bluuebunny/crossref_metadata_2025 huggingface dataset:
Local Antinociceptive and Hyper algesic Effects in the Formalin Test after Peripheral Administration of Adenosine Analogues in Mice
Authors: Karlsten Rolf , Gordh Torsten , Post Claes
Published: March 2009

Abstract:Adenosine administered to humans has been reported to induce pain after intravenous administration. On the other hand adenosine analogues have been shown to possess antinociceptive effects after peripheral and intrathecal administration in animals. The aim of the present study was to investigate the effect of peripheral administration of adenosine agonists with different affinities for the A1 and A2 adenosine receptors on a persistent pain stimulus using the formalin test. The drugs chosen were, R‐phenylisopropyl‐adenosine (R‐PIA) with high affinity for the A1 receptor, N‐ethylcarboxamide‐adenosine (NECA) with almost equal affinity for the A1 and A2 receptor and 2‐(2‐aminoethylamino)‐carbonylethylphenylethylamino‐adenosine (APEC) with high affinity for the A2 receptor. The drugs were mixed with formalin and administered subcutaneously into the dorsal hind paw in mice to study the local effects. They were also injected separately from the formalin solution in different paws to evaluate the systemic effect. The total time of licking the injected paw during the first 5 min. was recorded. In high doses all compounds reduced the licking activity, but a low dose of APEC (1 μM) injected together with the formalin solution had an algesic effect. All effects were antagonized by theophylline. These results suggests that A1 adenosine receptors mediate a local peripheral antinociceptive effect and the involvement of local peripheral A2 receptors in the enhancement of the algesic response.
Evidence for Cytochrome P450 2E1–Mediated Toxicity of N‐Nitrosodimethylamine in Cultured Perivenous Hepatocytes from Ethanol Treated Rats
Authors: Anundi Irene , Lindros Kai O.
Published: March 2009

Abstract:The involvement of cytochrome P450 in the liver toxicity of the potent carcinogen, N‐nitrosodimethylamine (NDMA) was investigated in hepatocytes isolated from the periportal or perivenous region by digitonin‐collagenase perfusion. Exposure of hepatocytes in culture to NDMA (0.5 or 5 mM) for up to 18 hrs caused little damage, but after 42 hr loss of cell viability became evident, and the extent of cell death was higher in perivenous cells than in periportal cells. Pretreatment of rats with ethanol caused a dramatically enhanced cell damage in perivenous cells (80%) compared to periportal cells (45%). This ethanol pretreatment caused a several‐fold induction of cytochrome P450 2E1, as determined both with Western blot and as NDMA demethylase activity, and the effect was observed almost exclusively in perivenous cells. Isoniazid, an inhibitor of cytochrome P450 2E1, completely protected against NDMA toxicity. Glutathione dependent cytoprotective mechanisms and lipid peroxidation did not appear to be critical in NDMA toxicity, as evidence by lack of potentiation of toxicity by buthionine sulfoximine, an inhibitor of glutathione synthesis, and by the absence of increased lipid peroxidation. Instead, the higher expression of cytochrome P450 2E1 in the perivenous cells seems to be the main determinant for the regiospecific toxicity of NDMA, and, consequently, probably also for the associated genotoxicity.
A Novel Peptide Toxin fromTrimeresurus wagleriActs Pre‐ and Post‐Synaptically to Block Transmission at the Rat Neuromuscular Junction*
Authors: Aiken Simon P. , Sellin Lawrence C. , Schmidt James J. , Weinstein Scott A. , McArdle Joseph J.
Published: March 2009

Abstract:The neuromuscular effects of a peptide toxin (peptide I) from venom ofTrimeresurus wagleriwere investigated using the rat extensor digitorum longus muscle/peroneal nerve preparation. Sub‐micromolar concentrations depressed endplate currents (EPCs) produced in response to nerve stimulation. Since quantal content of EPCs was not altered, it appears that the site of action is post‐synaptic. However, higher concentrations (1.4–2.9 μM) also inhibited spontaneous release of transmitter. Nerve stimulation in the presence of peptide I caused ‘rundown’ of EPC amplitude, evidence that the peptide acts pre‐synaptically to interfere with transmitter release. Recovery from this effect occurred within 3–5 min. of washing, but EPC amplitude took 20–30 min. to recover. The dual action of this peptide makes it unusual amongst naturally‐occurring toxins, and these data suggest that further investigation of the peptide (and its analogues) could yield new information about neurotransmitter release.
Exogenous Modification of Nitrovasodilator‐Induced Cyclic GMP Formation in Human Lymphocytes
Authors: Vuorinen Pauli
Published: March 2009

Abstract:The effects of exogenous guanosine 5′‐triphosphate (GTP), guanosine 5′‐(γy‐thio)triphosphate (GTPγS), cysteine and Trolox C., a water soluble vitamin E analogue, were studied on basal and nitrovasodilator‐induced cyclic GMP formation in isolated human lymphocytes. Incubation of lymphocytes in the presence of GTP (0.1 mM) and GTPγS (0.1 mM) increased cyclic GMP more than twofold. SIN‐1 and sodium nitroprusside dose‐dependently increased cyclic GMP, but nitroglycerin and sodium nitrite were ineffective. GTP and GTPγS potentiated SIN‐1‐ and sodium nitroprusside‐induced cyclic GMP formation. In the presence of GTP and GTPγS, nitroglycerin, but not sodium nitrite, was able to increase lymphocyte cyclic GMP. Cysteine (1 mM) enhanced cyclic GMP formation induced by sodium nitroprusside and nitroglycerin. Trolox C (0.1 mM) potentiated SIN‐1‐induced cyclic GMP formation. These results indicate that exogenous GTP and GTPγS enhance guanylate cyclase stimulation by spontaneous nitric oxide releasers and nitroglycerin in lymphocytes. Cysteine, a redox‐compound and Trolox C, an antioxidant, have different effects on guanylate cyclase activation by nitric oxide releasers, SIN‐1 and sodium nitroprusside.
Drug Metabolism in Rats with Cancer Induced by N‐Nitrosodiethylamine and Phenobarbital
Authors: Aitio Mirja‐Liisa , Hietanen1 Eino , Béréziat Jean‐Claude , Arvela Pentti , Bartsch Helmut
Published: March 2009

Abstract:The metabolism ofR‐ andS‐warfarinin vivoandin vitro, bufuralolin vitro, and antipyrine and debrisoquinein vivowere studied in rats with cancer induced byN‐nitrosodiethylamine and phenobarbital treatment. Microsomal cytochrome P‐450 content was greatly reduced in both healthy and cancerous parts of the livers of tumour‐bearing animals. The specific activities ofR‐warfarin and bufuralol 1′‐hydroxylases were significantly elevated in rats with cancer. The activities ofS‐warfarin hydroxylases expressed per mg microsomal protein were reduced in animals with cancer, whereas those ofR‐warfarin and bufuralol 1′‐hydroxylases were not. The urinary excretion ofR‐7‐hydroxywarfarin was increased and those ofS‐6‐ andS‐4′‐hydroxywarfarin decreased in rats with cancer. The correlations between microsomal formation and urinary excretion of all warfarin metabolites were poor, except forR‐7‐hydroxywarfarin. Antipyrine oxidation was increased in the cancerous state but the urinary metabolic profiles were similar in rats with cancer and in controls. The metabolism of debrisoquine was decreased in tumour‐bearing animals. Antipyrine metabolism did not show any correlation with either warfarin or debrisoquine metabolism, whereas several relationships were observed between warfarin and debrisoquine metabolism and between warfarin and bufuralol metabolism.
Effects of an Interferon Inducer Bropirimine on Bleomycin‐Induced Lung Fibrosis in Hamsters*
Authors: Zia Shaheen , Hyde Dallas M. , Giri Shri N.
Published: March 2009

Abstract:The antifibrotic effect of an interferon inducer, bropirimine (2‐amino‐5‐bromo‐6‐phenyl‐4(3H)‐pyrimidinone, ABPP) was evaluated in bleomycin (BLM)‐hamster model of lung fibrosis. ABPP is an orally active biological response modifier and has immunomodulatory, antiviral, and antineoplastic activities. The hamsters were randomized in four groups and treated with either bropirimine (100 mg/kg, intraperitoneally) suspended in carboxymethylcellulose (CMC, 10 mg/10 mg/ml) or CMC alone each day for sixteen days. After two days, the hamsters received either single bolus of BLM (7.5 U/5 ml/kg) or an equivalent volume of saline by the transoral endotracheal route. Groupings were assigned as: CMC + saline (CS), ABPP + saline (AS), CMC + BLM (CB) and ABPP + BLM (AB). Animals were sacrificed at fourteen days after intratracheal installation of either BLM or saline. Their lungs were lavaged and processed for morphometric and biochemical studies. ABPP had little effect in preventing BLM‐induced weight loss and lung injury. ABPP was found to reduce the BLM‐induced accumulation of collagen in the lung as measured by hydroxyproline content. The hamsters in AB group had significantly less collagen than the hamsters in CB group: 995 and 1157 μg hydroxyproline/lung, respectively. Administration of ABPP prevented the BLM‐induced increase in the lung prolyl hydroxylase activity. The total number of monocytes and eosinophils recovered from the bronchoalveolar lavage fluid (BALF) of the AB group were significantly lower than that of the animals in CB group. However, the BALF supernatant protein content from animals in AB group (7.9 mg/lung) was significantly higher than that of CB group (4.5 mg/lung). There were no differences in morphometric estimates of the volume of parenchymal lesions and total number of cells recovered in the BALF between CB and AB groups. Results of this study suggest that ABPP has an inhibitory effect on collagen accumulation, and monocyte and eosinophil infiltration, but it potentiates BLM‐induced increases in the pulmonary vascular permeability.
Diminution in Kerosene‐Mediated Induction of Drug Metabolizing Enzymes by Asbestos in Rat Lungs
Authors: Arif Jamal M. , Khan Sikandar G. , Aslam Mohammad , Mahmood Nayyara , Rahman Qamar
Published: March 2009

Abstract: In order to determine the pulmonary toxicity of kerosene and its ignition product (soot) in asbestos exposed subjects, the activities of phase I and phase II drug metabolizing enzymes in rat lungs after single intratracheal coexposure to Indian chrysotile asbestos and kerosene or its soot and Indian chrysotile were assayed. Exposure to kerosene or its soot resulted in a significant increase in the level of microsomal cytochrome P‐450 and the activity of P‐450 dependent monooxygenase, benzo(a)pyrene hydroxylase, as well as in the activities of microsomal epoxide hydrase and cytosolic glutathione‐S‐transferase (GST). However, in chrysotile exposed animals a reverse pattern in these parameters was recorded. The co‐exposure to chrysotile and kerosene or chrysotile and soot led to a significant depletion in cytochrome P‐450 level and a decrease in the activities of benzo(a)pyrene hydroxylase, epoxide hydrase and GST when compared to kerosene and soot controls, respectively. These results suggest that asbestos by altering the pulmonary drug metabolizing enzyme system may increase the toxic potential of kerosene and its ignition product in the respiratory system.
Saturation Analysis in Receptor Binding Assays: An Evaluation of Six Different Calculation Techniques
Authors: Hall Håkan
Published: March 2009

Abstract: Randomized errors to varying extents have been introduced in a constructed data set simulating receptor binding saturation analyses. The parameters Bmax and Kd were then determined using six different evaluation techniques, four linear and two non‐linear. It is concluded that a non‐linear evaluation gives more reliable results, especially when errors are large. Furthermore, an inevitable correlation between Bmax and Kd regardless of evaluation technique results in possible misinterpretations of simultaneous changes in both parameters.
Effects of Prostanoids and Indomethacin on Isolated Smooth Muscle from the Human Lower Oesophagus
Authors: Tøttrup Anders , Forman Axel , Raundahl Uffe , Andersson Karl‐Erik
Published: March 2009

Abstract:Smooth muscle strips representing the longitudinal and the circular muscle layers of the oesophageal body and the oesophagogastric junction of the human oesophagus were mounted in organ baths and isometric tension recorded. Transmural field stimulation was applied to strips from both layers of the oesophageal body and to strips from the longitudinal muscle layer of the oesophagogastric junction. This resulted in contractions after cessation of the stimulus train in circular muscle, and in contractions during stimulation in longitudinal muscle preparations. Indomethacin lowered active tension in strips from the circular muscle layer of the oesophagogastric junction, and decreased responses to transmural field stimulation in all strips from the longitudinal muscle layer. The response to transmural field stimulation was increased in strips from the circular muscle layer of the oesophageal body, suggesting an inhibitory function of endogenous prostanoids in this muscle layer. Prostaglandin (PG) F2αand the thromboxane A2mimic U‐46619 increased the responses to transmural field stimulation in all muscle types and the active tension in circular muscle from the oesophagogastric junction. PGE1and PGE2increased the responses to transmural field stimulation strips from the longitudinal muscle layer. In circular muscle strips from the oesophageal body responses to transmural field stimulation were inhibitied. PGE1decreased active tension in circular muscle strips from the oesophagogastric junction, whereas PGE2produced inconsistent effects. These results suggest a role of prostanoids in the regulation of neuromuscular function in the human lower oesophagus. Moreover, exogenous prostaglandins may modulate oesophageal motor function.
Pharmacokinetics of Imipenem/Cilastatin Sodium in Children with Peritonitis
Authors: Claesson Gösta , Eriksson Margareta , Rogers J. D.
Published: March 2009

Abstract: Fifteen children (3‐12 years) with peritonitis were given imipenem/cilastatin intravenously (15 or 25 mg/kg) every six hours for 3‐14 days. One day during treatment days 2‐8, multiple blood and urine samples were collected from each individual over a six hour dosing interval. Twelve children completed the study. The urinary recovery of imipenem and cilastatin averaged 50‐70% of the administered dose. The plasma t1/2 for imipenem averaged 55 min. while that for cilastatin was even more rapid (~ 38 min.). Little or no accumulation of either imipenem or cilastatin was observed for this regimen in this age group of paediatric patients. Steady state conditions prevailed within 2 days of initiation of therapy. The pharmacokinetics of imipenem and cilastatin in paediatric patients 3‐12 years of age appear similar to those observed for adults.
Kava Pyrones and Resin: Studies on GABAA, GABAB and Benzodiazepine Binding Sites in Rodent Brain
Authors: Davies Les P. , Drew Colleen A. , Duffield Pat , Johnston Graham A. R. , Jamieson Dana D.
Published: March 2009

Abstract: Kava, an intoxicating beverage prepared from the pepper plant Piper methysticum, is widely consumed by the indigenous peoples in the islands of the South Pacific. As the first of a series of studies on the neuropharmacological interactions of kava with CNS receptors we tested purified pyrones and kava resin for activity on GABA and benzodiazepine binding sites in rat and mouse brain membranes. Only weak activity was observed on GABAA binding sites in washed synaptosomal membranes prepared from rat brain and this was abolished by extraction of the membranes with Triton X‐100, suggesting that lipid soluble components were involved. No effects were observed on GABAa binding sites in rat brain membranes in vitro. Kava resin and pyrones exerted some weak effects on benzodiazepine binding in vitro but this did not correlate with pharmacological activity. In addition, in ex vivo studies, no effects were observed on [3H]diazepam binding to brain membranes prepared from mice in which selected kava constituents were injected intraperitoneally, whereas similarly administered diazepam (5 mg/kg) inhibited [3H]diazepam binding by >95%. Similar lack of activity was observed in in vivo binding studies; injection of kava resin failed to influence the CNS binding of the benzodiazepine‐receptor ligand [3H]Ro15‐1788 injected into mice prior to sacrifice. The pharmacological activities of kava resin and pyrones do not appear to be explained by any significant interaction with GABA or benzodiazepine binding sites.
Involvement of Opioid Mechanisms in Peripheral Motor Control of Detrusor Muscle
Authors: Berggren A. , Rubenson A. , Sillén U.
Published: March 2009

Abstract:Isometric recordings of mechanical activity in muscle strips from rat and human detrusor were performed and the effect of μ‐ and δ‐opioid receptor stimulation and blockade on detrusor contraction induced by electrical field stimulation was tested. Stimulation of the opioid μ‐receptor with morphine (10‐13‐10‐4M) and DAGO (10‐13‐10‐6M) had no significant effect on electrical field stimulation except at one concentration of morphine (10‐6M). Naloxone (10‐10‐10‐5M) caused a significant facilitation of the electrical field stimulation‐induced contraction, which was counteracted by morphine (10‐8M) and the δ‐agonist DPDPE (10‐8M) in both rat and human detrusor. Addition of atropine (10‐6M) or hexamethonium chloride (10‐6M) or spantide (10‐6M) did not alter the facilitating effect of naloxone in the rat detrusor. Hexamethonium (10‐5M) decreased the facilitating effect of naloxone on electrical field stimulationinduced contractions in the human detrusor, indicating involvement of ganglionic mechanisms. In human detrusor about 15% of the contractile response was found to be atropine‐resistant (10‐6M) and one third of this was found to be resistant to tetrodotoxin (1.5 × 10‐6M). The atropine resistant‐response in human detrusor was facilitated by naloxone to the same extent as the atropine‐sensitive part. Adrenergic blockade per se, achieved with phentolamine mesylate (10‐6M) and propranolol (10‐6M), caused a significant facilitation of the electrical field stimulation‐induced contraction in the rat detrusor but did not affect the facilitating effect of naloxone (10‐13‐10‐5M). Addition of the δ‐agonist DPDPE (10‐13‐10‐5M) did not significantly change the detrusor response to electrical field stimulation in rat detrusor, but the δ‐antagonist naltrindole (10‐13‐10‐5M) caused a significant facilitation at the highest concentration. In human detrusor, DPDPE 10‐8M significantly reduced the response induced by electrical field stimulation. Conclusion: Blockade of the opioid receptors with naloxone facilitates the detrusor contraction elicited by electrical field stimulation. The existence of a tonic, inhibitory action on the detrusor nerve mediated detrusor contraction by opioid μ‐ and possibly δ‐receptors is suggested.
Changes in Concentration of Essential Metals in Kidneys and Urine as Indices of Gentamicin Nephrotoxicity in Female Wistar Rats
Authors: Chmielnicka Jadwiga , Szymańska Jadwiga A. , Brzeźnicka Elźbieta A. , Kaluźyński Andrzej
Published: March 2009

Abstract:Wistar rats were treated with gentamicin in single (80 mg/kg) or repeated doses (7 × 40 mg/kg) subcutaneously. Total protein as well as excretion of essential metals (Cu, Zn) with the urine were determined 24 hr after 1, 3 and 7 dosages as well as 3 and 7 days after the termination of administration. At the same time kidneys were examined histopathologically by light microscopy. Simultaneously, Cu, Zn and metallothionein levels in kidneys and liver were determined. Rats receiving gentamicin demonstrated progressive renal proximal tubular necrosis at the end of 7 days administration. At the same time elevated copper and zinc levels were observed in urine. These essential metals seem to be an indicator of gentamicin nephrotoxicity.
Sensory Irritation Effects of Methyl Ethyl Ketone and its Receptor Activation Mechanism
Authors: Hansen Lea Frimann , Knudsen Anders , Nielsen Gunnar Damgård
Published: March 2009

Abstract: The burning and painful effect in nose and eyes, termed sensory irritation, of methyl ethyl ketone varpours was investigated in a mouse bioassay. Sensory irritation is mediated via the trigeminal nerves and results in a reflexively induced decrease in respiratory rate in mice. Methyl ethyl ketone was used as a model substance for ketones. At the lower exposure concentrations a partial fading (desensitization) of the response was seen. Little desensitization was seen at higher concentrations. n‐Propanol, a model substance for alcohols, desensitized the receptor at all exposure levels. Preexposure to propanol did not influence the response at high methylethyl ketone concentrations. This suggests that the two substances bind to different receptive sites with different properties, if the ketone response is due to a high exposure concentration. A decrease in tidal volume was also mediated from the upper respiratory tract. The tidal volume effect is mediated by nerves different from those mediating the frequency response, as the time‐response relationship, the desensitization pattern, the maximum response and the apparent dissociation constants were different for the two types of effect. Neither the location nor the perceived response related to the volume response is known.
Enzyme Activities in the Term Human Placenta: In Vitro Effect of Cadmium
Authors: Boadi William Y. , Urbach Jacob , Barnea Eytan R. , Brand Joseph M. , Yannai Shmuel
Published: March 2009

Abstract: The effect of cadmium (Cd) as CdCl2 on some placental enzyme activities were studied after explants had been incubated with the salt for 6 or 24 hr. The results indicated that, for both incubation periods, Cd at low doses had a stimulatory effect on aryl hydrocarbon hydroxylase (AHH) (a phase I enzyme) and on quinone reductase and catecholamine‐O‐methyltransferase (COMT) (both phase II enzymes). This effect was dose‐ and time‐dependent. Only the activities of AHH and COMT showed a biphasic response, (i.e., increases at the lower dose levels and decreases with the higher ones), whereas that of quinone reductase continually increased with all the dose levels of the metal administered. Glucose‐6‐phosphate dehydrogenase (G‐6‐PD) activity was found to be inhibited at all the dose levels of Cd tested, the effect also being time‐ and dose‐dependent. In conclusion, it appears that the use of placental explants can serve as a valuable means for studying the toxic effects of certain xenobiotics, as reflected in the activity of various important enzymes.
Naloxone Counteracts the Fast Development of Tolerance to Morphine in Guinea‐Pig Ileum
Authors: Hustveit Olav , Setekleiv Johannes , Øye Ivar
Published: March 2009

Abstract:The ability of naloxone to inhibit the fast development of tolerance to morphine was examined in the guinea‐pig ileum preparation. Dose‐response curves were obtained either non‐cumulatively with morphine alone or cumulatively with morphine alone and in combination with different concentrations of naloxone. We present some theoretical considerations concerning the competitive interaction between agonist and antagonist on a receptor. According to these theories, it is possible to perform dose‐response experiments for an agonist in combination with different concentrations of antagonist and extrapolate to the dose‐response curve for agonist alone and to the dissociation constant for the antagonist. EC50values for morphine alone obtained either non‐cumulatively or by extrapolation are almost identical and are significantly lower than those obtained cumulatively. The results indicate that tolerance developes very quickly when dose‐response curves are obtained cumulatively with morphine alone and that low concentrations of naloxone counteract the development of tolerance.
Metrifonate and Tacrine: A Comparative Study on their Effect on Acetylcholine Dynamics in Mouse Brain
Authors: Nordgren I. , Karlén B. , Kimland M.
Published: March 2009

Abstract: Tetrahydroaminoacridine (THA) and metrifonate are cholinesterase inhibitors used in the treatment of Alzheimer's disease. In experimental animals they inhibit acetylcholinesterase activity and have been reported to increase levels of brain acetylcholine. This paper presents results from studies of their effect at two dose levels on the dynamics of acetylcholine in mouse brain. Metrifonate at two doses (10 and 30 mg/kg intraperitoneally), known to cause cholinesterase inhibition, had no effect on levels of acetylcholine or choline or on the rate of synthesis of acetylcholine. THA (3 mg/kg intraperitoneally) had no effect on levels of acetylcholine and choline but had a shortlasting decreasing effect on the synthesis rate of acetylcholine. THA (10 mg/kg intraperitoneally) increased levels of acetylcholine and choline and markedly decreased the synthesis rate of acetylcholine. At this dose, the animals showed severe cholinergic effects, e.g. tremor and salivation. It is suggested that a moderate cholinesterase inhibition in brain facilitates cholinergic nerve transmission which is obtained at a broader dose range for metrifonate than for THA.
Excessive Accumulation of Hepatic Copper in LEC Rats Aged 80 Days without Hepatitis and 130 Days with Hepatitis
Authors: Sugawara Naoki , Sugawara Chieko , Sato Masao , Takahashi Hidetoshi , Mori Michio
Published: March 2009

Abstract: The Cu concentration was about 40 and 60 times higher in the liver in Long‐Evans with a cinnamon‐like coat color (LEC) rats aged 80 days (without hepatitis) and 130 days (with hepatitis), respectively than in the liver in Fischer rats. Most hepatic Cu was recovered in the cytosol fraction. Furthermore, about 96% and 84% of the cytosolic Cu was found in the metallothionein region on a Sephadex G‐75 column in LEC rats aged 80 and 130 days, respectively. The hepatic metallothionein concentration was about 130 to 140 times higher in LEC rats than in Fischer rats when the concentration was expressed as metallothionein‐bound Cu. Three forms of Cu‐metallothionein were isolated by DEAE‐cartridge. Although the concentration of hepatic Cu‐metallothionein and its composition of polymorphic form were not changed greatly in hepatitis phase (in the 130‐day‐old LEC rats), activities of serum enzymes, aspartate aminotransferase (GOT) and alanine aminotransferase (GPT) were increased significantly. The LEC rat showed a significantly low concentration of biliary Cu and markedly low activity of ceruloplasmin (as ferroxidase). Serum Cu showed a low concentration in the 80‐day‐old LEC rats, but recovered to the control level in the 130‐day‐old LEC rats. The abnormal accumulation of Cu may be due to the inherent reduction of excretion of Cu into the bile and blood. Such deposition may be a trigger for the onset of the spontaneous hepatitis occurring at 90‐120 days after birth and for the onset of hepatoma later.
Effects of Felodipine on Utero‐Placental Blood Flow in Normotensive Rabbits
Authors: Lundgren Yen , Thalén Pia , Nordlander Margareta
Published: March 2009

Abstract: The utero‐placental blood flow was investigated in anaesthetized normotensive pregnant rabbits after repeated administration of a high dose of the antihypertensive calcium antagonist felodipine and in untreated controls. By means of the microsphere technique blood flow was also determined in the lungs, skin, intestine, skeletal muscle and kidneys during chloralose anaesthesia. Felodipine reduced mean arterial blood pressure, which was associated with a marked reduction in vascular resistance in the skeletal muscle vascular bed, where blood flow was increased seven‐fold. In contrast, blood flow to placentae and kidneys were reduced. The pronounced reduction in placental blood flow may limit foetal nutrition and hence explain reported foetal digital defects after administration of high doses of felodipine to pregnant normotensive rabbits.
On the Pharmacological and Physiological Role of Glibenclamide‐Sensitive Potassium Channels in Colonic Smooth Muscle
Authors: Richardson David , Alibhai Karim N. , Huizinga Jan D.
Published: March 2009

Abstract:Actions of activators of glibenclamide sensitive K+channels on canine colonic circular muscle were investigated. Cromakalim as well as its (‐) enantiomer lemakalim caused inhibition of spontaneous phasic contractile activity (EC50's 4.4 ± 0.1 × 10‐7M and 2.3 ± 0.4 × 10‐7M, respectively) and of carbachol induced activity (EC50's: 9.4 ± 5.1 × 10‐7M and 4.3 ± 1.4 × 10‐7M, respectively). Cromakalim and lemakalim effects were completely inhibited by glibenclamide. Additive effects between K+channel activators and other drugs relaxing colonic muscle (the L‐type calcium channel blocker D600 and forskolin) were seen. A physiological role for specific glibenclamide sensitive K+channels, if existing, remains unresolved. The present study indicates that the non‐adrenergic inhibitory nerves do not act through these channels, neither does stimulation of muscarinic or β‐adrenergic receptors.
Acute and Subacute Effects of Doxorubicin on Postextrasystolic Potentiation in Guinea Pig Papillary Muscles
Authors: Asayama Jun , Yamahara Yasuhiro , Matsumoto Takashi , Miyazaki Hiroshi , Tatsumi Tetsuya , Inoue Miho , Ohta Bon , Omori Itsuki , Inoue Daisuke , Nakagawa Masao
Published: March 2009

Abstract:To investigate the effects of doxorubicin on postextrasystolic potentiation (PESP), isolated guinea pig papillary muscles were field‐stimulated and the resulting isometric force was recorded. Postextrasystolic contraction was evoked following trains of 37 regular stimulations. The effects of acute doses of doxorubicin (0.2 mM) on regular contractions and postextrasystolic contractions were examined for 2 hr. The effects of subacute doses of doxorubicin (total dose 5 mg/kg intraperitoneally) on the relationship between %PESP (postextrasystolic/regular contraction) and both the extra‐stimulus coupling interval and the postextrasystolic interval were examined. Acute administration of doxorubicin decreased the amplitude of postextrasystolic contractions more than that of regular contractions. Thus, %PESP in the doxorubicin‐treated group decreased significantly over time. There was no similar decrease in the control papillary muscles. Both the extra‐stimulus coupling interval and the postextrasystolic interval had less of an effect on %PESP in doxorubicin‐treated animals than in control animals. Since PESP depends upon sarcoplasmic reticulum activity, our results indicate that acute and subacute exposure to doxorubicin impairs the activity of the sarcoplasmic reticulum of guinea pig papillary muscles.
The Effect of High Calcium Intake on Intracellular Free [Ca2+] and Na+‐H+Exchange in DOC‐NaCl‐Hypertensive Rats
Authors: Wuorela Heikki
Published: March 2009

Abstract:The effects of calcium supplementation on blood pressure, intracellular free calcium concentration ([Ca2+],) and rate of Na+‐H+exchange were studied in DOC‐NaCl‐hypertensive rats. All the animals were uninephrectomized and divided into two main groups: the first group received deoxycorticosterone (DOC) (25 mg/kg, s.c.) once a week and had 0.7% NaCl as drinking fluid while the other received equal volumes of saline and tap water to drink. The animals were further divided according to dietary calcium intake: in the Control and DOC groups the chow contained 1.1% calcium, in the Calcium and DOC + Calcium groups, 2.5%. After 6 and 8 weeks, blood pressure in the DOC group was higher than in the Control group; on the other hand, the development of hypertension was attenuated in the DOC + Calcium compared with the DOC group. The Control and Calcium groups did not differ from each other. Platelets and lymphocytes were used as experimental models to study changes in the regulation of [Ca2+]i, evaluated by fluorescent indicators indo‐1 and quin‐2. In lymphocytes, basal [Ca2+]iwas highest in the DOC group, but similar in DOC + Calcium and Control groups. In platelets, both basal and thrombin‐stimulated [Ca2+]iwere higher in the DOC and DOC + Calcium groups than in the Control group. In both cell types [Ca2+]iwas similar in Control and Calcium groups. In addition, platelets were used to study the ability of the cells to recover from intracellular acidification by first blocking the Na+‐H+exchange in a Na+‐free medium and then restarting the exchange mechanism by increasing the extracellular Na+concentration at constant speed. Changes in [pH]iwere monitored by fluorescent indicator BCECF. The rate of Na+‐H+exchange in the recovery phase did not reveal differences between the experimental groups. Vascular smooth muscle function was examined by determining concentration‐response curves for noradrenaline in mesenteric arterial rings and a shift to the left was observed in the DOC and DOC + Calcium groups compared with the Control group. The present data indicate that high calcium intake attenuates the development of mineralocorticoid‐salt hypertension. The DOC‐induced elevation of blood pressure is associated with higher [Ca2+]iin platelets and lymphocytes, evidencing disturbances in cellular calcium handling. However, possibly due to differing characteristics in regulatory mechanisms between these cell types, supplementary calcium reduced [Ca2+]ionly in lymphocytes. The assumed elevation in intracellular sodium did not cause detectable changes in the Na+‐H+exchange rate in platelets. Enhanced vascular responses to noradrenaline observed in the DOC group were not altered by high calcium intake.
Picroliv and its Components Kutkoside and Picroside I Protect Liver Against Galactosamine‐Induced Damage in Rats
Authors: Dwivedi Yogesh , Rastogi Ravi , Garg N. K. , Dhawan B. N.
Published: March 2009

Abstract: D‐Galactosamine (800 mg/kg, intraperitoneally) caused significant decrease in the activities of 5′‐nucleotidase, glucose‐6‐phosphatase and cytochrome P450 and increase in activities of γ‐glutamyl transpeptidase, succinate dehydrogenase, acid phosphatase and acid ribonuclease in liver after 24 hr. The levels of RNA, protein and glycogen decreased while total lipids, phospholipids, cholesterol and lipid peroxides increased. It also increased the serum levels of transaminases, alkaline phosphatase and bilirubin while protein concentration decreased significantly. Oral administration of Picroliv (12 mg/kg/day for 7 days), a standardised iridoid glycoside fraction of Picrorhiza kurroa, significantly prevented the biochemical changes in liver and serum of galactosamine‐toxicated rats. Kutkoside (12 mg/kg/day for 7 days) also protected against changes in most of the hepatic and serum constituents studied. Another iridoid glycoside from Picroliv, Picroside I, at the same dose level could only prevent toxicant‐induced changes in acid phosphatase, phospholipids and lipid peroxides in liver and alkaline phosphatase in serum. Mixture of Picroside I and Kutkoside in the ratio of 1:1.5 at 12 mg/kg dose elicited lesser response than Picroliv.
Bioavailability of Two Soviet Sustained‐Release Theophylline Formulations in Comparison with TheoDur
Authors: Kiivet Raul Allan , Teder Priit , Pruunsild Toomas , Svensson Jan‐Olof
Published: March 2009

Abstract: The pharmacokinetic parameters of two theophylline preparations of Soviet origin (Theobiolongas® and Theopaek®) were compared with the reference preparation TheoDur®. The three sustained‐release preparations were administered in a single oral dose (400 mg) to healthy volunteers. Blood samples were drawn over 36 hr and plasma concentrations of theophylline were measured by HPLC. Significant differences in the pharmacokinetic parameters were observed between the drugs. Compared to TheoDur®, the two Soviet drugs, Theobiolongas® and Theopaek®, had lower bioavailability (86% and 82%, respectively), and higher rate of absorption. An 8‐hr dosing interval should be preferred for Theobiolongas® and Theopaek® while twice‐daily administration appears to be appropriate for these preparations only in exceptional cases.
Forskolin but Not Cholera Toxin Bypasses Flufenamate‐Induced Inhibition of cAMP Production in Anterior Pituitaries
Authors: Bourne Gregory A.
Published: March 2009

Abstract: The pharmacological activators of adenylyl cyclase (cholera toxin and forskolin) were utilized in the present study to determine whether they could bypass the inhibitory effects of flufenamate on cAMP production in rat hemipituitaries. During 2 hr incubations, 10 μM flufenamate inhibited gonadotropin‐releasing hormone (GnRH)‐stimulated (25 nM) cAMP production. Flufenamate did not affect GnRH‐receptor interactions as evidenced by its inability to significantly affect either the binding affinity or the binding capacity for GnRH. Additionally, flufenamate inhibited the cholera toxin‐stimulated cAMP production, but was ineffective against forskolin‐induced activation of adenylyl cyclase. These results indicate that forskolin can be used to restore cAMP production in the presence of flufenamate. Since GnRH and cholera toxin stimulate cAMP production via the GnRH receptor and the Gs protein respectively, and forskolin exerts its stimulatory effects via the catalytic component, the data are consistent with the possibility that flufenamate exerts its inhibitory effect at the level of the Gs protein.
The Use of Flufenamate and Forskolin to Evaluate the Role of cAMP in Gonadotropin‐Releasing Hormone‐Stimulated Luteinizing Hormone Secretion from Pituitaries of Ovariectomized Rats
Authors: Das Saswati , Bourne Gregory A.
Published: March 2009

Abstract: Flufenamate which inhibited gonadotropin‐releasing hormone (GnRH)‐stimulated cAMP production in pituitaries from ovariectomized (72 hr) rats, was used to determine whether ovariectomy induces a change in the role of cAMP as a mediator of luteinizing hormone (LH) secretion. Additionally, the study evaluated the practicability of utilizing forskolin to restore intracellular cAMP concentrations in the presence of flufenamate. Infusions of flufenamate to perifused pituitary tissue blocks did not affect the protein synthesis‐independent component of GnRH‐stimulated LH secretion, but completely inhibited the protein synthesis‐dependent component. Dibutyryl cAMP (dbcAMP) and forskolin potentiated the GnRH‐stimulated responses, and restored the LH secretion inhibited by flufenamate, even though these agents were ineffective secretagogues when administered singly. The LH responses affected by forskolin were dependent on protein synthesis, while dbcAMP affected both the protein synthesis‐dependent and ‐independent components of GnRH‐stimulated LH secretion. Since the effects of dbcAMP on the protein synthesis‐independent component of LH secretion might be due to interactions with GnRH receptors, the results suggest that forskolin might be a better choice for restoring intracellular cAMP levels in the presence of flufenamate when assessing the role of cAMP in gonadotropes. The study also indicates that ovariectomy does not result in a change in the role of cAMP, which appears to be a pivotal, but indirect mediator of the protein synthesis‐dependent component of GnRH‐stimulated LH secretion.
Responses of Hepatic Xenobiotic Metabolizing Enzymes of Mouse, Rat and Guinea‐Pig to Nickel
Authors: Lşcan Mümtaz , Çoban Tülay , Eke Benay C.
Published: March 2009

Abstract:The effects of nickel (Ni) on hepatic monooxygenase activities (aniline 4‐hydroxylase, AH; ethylmorphine N‐demethylase. EMND; aminopyrine N‐demethylase, AMND), cytochrome P‐450, cytochrome b5, microsomal haem and reduced glutathione (GSH) levels, and glutathione S‐transferase (GST) activities toward several substrates (1, chloro‐2‐4‐dinitrobenzene, CDNB; 1,2 dichloro‐4‐nitrobenzene, DCNB; ethacrynic acid, EAA) in mice, rats and guinea‐pigs were studied. Ni (59.50 mg NiCl2· 6H2O/kg. subcutaneously) was administered to the animals 16 hr prior to sacrifice. Ni significantly inhibited AH, EMND, AMND activities, and decreased cytochrome P‐450, cytochrome b5(except in the livers of rats), and microsomal haem levels in the livers of all the animal species examined. However, the depressions were more profound in livers of mice than in those of the other two species. The hepatic GSH level was significantly inhibited in mice whereas no alteration was observed in rats. In guinea‐pigs, the hepatic GSH level was significantly increased by Ni. The hepatic GST activity toward the substrate CDNB was significantly depressed in mice, unaltered in rats and significantly increased in guinea‐pigs by Ni. The hepatic GST activity toward DCNB was significantly inhibited in mice whereas no significant alteration was observed in rats. In guinea‐pigs, Ni caused significant increase in hepatic GST activity for DCNB. However, hepatic GST activity toward EAA was significantly inhibited in mice whereas significantly increased in rats and guinea‐pigs. These results seem to indicate that i) there exists quantitative, but not qualitative, differences among the hepatic monooxygenases of rodents in response to Ni, mice being more sensitive than rats and guinea‐pigs, ii) the influence of Ni on hepatic GSH level varies depending on the animal species and iii) the hepatic GSTs of rodents are differentially regulated by Ni.
Production of Limbic Motor Seizures and Brain Damage by Systemic and Intracerebral Injections of Paraquat in Rats
Authors: Bagetta G. , Corasaniti M. T. , Iannone M. , Nisticò G. , Stephenson J. D.
Published: March 2009

Abstract:The behavioural and neuropathological effects of both systemic and intrahippocampal injections of paraquat dichloride (1,1′‐dimethyl 4,4‐bipyridinium dichloride) were studied in rats.Paraquat(0.1–1.0 μmol) injected into the dorsal hippocampus, produced limbic motor seizures within a few minutes of injection followed by neuronal damage in the CA1 and CA3 pyramidal cell layers, pyriform cortex, dentate granule cell layer and in the hilus fascia dentata at 24 hr (n = 9 rats). A smaller dose of paraquat (10 nmol) was ineffective. The effects of intrahippocampal injections of paraquat (1 μmol) were prevented by administering it together with atropine (50 nmol; n = 6 rats) or by giving it 60 min. after MK 801 (0.3 mg · kg‐1intraperitoneally). Systemic injections of paraquat (20‐100 mg · kg‐1) also produced forelimb clonus and rearing in 10 out of 15 animals. Neuronal cell death was found 24 hr later in 9 of these rats and was restricted to the pyriform cortex, the brain region with the highest concentrations of paraquat. Atropine (150 mg · kg‐1intraperitoneally given 60 min. previously) completely prevented the motor seizures but cell death still occurred in 2 of the 6 animals tested. In conclusion, both systemic and intrahippocampal injections of paraquat produced behavioural excitation accompanied 24 hr later by brain damage and antagonist studies suggested involvement of muscarinic and NMDA receptors in the neurotoxic mechanism.
Effect of Antioxidants on Hypoxia/Reoxygenation‐Induced Injury in Isolated Perfused Rat Liver
Authors: Younes M. , Kayser E. , Strubelt O.
Published: March 2009

Abstract:Isolated perfused livers from rats fasted overnight were subjected to 30 min. of hypoxia followed by reoxygenation for 60 min., resulting in marked cytotoxicity as evidenced by an enhanced release of cytosolic enzymes (lactate dehydrogen‐ase: 14‐fold over controls, glutamate‐pyruvate‐transaminase: 12‐fold over controls) and glutathione (twofold over controls) into the perfusate, by calcium accumulation (by a Factor of 1.4) in the tissue and by an 80% inhibition of bile secretion. Virtually no mitochondria1 injury became apparent and no evidence for lipid peroxidation could be found. In the presence of ascorbate, an augmentation of hepatic injury was observed. This might be due to the pro‐oxidant activity of ascorbate in the presence of ionized iron, which is easily released from high molecular weight stores under reductive (e.g. hypoxic) conditions. The water soluble vitamin E analogue trolox C as well as propyl gallate clearly protected the liver against hypoxiaireoxygenation injury, yielding further evidence for a causative role of oxidative stress in this model. Due to their water solubility and their high efficacy as free radical scavengers, these antioxidants might be of therapeutic value.
Exogenous GTP Increases Cyclic GMP and Inhibits Thrombin‐Induced Aggregation of Washed Human Platelets: Comparison with ATP, Adenosine and Guanosine
Authors: Vuorinen Paul , Laustiola Kai E.
Published: March 2009

Abstract:The effects of exogenous guanosine 5′‐triphosphate (GTP), guanosine, adenosine 5′‐triphosphate (ATP) and adenosine on platelet aggregation, serotonin secretion and cyclic nucleotide accumulation were studied using thrombin‐stimulated washed human platelets. GTP (10 μM‐1 mM) dose‐dependently inhibited thrombin‐induced aggregation and serotonin secretion. The inhibition of aggregation was accompanied by an increase in platelet cyclic GMP. GTP did not affect cyclic AMP concentration. Adenosine (1 μM‐1 mM) dose‐dependently inhibited thrombin‐induced aggregation and serotonin secretion, and increased cyclic AMP. ATP at high concentrations (100 μM‐1 mM) inhibited aggregation and serotonin secretion, and 1 mM ATP increased cyclic AMP. Guanosine was relatively ineffective in preventing aggregation and serotonin secretion and did not affect cyclic GMP. The rank order of inhibition of thrombin‐induced aggregation of washed human platelets was adenosine > GTP > ATP > guanosine. In conclusion, exogenous GTP inhibits thrombin‐induced aggregation and serotonin secretion of washed human platelets by increasing cyclic GMP. The results raise the possibility of a cell membrane site of action for GTP in platelets which mediates the activation of soluble guanylate cyclase suggesting that GTP may have a local antithrombotic effect alsoin vivo.
Lack of Effect of Certain Histamine H2‐Receptor Blockers on the Glucuronidation of 7‐Hydroxy‐4‐methylcoumarin by Human Liver Microsomes
Authors: Irshaid Yacoub , Abu‐Khalaf Mahmood
Published: March 2009

Abstract:Contrary to the general belief that cimetidine and ranitidine spare glucuronidation of drugs, some authors have indicated that both cimetidine and ranitidine could inhibit the glucuronidation of paracetamol (acetaminophen) by cultured rat hepatocytes. Thus, we tested the effect of three histamine H2‐receptor blockers (cimetidine, ranitidine and famotidine) on the glucuronidation of 7‐hydroxy‐4‐methylcoumarin (7‐OH‐4‐MC) by human liver microsomes. None of the drugs studied produced significant inhibition of the glucuronidation of 7‐OH‐4‐MC when used at concentrations up to 1.5 mM. Thus, even the new H2‐receptor blocker, famotidine, spares glucuronidation. These findings further support the previous reports which suggest that glucuronide conjugation in humans is spared by H2‐receptor blockers.
Lipid Peroxidation of Erythrocyte Membrane Induced by Lipoamide Dehydrogenase in the Presence of ADP‐Fe3+
Authors: Miura Toshiaki , Muraoka Sanae , Ogiso Taketo
Published: March 2009

Abstract: Lipid peroxidation of rat erythrocyte membranes was induced by lipoamide dehydrogenase (LADH) (EC 1.8.1.4) in the presence of ADP‐Fe3+. Superoxide dismutase (SOD) (EC 1.15.1.1) strongly inhibited the peroxidation reaction but catalase did not. Hydroxyl radical scavengers, mannitol and dimethylsulfoxide did not inhibit the lipid peroxidation. These results indicated that the lipid peroxidation was a superoxide (O2‐)‐dependent reaction, but the hydroxyl radical was not involved. ADP‐Fe3+, in the presence of LADH, was reduced more rapidly under aerobic than anaerobic conditions and SOD under aerobic conditions strongly inhibited the iron reduction, indicating that O2‐ plays a predominant role in iron reduction. Hydrogen peroxide enhanced of generation by LADH, but the peroxidation reaction was not affected. In the presence of lipoamide, lipid peroxidation was also induced but the reactions were not inhibited by SOD. Evidently, the lipid peroxidation induced in the presence of lipoamide was O2‐ ‐independent. Dihydrolipoamide may be involved in the peroxidation reaction.