of the lysosomes persisted for up to 5 weeks after cessation of administration. Pentamidine was highly enriched in the lysosomal fraction (30‐50 times more than in the liver homogenate). It was calculated that the lysosomal pentamidine accounted for practically all pentamidine distributed to the liver. The demonstrated accumulation of pentamidine in the lysosomes may explain the known large volume of distribution of this drug and may be one mechanism for organ toxicity.
Transfer of Lindane and Pentachlorobenzene from Mother to Newborn Rabbits
Authors: Pompa G. , Fadini L. , Di Lauro F. , Caloni F.
Published: March 2009

After administration of γ‐hexachlorocyclohexane (lindane) (30 mg/kg) to sixteen pregnant rabbits, the transfer and distribution of this insecticide and its metabolite pentachlorobenzene, in foetuses and newborns at the 5th, 10th and 20th days after birth, were investigated. Over one lactation the mothers excreted via the milk about 30% of the lindane present in tissues at the 28th day of pregnancy. The total amount of lindane transferred via milk to 5 day‐old newborns was higher than that transferred across the placenta during pregnancy. Lindane concentrations in newborns decreased in spite of the efficient transfer to off‐spring by lactating mothers. This cannot be explained by growth alone and indicates that newborns are able to actively metabolize the insecticide. The pentachlorobenzene metabolite produced after lindane administration to the mothers crossed the placental barrier with difficulty during pregnancy, but was readily transferred to off‐spring via milk. Pentachlorobenzene levels in neonates increased during lactation by transfer and also as a consequence of endogenous production. At the 20th day of lactation the pentachlorobenzene concentration in maternal and foetal tissues was higher than that of lindane.
Chlormethiazole and Dizocilpine Block the Behavioural, but Not the Neurotoxic Effects of 5,7‐Dihydroxytryptamine in Mice
Authors: Snape M. F. , Colado M. I. , Green A. R.
Published: March 2009

Intracerebroventricular administration to mice of 5,7‐dihydroxytryptamine at a dose of 300 μg resulted in convulsive behaviour and death (latency 7.6±1.7 min.). Pretreatment with dizocilpine or chlormethiazole resulted in a dose dependent inhibition of the convulsive behaviour. A dose of dizocilpine of 0.12 μmol/kg or chlormethiazole at a dose of 150 μmol/kg prevented seizures for 30 min. Injection of 5,7‐dihydroxytryptamine (75 μg, intracerebroventricularly) produced an approximate 50% neurotoxic loss of cerebral 5‐hydroxytryptamine (5‐HT) and its metabolite 5‐hydroxyindole acetic acid (5‐HIAA) 8 days later. This loss was not prevented by administration of either dizocilpine (4.5 μmol/kg intraperitoneally) or chlormethiazole (300 μmol/kg intraperitoneally) given 5 min. before and 55 min. after the 5,7‐dihydroxytryptamine injection. It is proposed that chlormethiazole and dizocilpine may protect against 5,7‐dihydroxytryptamine‐induced seizures because of their anticonvulsant activity, but that they do not prevent the neurotoxic effects of the compound. The data also suggest that the neurotoxic effects of substituted amphetamines such as 3,4‐methylene dioxymethamphetamine (MDMA or Ecstasy) do not result from the formation of a 5,7‐dihydroxytryptamine like compound.
Comparison of the Effects of Propofol and Thiopental on the Pattern of Maximal Electroshock Seizures in the Rat
Authors: Hasan Zuheir A. , Woolley Dorothy E.
Published: March 2009

The anticonvulsant effects of propofol and thiopental (thiopentone) were determined by measuring the durations of the various phases of maximal electroshock seizures in the rat. Five min. after intraperitoneal administration of subanaesthetic (6.25, 12.5 and 25 mg/kg) and 50 mg/kg doses of propofol, the 2 highest doses abolished both tonic hindlimb extensor phases (full and partial extension) in all rats and decreased the duration of the total tonic phases of the seizure. Although the lowest dose produced no effect, the 12.5 mg/kg dose decreased the duration of both the full and partial tonic extensor phases and increased the duration of tonic flexion, showing that even this low dose had anticonvulsant activity. Subanesthetic doses of thiopental (5, 10 and 20 mg/kg) produced similar changes in the maximal electroshock seizures except that even the lowest dose also significantly decreased the duration of total extension and total tonus. Postseizure depression was prolonged only by the highest dose of propofol. Thus, even low doses of either propofol or thiopental, that produced only minimal behavioural effects, had marked anticonvulsant effects against electrically induced convulsions in the rat. No evidence of enhanced convulsant maximal electroshock seizures patterns was observed at any dose.
Lipoperoxidative Damage on Lead Exposure in Rat Brain and its Implications on Membrane Bound Enzymes
Authors: Sandhir Rajat , Julka Deepinder , Dip Gill Kiran
Published: March 2009

We have investigated the effect of lead exposure on lipid peroxidation, a deteriorative process of the membranes, in the different regions of the brain. Lead treatment (50 mg/kg b.wt. intragastrically) for a period of eight weeks to rats resulted in a significant accumulation of lead in all the regions of brain, at maximum in hippocampus. The lipid peroxidation was accentuated following lead exposure and there was a linear correlation between the increase in lipid peroxidation and increase in lead levels (r = 0.75). The antioxidant capacity of the neuronal cells in terms of the activity of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase was diminished. Lead treatment also altered the glutathione status i.e. levels of reduced glutathione were lowered, accompanied with the accumulation of oxidized glutathione. Furthermore, the activity of glutathione reductase was significantly lowered in lead‐treated animals. The activity of membrane bound enzyme acetylcholinesterase was significantly inhibited following lead exposure and there was a linear correlation between the increase in lipid peroxidation and decrease in acetylcholinesterase activity (r = ‐ 0.83). It appears from the results that lead may exert its neurotoxic effects via peroxidative damage to the mebranes.
Immunoglobulin Levels in Workers Exposed to Inorganic Mercury
Authors: Queiroz M. L. S. , Perlingeiro R. C. R. , Dantas D. C. M. , Bizzacchi J. M. Annichino , De Capitani E. M.
Published: March 2009

The serum immunoglobulin (IgG, IgM and IgA) concentrations of 44 mercury‐exposed workers were examined and compared with those of non‐exposed, age‐ and sex‐matched individuals. At the time of testing, the exposed population had a mean (+ S.D.) mercury urinary concentration of 24.7+ 19.1 and in 40 of them urinary mercury levels were below the currently accepted limit of 50 μg/g creatinine. Increased IgG, IgA and IgM levels were found in the mercury‐exposed individuals and in 16, a second evaluation was performed six months later. During the intervening six months, the level of hygiene was improved throughout the plant, and urinary mercury concentrations were determined monthly in each worker. Despite a significant reduction in mercury urinary concentrations, serum immunoglobulin levels did not return to the normal range. There was no correlation between the length or level of exposure and the immunoglobulin levels. Liver protein synthesis, as studied by factor V, prothrombin time, prealbumin and transaminase activity, was normal and liver injury, as evaluated by serum aspartate and alanine aminotransferase activities (AST and ALT, respectively), was not observed. No haemotological abnormalities were noted. These results indicate that “safe” levels of mercury exposure may lead to humoral immunological stimulation.
Function of the Auditory and Visual Systems, and of Peripheral Nerve, in Rats after Long‐Term Combined Exposure to n‐Hexane and Methylated Benzene Derivatives. I. Toluene
Authors: Nylén Per , Hagman Maud , Johnson Ann‐Chrístin
Published: March 2009

Rats were exposed to n‐hexane, toluene, or toluene together with n‐hexane, each solvent 1000 p.p.m. (1000+ 1000 p.p.m. in combined exposure), 21 hr/day, 7 days/week during 28 days. Neurophysiological recordings were made 2 days, 3 months, and one year after end of exposure. A reduction in auditory sensitivity, recorded by click evoked auditory brainstem response, was observed 2 days after exposure to toluene alone, or to toluene together with n‐hexane, but not after exposure to n‐hexane alone. The reduction lasted one year after the exposure. Three months after combined exposure, a synergistic enhancement of loss of auditory sensitivity was observed in the mixed exposure group. One amplitude in the flash evoked potentials was lowered in the n‐hexane exposed group 2 days after exposure. No such reduction was seen after simultaneous exposure to toluene. Exposure to n‐hexane alone caused a marked decrease in peripheral nerve conduction velocity 2 days and 3 months after exposure, while exposure to n‐hexane together with toluene had only a small effect on this velocity.