bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Chloroquine on Some Carbohydrate Metabolic Pathways: Contents of GHS, Ascorbate and Lipid Peroxidation in the Rat
Authors: Abdel‐Gayoum A. A. , Haider S. S. , Tash F. M. , Ghawarsha K.
Published: March 2009

Abstract: Adult male rats were treated intraperitoneally with chloroquine (5 mg/kg/day) for 9 days. A reduction in the fasting plasma glucose level by 17.6% and ascorbic acid by 45% were discernable. The treatment caused significant increase in liver lactate dehydrogenase and glucose‐6‐phosphate dehydrogenase activities and reduced the activity of succinate dehydrogenase enzyme. Chloroquine also caused significant reductions in the contents of reduced glutathione and ascorbic acid in the brain and erythrocytes with a significant increase in lipid peroxidation.
Mutagenicity of Crude Senna and Senna Glycosides in Salmonella typhimurium
Authors: Sandnes Dagny , Johansen Toril , Teien Gerd , Ulsaker Gunnar
Published: March 2009

Abstract: The mutagenicity of senna glycosides and extracts of senna folium and senna fructus was investigated in the Salmonella typhimurium reversion assay. Senna glycosides were inactive in all strains, except for a slight, but significant increase in mutant frequency in TA102 in the absence and presence of liver microsomes. Extracts of senna fructus and senna folium demonstrated weak activity in TA97a, TA100 and TA102 in the presence of liver microsomes, and in TA97a and TA102 in the absence of liver microsomes. A strong increase in mutant frequency (3‐ to 5‐fold above background frequency) was observed with all extracts in TA98 in the presence of liver microsomes. This activity increased further following enzymatic hydrolysis with hesperidinase of extracts of senna fructus from one source, and could be correlated to the release of the flavonol aglycones kaempferol and quercetin. The weak or lacking activity of anthraquinone aglycones in the tested strains of Salmonella typhimurium indicates that mutagenicity can not be attributed solely to the anthraquinone content of these plant materials. The chemical nature of other mutagenic components has not been elucidated.
Enhancement of Morphine‐Induced Analgesia and Attenuation of Morphine‐Induced Side‐Effects by Cocaine in Rats
Authors: Kauppila Timo , Mecke Ernst , Pertovaara Antti
Published: March 2009

Abstract:Effect of cocaine on morphine‐induced analgesia and the accompanying respiratory depression, bradycardia and hypolocomotion/sedation was studied in rats. Cardiovascular and respiratory effects were studied under pentobarbitone‐induced anaesthesia. Cocaine enhanced morphine‐induced analgesia in the formalin test, hot plate test and heatinduced tail withdrawal test in intact rats. However, in spinal rats a similar combination of cocaine with morphine did not produce increased latencies in the tail withdrawal test. Of the three analgesic tests used, the formalin test was the most sensitive to the enhancement, as well as to the effects of morphine or cocaine alone. Morphine at the dose of 6 mg/kg produced complete analgesia in the formalin test, significant hypolocomotion/sedation, significant bradycardia and significant decrease in the respiratory rate. At an equianalgesic dose (complete analgesia in the formalin test) of morphine (3 mg/kg)‐cocaine (5 mg/kg)‐combination no significant changes in heart rate, respiratory rate or locomotion(/alertness) were observed. Changes in skin blood flow determined by the laser Doppler flow method were not significant in any of the experimental conditions. The results indicate that cocaine enhances morphine‐induced analgesia, mainly due to supraspinal mechanisms. In contrast, the morphine‐induced bradypnoea, bradycardia and hypolocomotion/sedation are attenuated by cocaine.
Breathing Zone Concentrations of Methylmethacrylate Monomer During Joint Replacement Operations
Authors: Darre Erik , Jergensen Lasse Garde , Vedel Peter , Jensen Jørgen Steen
Published: March 2009

Abstract: By use of a methylmethacrylate (MMA) Dräger tube and bellow bump, the breathing zone concentrations of MMA monomer were measured for the operating surgeon during cementation of the components of hip and knee joint prostheses. The highest recordings (50–100 p.p.m.) were encountered during cementation of the acetabular cups with conventional polymethylmethacrylate cement. Such exposure could be eliminated by the use of personal protection equipment, local punctual field suction or change to a MMA/n‐decylmethacrylate/isobornylmethacrylate bone cement.
Relationship between Histamine, Lipoxygenase and Cyclooxygenase Products in Antigen‐Induced Contraction in Guinea‐Pig Tracheal Tube Preparations
Authors: Lindström E. G. , Grundstrom N. , Hammarström S. , Andersson R. G. G.
Published: March 2009

Abstract:We have used a tracheal tube preparation to study antigen‐induced contraction in sensitized guinea pig airways. Treatment with both the cyclooxygenase inhibitor indomethacin and the lipoxygenase inhibitor MK‐886 (L‐663,536) affected this contraction in preparations with intact epithelium. Indomethacin potentiated and MK‐886 inhibited part of the contraction. Leukotriene release from tracheal tubes was measured after antigen challenge, and was found to be significant in preparations with an intact epithelium. When the epithelium was removed, the histamine receptor antagonist mepyramine reduced antigen‐induced contraction by 90%. Our results show that when the epithelium is absent, histamine is the most important mediator in the contraction. With the epithelium left intact, the contraction is more complex: both the cyclooxygenase and lipoxygenase pathways are involved, and our Findings indicate that eicosanoid production is associated with the airway epithelium.
Frequency‐ and Potential‐Dependency of the Negative Inotropic Action of Various Dihydropyridine and Non‐Dihydropyridine Calcium Antagonists
Authors: Herzig Stefan , Lüllmann Heinz , Sieg Hartmut
Published: March 2009

Abstract:Transmembrane voltage and beat frequency are important determinants of the action of several organic calcium antagonists. This is well‐known for the cationic amphiphilic calcium antagonists. We intended to assess the functional impact of these phenomena in cardiac muscle with special regard to dihydropyridines. Therefore, concentration‐response curves were constructed in isolated guinea‐pig left atria for the negative inotropic effect of various compounds. The dihydropyridines nifedipine, racemic nitrendipine, nisoldipine, and felodipine, and the enantiomers of isradipine were investigated at different stimulation frequencies (1 Hz, 2.5 Hz, 4.5 Hz), and at different extracellular K+concentrations (2.7 mM, 5.4 mM, 10.8 mM). These drugs were compared with the cationic amphiphilic compounds gallopamil, verapamil and diltiazem. The potency of some dihydropyridines, particularly nitrendipine, could be modulated to a remarkable extent, covering several orders of magnitude. The potential‐dependency of the drugs depended on stimulus frequency and ranged from less than a half to two orders of magnitude. At 2.5 Hz, the rank order of extent of potential‐dependency was gallopamil > nitrendipine > diltiazem > verapamil = (+)‐isradipine > (‐)‐isradipine ≥ nisoldipine ≥ felodipine = nifedipine. Based on data obtained from binding studies in intact atria and from patch‐clamp measurements of calcium current blockade, a mathematical model was used which describes the observed potency changes. The model was based on the assumptions that 1) binding takes place at a site with a time‐varying affinity, and that 2) alteration of experimental condition (frequency, membrane potential) changes the proportion of time the calcium channels display the high‐affinity or the low‐affinity state.
Experimental Evaluation of the Effects of Pravastatin on Electrophysiological Parameters of Rat Skeletal Muscle
Authors: Pierno Sabata , Luca Annamaria De , Tricarico Domenico , Ferrannini Ermanno , Conte Tommaso , D'Alò Gioacchino , Camerino Diana Conte
Published: March 2009

Abstract:The effects of daily chronic treatment for 6 months with pravastatin was evaluated on the performance of the skeletal muscle system of different rat groups. At all doses (0.1 mg/kg‐20 mg/kg) the righting reflex and the electromyographic signals observedin vivodid not show any abnormality. At the end of the treatment the Extensor digitorum longus muscles were dissected from treated and control rats and their passive and active electrical parameters were analyzedin vitroby standard microelectrodes technique. Pravastatin did not modify the chloride conductance nor the excitability characteristics of the fibers. Chronic treatment with pravastatin does not produce any alteration of skeletal muscle function.
Bioactivation of Halogenated Hydrocarbons by Rabbit Pulmonary Cells*
Authors: Nichols William K. , Covington Mark O. , Seiders Christopher D. , Safiullah Shaheen , Yost Garold S.
Published: March 2009

Abstract:I,1‐Dichloro‐2,2‐bis (4′‐chlororphenyl)ethane (DDD), 1,2‐dibromoethane (DBE) and trichloroethylene are three halogenated hydrocarbons that selectively bind to pulmonary epithelial cells and that may be pneumotoxic. The susceptibility of pulmonary cells and the mechanisms of cytotoxicity of these compounds were evaluated using enriched subpopulations of isolated rabbit lung cells incubated with DDD, DBE, and trichloroethylene. These chlorinated and brominated hydrocarbons were studied to evaluate their ability to induce selective pneumotoxicity by their bioactivation in three cell types, i.e. Clara cells, alveolar type II cells, and alveolar macrophages. Evidence of cytochrome P‐450 bioactivation was assessed by utilizing the suicide inhibitor, 1‐aminobenzotriazole (ABT) to ameliorate cytotoxicity. DDD, DBE and trichloroethylene were cytotoxic to Clara cells, type II cells and alveolar macrophages and the order of cell susceptibility to DDD was Clara > type II > macrophages. DBE and trichloroethylene were nonselectivey cytotoxic. ABT reduced the cytotoxic effects of DDD and DBE in Clara cells. These studies indicated that all three compounds were toxic to isolated lung cells and that bioactivation of DDD and DBE in rabbit Clara cells to a cytotoxic intermediate was mediated, at least in part, by cytochrome P‐450 oxidation.
Pharmacokinetics of the Oxime HI‐6 from a Mixture with Atropine Sulphate in Dogs
Authors: Jovanović Dušan , Kovačević Veljko , Maksimović Matej
Published: March 2009

Abstract: The pharmacokinetics of the oxime HI‐6 from an aqueous solution and from a mixture containing HI‐6 and atropine (in doses similar as proposed for their combination in an automatic injector) was studied in German shepherd dogs. A standard manual injection of mixed drugs was followed by enhanced resorption of HI‐6 while the elimination curves were quite similar. A comparison of the parameters describing relative bioavailability at the 80% probability level did not reveal any significant differences between the formulations of HI‐6. The increase in HI‐6 level in blood of animals receiving a mixture is more likely to be attributed to the local vasodilatation than to the systemic cardiovascular effects of atropine.
Effects of Toluene and n‐Hexane on Rat Synaptosomal Membrane Fluidity and Integral Enzyme Activities
Authors: Engelke Maria , Diehl Horst , Tähti Hanna
Published: March 2009

Abstract: The effects of toluene and n‐hexane on rat synaptosomal membrane fluidity and the integral enzymes acetylcholinesterase (AChE) and ATPase were studied in vitro. The synaptosome membranes were isolated in Percoll and sucrose gradients. After adding toluene and n‐hexane to the incubation mixture (37°) in 2,4,6 and 8 mM concentrations, the fluidity changes were measured by the lateral pyrene diffusion method from Percoll‐isolated membranes, and the ATPase and acetylcholinesterase activities were determined from both synaptosome isolations. Addition of toluene caused a linearly correlated increase of the synaptosomal membrane fluidity and a linear decrease of the AChE activity. The ATPase activity did not decrease linearly but dose‐dependently. In contrast to the effects of toluene in vitro, addition of n‐hexane in the same concentration range had no comparable influence on membrane fluidity nor on the activities of both integral enzymes despite its even higher lipid/water partition coefficient. Toluene increases synaptosomal membrane fluidity and at the same time inhibits the integral enzymes, probably by disturbing the lipid/protein interaction.
Morphine and the Endogenous Opioid Dynorphin in the Brain Attenuate Digoxin‐Induced Arrhythmias in Guinea Pigs
Authors: Rabkin Simon W.
Published: March 2009

Abstract:The effects of the opioid receptor agonists morphine and dynorphin on digoxin‐induced arrhythmias were examined in guinea pigs that had received intravenous digoxin (50 μ/kg bolus plus 500 μ/kg/hr intravenously). Animals received either morphine (50 or 100 μg/kg) or dynorphin A(1‐13) (50 or 100 μg/kg) or saline (the diluent) into the lateral cerebral ventricle (intracerebroventricularly) prior to digoxin. Morphine and dynorphin produced significant (P <0.05) dose‐dependent increases in the threshold of digoxin‐induced arrhythmias. The mean digoxin dose at the development of fatal arrhythmias was 775 ± 42 μg/kg in the control group but was significantly higher namely 958 ± 45 μg/kg after 100 μg/kg of morphine ICV, and 984 ± 47 μg/kg after 100 μg/kg of dynorphin A (1‐13) intracerebroventricularly. In the absence of digoxin, the highest doses of each of these opioids did not produce arrhythmias. Changes in blood pressure and heart rate were unlikely explanations for the observed actions of these opioids as morphine accentuated the increase in blood pressure that accompanied digoxin while dynorphin was associated with a lower blood pressure with digoxin, despite similar effects on arrhythmias. In the control group, fatal digoxin‐induced arrhythmias were ventricular tachyarrhythmias in two‐thirds of cases and complete heart block in the rest. Morphine and dynorphin reduced the development of ventricular tachyarrhythmias. The role of the cholinergic system was explored, with morphine, utilizing atropine sulfate which crosses the blood brain barrier and atropine methylnitrate which does not enter the CNS. Atropine sulfate but not atropine methylnitrate reversed the effects of morphine on digoxin‐induced arrhythmias. These data indicate that opioids in the brain alter the threshold for the development of digoxin‐induced arrhythmias, and central cholinergic mechanisms are involved in the action of morphine on cardiac arrhythmias.
Different Regiospecificity in the Hydroxylation of the Antidepressant Desmethylimipramine Between Rat Brain and Liver
Authors: Hansson T. , von Bahr C. , Marklund M. , Svensson J.‐O. , Ingelman‐Sundberg M. , Lundström J.
Published: March 2009

Abstract:Incubation of the tricyclic antidepressant desmethylimpramine (DMI) with rat liver or brain microsomes in the presence of NADPH or t‐butyl‐hydroperoxide (TBH) revealed different regiospecificities in the hydroxylation reactions between the tissues. In brain preparations 10‐OH‐DMI was formed in reactions supported by NADPH or TBH, whereas in the latter case also an unidentified metabolite could be detected. Inclusion of exogenous NADPH‐cytochrome P450 reductase in the brain preparations caused a 10‐fold higher rate of 10‐hydroxylation but no 2‐OH‐DMI could be detected. By contrast, liver microsomal preparations in the presence of NADPH catalyzed formation of both 2‐ and 10‐OH‐DMI, whereas only 10‐OH‐DMI was formed in TBH‐supported reactions. The results indicate that antidepressant drugs can be metabolized in brain with different stereospecificity as compared to liver.
Enrichment of Metabolites in the Cerebrospinal Fluid of Cod (Gadus morhua) Following Oral Administration of Hexachlorobenzene and 2,4′,5‐Trichlorobiphenyl
Authors: Ingebrigtsen K. , Hektoen H. , Andersson T. , Wehler E. Klasson , Bergman Å. , Brandt I.
Published: March 2009

Abstract:The disposition of14C‐labelled hexachlorobenzene (HCB) and 2,4′,5‐trichlorobiphenyl (triCB) was studied in cod (Gadus morhua) and rainbow trout (Oncorhynchus mykiss). For both compounds tape section autoradiography revealed substantial amounts of radiolabeled material in the central nervous system (CNS) of cod, whereas only traces of radioactivity were observed in the CNS of rainbow trout. Furthermore, an enrichment of radiolabeled compound in the cerebrospinal fluid (CSF) was observed in the cod, whereas no radioactivity could be detected in the CSF of rainbow trout. According to autoradiography, the CNS of cod dosed with HCB contained the parent compound, whereas the major part of radioactivity in CSF was due to HCB metabolites. Thin‐layer chromatography of extracts from cod dosed with triCB showed the presence of parent compound in the CNS, whereas part of the radioactivity in the CSF was due to triCB metabolites. The activities of cytochrome P‐450 and UDP‐glucuronosyltransferase in the CNS of cod and rainbow trout were determined in microsomal and mitochondrial fractions. Both species expressed activities which were in the same order of magnitude as those reported for the corresponding fractions from rat brain. Incubation of triCB with cod brain mitochondria and microsomes resulted in the formation of two polar metabolites. It is suggested that cod may be more vulnerable than raindow trout regarding neurotoxicological effects of HCB, triCB and related environmental pollutants.
Calcium Entry Blockade as a Mechanism for Chlordimeform‐Induced Inhibition of Motor Activity in the Isolated Guinea‐Pig Ileum
Authors: Candura Stefano M. , Marraccini Paolo , Costa Lucio G. , Manzo Luigi , Rossi Anna , Coccini Teresa , Tonini Marcello
Published: March 2009

Abstract:Central and peripheral α2‐adrenoceptors, including those of the gastrointestinal tract, have been indicated as a toxicity target of formamidine pesticides in mammals. In this study, the inhibitory effect of chlordimeform on twitch contractions from electrically‐stimulated longitudinal muscle‐myenteric plexus preparations (LMMPs) of the guinea‐pig ileum was found to be resistant to the action of the α2‐adrenoceptor antagonist idazoxan. This drug was also ineffective on chlordimeform‐induced inhibition of peristalsis recorded in whole ileal segments. As expected, idazoxan antagonized the inhibitory effect of the α2‐adrenoceptor agonist clonidine on twitch contractions and peristaltic activity. Chlordimeform reduced the amplitude of direct mechanical responses to a variety of spasmogens such as acetylcholine, histamine and substance P, suggesting a muscular site of action. Moreover, in Ca2+‐free, K+‐depolarized LMMPs, chlordimeform inhibited submaximal contractions caused by addition of exogenous calcium, through an action apparently similar to that of the Ca2+entry blocker nifedipine. Both chlordimeform‐ and nifedipine‐induced inhibition of calcium contractions were reversed by the calcium channel activator BAY K 8644. This compound also partially prevented the inhibitory action of chlordimeform on peristaltic activity. On the whole, these results indicate that chlordimeform‐induced depression of motor activity in the guinea‐pig ileum is, at least in part, related to inhibition of transmembrane Ca2+fluxes responsible for smooth muscle contraction.
Evidence of Active Transport of Cadmium Complexing Dithiocarbamates into Renal and Hepatic Cells in Vivo
Authors: Gale Glen R. , Smith Alayne B. , Jones Mark M. , Singh Pramod K.
Published: March 2009

Abstract: A study was made of the effects of certain inhibitors of transport systems on the actions of four cadmium (Cd) complexing N,N‐disubstituted dithiocarbamates (DTCs) in mobilizing murine renal and hepatic Cd in vivo. Probenecid, the prototypical antagonist of organic anion transport in the kidney, when given 1 hr prior to each DTC, sharply suppressed the DTC‐induced reduction of renal Cd but was virtually without effect on mobilization of Cd from liver. Sulfinpyrazone, which blocks tubular reabsorption of uric acid and also inhibits transport of a variety of organic acids, inhibited markedly the mobilization of both renal and hepatic Cd by DTCs. Phlorizin, an inhibitor of tubular sugar reabsorption, did not affect the Cd mobilizing actions of DTCs in any consistent fashion. We propose that the high degree of selectivity of DTCs in mobilizing renal and hepatic Cd is dependent, at least in part, upon active transport of DTCs into these tissues via the organic anion transport systems. This report presents the first evidence that compounds of the (R)2NCSS class may gain access to intracellular space by an active, carrier‐mediated process.
Could the Pharmacological Differences Observed Between Angiotensin II Antagonists and Inhibitors of Angiotensin Converting Enzyme be Clinically Beneficial?
Authors: Levens Nigel R. , de Gasparo Marc , Wood Jeanette M. , Bottari Serge P.
Published: March 2009

Abstract:Over the past several years, angiotensin I converting enzyme (ACE) inhibitors, compounds that block the formation of angiotensin II (ANG II), have become widely used in the treatment of cardiovascular disease. Recently, a new class of orally active, non‐peptide inhibitors of the renin‐angiotensin system, the ANG II receptor antagonists have also become available. Since both classes of compounds block the renin‐angiotensin system, although at different sites, it remains to be determined whether blockade of ANG II receptors will have any specific advantage over inhibition of ACE. The following review assesses the actions of ANG II antagonists and suggests ways in which blockade of ANG II receptors may differ both pharmacologically and clinically from inhibition of ACE.
β‐Adrenergic Responsiveness of the Gastrointestinal Tract in Diabetic Rats
Authors: Öztürk Yusuf , Altan V. Melih , Yildizoǧlu‐Ari Nuray
Published: March 2009

Abstract:Recently, decreased gastrointestinal β‐adrenergic responses in experimental diabetes have been demonstrated. Gastrointestinal responses to β‐adrenoceptor agonists are impaired in both insulin‐dependent and non‐insulin‐dependent diabetic rat. Insulin treatment improves the impaired gastrointestinal β‐adrenergic responsiveness of diabetic rats. The improvement seen with insulin treatment on β‐adrenergic responsiveness is closely related to protein biosynthesis. The decreased β‐adrenergic responses in diabetic rat gastrointestinal tract seem to result from a decrease in the number of β‐adrenoceptors. It is most likely that the decreased gastrointestinal β‐adrenergic responsiveness is related to an impairment in the turnover of β‐adrenoceptors as a consequence of diabetes and that insulin has a beneficial effect on the impaired receptor turnover.
Effects of Endosulfan and Aldrin on Muscle Coordination and Conditioned Avoidance Response in Rats
Authors: Paul Vanaja , Balasubramaniam E. , Sheela S. , Krishnamoorthy M. S.
Published: March 2009

Abstract:The deteriorative effects after chronic endosulfan exposure on muscle coordination, learning and memory of rats were compared with that produced by aldrin which has been reported to have similar effects in experimental animals. A rota‐rod apparatus was used to study the muscle coordination and learning and memory were tested by recording the response to unconditioned and conditioned stimuli using a pole‐climbing apparatus. Aldrin but not endosulfan inhibited motor coordination in both sexes. A greater motor deterioration occurred in male group. This finding, together with the previous data which shows inhibition by its metabolite of motor activity, suggests that its metabolic product is responsible for this action. Like aldrin, endosulfan inhibited both learning ability and conditioned avoidance response. A change in the activities of brain monoamines or inhibition of perception and reflexes or both were proposed for these behavioural effects, since the former was reported to be produced by both compounds and the latter was found to occur in aldrin treated rats.
Absence of CYP3 A Genetic Polymorphism Assessed by Urinary Excretion of 6 β‐Hydroxycortisol in 102 Healthy Subjects on Rifampicin
Authors: Horsmans Y. , Desager J. P. , Harvengt C.
Published: March 2009

Abstract:A previous study has demonstrated that the urinary level of 6 β‐hydroxycortisol is a marker of liver CYP3A content after induction by rifampicin. To put in evidence an eventual genetic polymorphism for this cytochrome, the frequency distribution of 6 β‐hydroxycortisol excretion was investigated in 102 healthy Caucasians before and after 6 days of oral rifampicin administration (600 mg daily). After rifampicin treatment, a wide interindividual distribution was observed but no clear bimodality. Moreover the mean 6 β‐hydroxycortisol level was higher in women (n = 38) than in men (n = 64). These observations do not favour the existence of a CYP3A genetic polymorphism based on 6 β‐hydroxycortisol excretion but evoke a sexual dimorphism. However, CYP3A is composed of at least four enzymes and as the enzyme(s) responsible for Cortisol 6 β‐hydroxylation is (are) not perfectly known, it can not be excluded that a genetic polymorphism does exist for one enzyme of this family.
Extrahepatic Disposition of 3H‐Aflatoxin B1 in the Rainbow Trout (Oncorhynchus mykiss)
Authors: Larsson Pia , Ngethe Steven , Ingebrigtsen Kristian , Tjälve Hans
Published: March 2009

Abstract: Whole‐body autoradiography in rainbow trout (Oncorhynchus mykiss) after oral and intravenous administration of 3H‐labelled anatoxin B1 showed labelling of several extrahepatic tissues, such as the uveal melanin and the vitreous humour of the eyes, the trunk and head kidney, the olfactory rosettes and the pyloric caecae. Liquid chromatography of extracts of the vitreous humour showed that unmetabolized 3H‐AFB1 was the main labelled material present at this site. Liquid chromatography of extracts of the uveal melanin showed presence of aflatoxicol and aflatoxin B1 in proportions of about 3:1. The binding to the pigment is probably due to a hydrophobic type of interaction with the melanin. Microautoradiography showed that melanin‐containing cells in the trunk and head kidney and in the olfactory rosettes also accumulated high amounts of radioactivity. In the trunk kidney there was, in addition, a labelling of the second segment of the proximal tubules and of the distal tubules and the collecting ducts. Studies in vitro with microsomal and 12,000 x g supernatant preparations of the trunk kidney showed formation of DNA‐ and protein‐bound metabolites from the aflatoxin B1. It is probable that the bioactivation of the aflatoxin B1 is confined to the second segment of the proximal tubules. The labelling of the distal tubules and the collecting ducts, which was confined to the cytoplasm of the cells, may be related to excretion and/or absorption processes. Microautoradiography of the olfactory rosettes, showed labelling of the sensory epithelium, but not the indifferent epithelium. A low formation of protein‐bound aflatoxin B1‐metabolites was found in incubations with microsomal preparations of this tissue. The same observation was made in incubations with microsomal preparations of the head kidney. In the pyloric caeca bound metabolites were observed in vivo at a level comparable to that found in the trunk kidney. Our results suggest that retention and metabolism in some extrahepatic tissues might be of importance as concerns the toxicologic potential of aflatoxin B1 in the rainbow trout.
Studies on the Interaction between Formoterol and Salmeterol in Guinea‐Pig Tracheain Vitro
Authors: Jeppsson A.‐B. , Källström B.‐L. , Waldeck B.
Published: March 2009

Abstract:The actions of and interaction between formoterol and salmeterol were studied on guinea‐pig tracheain vitro.Tracheal strip preparations were contracted by 1 μmol/1 carbachol giving a near maximal contraction. Salmeterol in concentrations from 0.1 to 3 μmol/1 relaxed the tracheal smooth muscle by about 30 per cent of the maximum relaxation produced by theophylline. Formoterol caused a concentration‐dependent and almost complete relaxation with a pD2of 8.56. In the presence of salmeterol there was a rightward shift of the concentration‐response curve for formoterol. The pA2for salmeterol was estimated to 7.42. Similar experiments with isoprenaline indicated that salmeterol has a low affinity for β1‐adrenoceptors. Formoterol and salmeterol both inhibited in a concentration‐dependent manner the contractions evoked by stimulation of the vagus nerve in a tracheal tube preparation. The degree of inhibition decreased with increasing stimulation frequency. Complete inhibition was attained with salmeterol, but not with formoterol, at the highest frequency employed (45 Hz). The inhibiting effect of 10 μmol/1 salmeterol was not blocked by 10 μmol/1 sotalol, a β‐adrenoceptor antagonist. It is concluded that salmeterol, in comparison to formoterol, is a partial pradrenoceptor agonist and has, at high concentrations, an additional unspecific inhibitory action.
Aluminium Interferes with Signal Transduction in Neuroblastoma Cells
Authors: Shi Biao , Haug Alfred
Published: March 2009

Abstract: The effects of aluminium on inositol phosphate formation were examined in murine neuroblastoma cells labelled with [3H]‐myo‐inositol. In aluminium‐pretreated cells, the bradykinin‐triggered inositol triphosphate, IP3, release and the change in intracellular [Ca2+] were appreciably less compared with the control group. Stimulating digitonin‐permeabilized cells with non‐hydrolyzable guanosine 5′‐[gamma‐thio]‐triphosphate, GTP[S], inositol phosphate formation decreased in the presence of aluminium. A primary target of aluminium toxicity may reside on the guanine nucleotide‐binding protein(Gp)/phospholipase C system, at a site different from that of the GTP[S] binding site.
α‐ and β‐Adrenoceptors in Hypertension: Molecular Biology and Pharmacological Studies
Authors: Michel Martin C. , Philipp Thomas , Brodde Otto‐Erich
Published: March 2009

Abstract:Recent years have witnessed astonishing progress in our understanding of the molecular basis of adrenoceptor structure, function and regulation and revealed an unexpected heterogeneity of adrenoceptors demonstrating the existence of at least 11 subtypes. This paper discusses the implications of these advances on studies regarding a specific role of adrenoceptors in the development of genetic hypertension. The available data indicate that among the α‐adrenoceptor subtypes the α2A‐adrenoceptor is the most likely candidate for an alteration specifically linked to genetic hypertension in the animal model of the spontaneously hypertensive rat and possibly in some patients. Alterations of other α‐adrenoceptor subtypes may be specific for some forms of genetic hypertension but are unlikely to play an important role for blood pressure regulation. Most β‐adrenoceptor alterations appear to occur secondary to blood pressure elevation independently of whether hypertension has occured on a genetic basis or not. Moreover, the mechanisms regulating α‐ and β‐adrenoceptor responsiveness upon prolonged agonist exposure may be altered in hypertension and thereby contribute to the pathophysiology of this disease.
Serotonergic Receptors and Drugs in Hypertension
Authors: van Zwieten P. A. , Blauw G. J. , van Brummelen P.
Published: March 2009

Abstract:The possible role of 5‐hydroxytryptamine (5HT) and 5HT‐receptors in hypertension, already suggested by Page in 1954, has been subject to a renaissance of interest owing to the development of antihypertensive drugs which interact with 5HT‐receptors. These drugs, like ketanserin, urapidil and flesinoxan are used as tools to study the role of 5HT and its receptors in hypertension. Some arguments would plead in favour of a certain role of 5HT and 5HT‐receptors in the pathogenesis and maintenance of hypertension: hyperresponsiveness of blood vessels from hypertensive patients and animals to 5HT‐induced constriction; the antihypertensive/vasodilator activity of the 5HT2‐receptor antagonist ketanserin; enhanced sensitivity of platelets from hypertensives to 5HT. However, there are also several arguments which do not support a causal role of 5HT in hypertensive disease: 5HT is not a generally accepted pressor agent, whereas its concentration in the circulating blood is subthreshold; the 5HT2‐receptor antagonist ketanserin is the only agent of this type which lowers blood pressure, other 5HT2‐receptor blockers (ritanserin; LY 53587) being inactive. The various data and arguments available do not unequivocally support a relevant role of peripheral 5HT and its receptors in hypertensive disease. 5HT2‐receptor blockade may, however, have a favourable effect on the microcirculation under pathological conditions. The stimulation of central 5HT1A‐receptors by drugs like urapidil, 8‐OH‐DPAT or flesinoxan, has been demonstrated to induce peripheral sympathoinhibition and a fall in blood pressure. This mechanism appears to be a novel target for centrally acting antihypertensives, clearly different from that of clonidine and related drugs, which are centrally acting α2‐adrenoceptor agonists.
GTP‐Binding Proteins and Post‐Receptor Components in Hypertension
Authors: Insel Paul A.
Published: March 2009

Abstract:Alterations in neurohormonal response are a widely‐observed feature in various forms of hypertension. Such responses depend not only on levels of hormones/neurotransmitters, but also on receptors and post‐receptor components. With respect to G protein‐coupled receptors, such as those for catecholamines, angiotensin II, and bradykinin, it is possible that G‐proteins or G protein‐coupled effector molecules are altered in hypertension. In this article, several classes of Gαproteins and effectors which link to these proteins are briefly discussed. Evidence is presented in support of the concept that signal amplification in G protein‐coupled receptor systems occurs at the level of receptor activation of the G proteins. Limited data are as yet available that directly assess whether changes in the amount or properties of particular Gαproteins or G‐protein‐linked effectors, are altered in hypertension. The availability of antibody, cDNA and other genetic probes should prove highly useful in testing the hypothesis that such alterations are important for the pathogenesis and maintenance of the hypertensive state.
ß‐ADRENOCEPTORS IN BRAIN AND PINEAL FROM DEPRESSED SUICIDE VICTIMS.
Authors: De Paermentier F. , Crompton M.R. , Katona C.L.E. , Horton R.W.
Published: March 2009

ß‐Adrenoceptors were measured by saturation binding of [3H]CGP 12177 in nine brain regions and pineal from suicides, with a firm retrospective diagnosis of depression, and age and sex matched controls. Twenty one suicides had not recently received antidepressant drugs, 17 had been receiving drugs prior to death. In antidepressant drug‐free suicides, the number of total ß‐adrenoceptors was significant lower in temporal cortex (Brodmann area 38) and ß1‐adrenoceptors (Brodmann areas 21/22) was significant lower than matched controls. Suicides who died by violent means had significantly lower numbers of total ß‐ and ß1‐adrenoceptors in the frontal cortex and lower numbers of ß1‐adrenoceptors in temporal cortex (Brodmann areas 21/22) than matched controls. Suicides who died by non‐violent means had lower numbers of total ß‐adrenoceptors in occipital cortex controls and lower numbers of total β‐ and β1‐adrenoceptors in temporal cortex (Brodmann area 38) than matched controls. In antidepressant drug‐treated suicides, significantly lower number of ß‐adrenoceptor binding sites were found in temporal cortex (Brodmann area 38) and thalamus compared to matched controls. The lower number of ß‐adrenoceptors binding sites in the thalamus appeared to be related to drug treatment. There were no differences in ß‐adrenoceptor binding in the pineal gland between antidepressant‐free and antidepressant‐treated suicides and controls, although there were apparent differences between suicides and controls related to the time of death and season of death.
LIGHT THERAPY OF DEPRESSION; BASAL AND CLINICAL ASPECTS
Authors: Wetterberg Lennart
Published: March 2009

The effects of treatment with bright light in different forms of depressive conditions are described. The therapeutic mode rests on the hypothesis that they will normalize disturbed diurnal rhythms. The results have been more favourable when light has been given in the morning compared with in the evening, and in patients with seasonal depression rather than in those with non‐seasonal illness.
Recirculating, Retrograde Heart Perfusion According to the Langendorff Method for Evaluation of MTG – Methyl‐2‐tetradecylglycidate, McNeil 3716 – Cardiomyopathy
Authors: Bachmann Elisabeth , Weber Elisabeth
Published: March 2009

Abstract: Recirculating, retrograde heart perfusion according to the Langendorff method was used in an attempt to further elucidate the cardiotoxicity of methyl‐2‐tetradecylglycidate (McNeil 3716, MTG) and the excentric hypertrophy elicited by the compound. In subchronic experiments female rats were exposed to MTG 2 × 10 mg/kg and 2 × 25 mg/kg per day for 4 weeks. At various times hearts were perfused ex vivo for up to 2 hr with either 5 mmolar glucose or 0.5 mmolar palmitate as substrate. Substrate uptake (glucose or palmitate) and enzyme release (LDH‐lactic dehydrogenase or CPK‐creatinphosphate kinase) were assessed during perfusion. Biochemical analysis (ATP, ADP, AMP, c‐AMP, CP, creatine, pyruvate, lactate, glucose‐6‐phosphate, glycogen, phospholipids, triglycerides and non‐esterified fatty acids) were done in hearts before (drug effect) and after perfusion (stress of perfusion). Besides changes in energy metabolism and high‐energy phosphate production, as observed in previous experiments (Bachmann et al. 1984) massive changes were seen in energy reserves in heart tissue (ATP, CP, glycogen, phospholipids and triglycerides). As expected, MTG led to significant increases also in non‐esterified fatty acids content in hearts.
Enhanced Endogenous Ornithine Concentrations Protect Against Tonic Seizures and Coma in Acute Ammonia Intoxication
Authors: Seiler Nikolaus , Sarhan Shakir , Knoedgen Bernd , Hornsperger Jean‐Marie , Sablone Marcelin
Published: March 2009

Abstract:Pretreatment of mice with 5‐fluoromethylornithine (SFMOrn), a selective inactivator of ornithine aminotransferase, diminishes the accumulation of ammonia in the brain after administration of ammonium acetate, and antagonizes ammonia‐induced fatal tonic extensor convulsions. In about 50% of the treated animals the loss of the righting reflex and coma is prevented. Presumably these effects are based on the enhancement of urea formation by the increased liver ornithine concentrations. However, since brain ornithine concentrations are greatly enhanced by SFMOrn, it is not excluded that ornithine has direct effects on cellular events involved in ammonia‐induced seizure generation, even though 5FMOrn had no anticonvulsant properties in a series of established animal seizure models, including N‐methyl‐D,L‐aspartate‐induced convulsions. NMDA receptor antagonists are capable of preventing death, but do not protect against the generation of coma and tonic extensor convulsions in ammonium acetate intoxicated mice. Since no evidence was found for ammonia‐induced glutamate release from rat hippocampus, there is no convincing evidence for the idea that the tonic convulsions are mediated by NMDA receptors. L‐Methionine‐D,L‐sulfoximine (MSO)‐induced seizures can be partially antagonized by pretreatment with 5FMOrn. However, the effect is considerably smaller than against ammonia‐induced convulsions, although at the time of seizure onset brain ammonia levels of MSO‐intoxicated mice were lower than in the animals receiving ammonium acetate. This suggests that MSO‐convulsions are not entirely due to the elevation of brain ammonia concentrations, even though MSO administration mimicks effects of ammonia on cortical inhibitory neuronal interactions. Based on its potency and duration of action, administration of SFMOrn recommends itself as a highly effective method to antagonize toxic effects of ammonia.
Toxicity of Vitamin D Analogues in Rats Fed Diets with Standard or Low Calcium Contents
Authors: Mortensen Jens Thing , Brinck Peter , Binderup Lise
Published: March 2009

Abstract: Sprague‐Dawley rats were fed either a standard diet with 0.9/0.7% Ca/P or a semisynthetic low‐calcium diet with 0.5/0.4% Ca/P and treated orally for 28 days with 1α‐hydroxycholecalciferon [lα(OH)D3], a synthetic analogue of the physiologically active form of vitamin D3, lα,25‐dihydroxycholecalciferol [1α,25(OH)2D3], at dose levels of 0.2 and 2.0 μg/kg/day. The high dose caused severe hypercalcaemia with retarded growth, nephrosis, and structural bone changes in rats fed the standard diet. The same dose caused only slight hypercalcaemia without growth retardation or bone changes, and only minimally affected the kidneys in rats fed the low‐calcium diet. Hypercalcaemia with less pronounced pathological changes was found in the standard diet low‐dose rats, whereas no hypercalcemia or pathological changes were found in the low‐calcium diet low‐dose group. The rats fed the low‐calcium diet tolerated 1α(OH)D3 at dose levels up to 10 times higher than rats on the standard diet. The use of diets low in calcium and low in phosphorus will thus allow the administration of higher dosages of vitamin D compounds without causing hypercalcaemia. This may permit a better evaluation of the pharmacologic and toxic effects not directly associated with the calcium‐regulating properties of vitamin D metabolites and analogues.
Human Sperm Motility is Affected by Plasticizers and Diesel Particle Extracts
Authors: Fredricsson Bengt , Möller Lennart , Pousette Åke , Westerholm Roger
Published: March 2009

Abstract: In order to test various drugs and possibly hazardous compounds on living cells in vitro a system with human spermatozoa was employed. A population of human spermatozoa was transferred into a defined medium by a swim‐up procedure or by separation on a Percoll® gradient. Such a population is rather homogenous with respect to motility characteristics and was found to be useful for this purpose. Different modes of response were recorded, indicating various effect mechanisms. Effects of various phthalates used as plastic softeners in the production of medical equipment, and extracts from diesel particulate material were recorded. All these compounds interfered with sperm motility in a dose‐response fashion. Immediate effects of phthalates were modest, but upon prolonged exposure effects became more evident. Sperm motility was more affected by diethylhexyl and dibutyl phthalates. Significant effects were noted for the different phthalates with regard both to percent motility and to some of the various qualities of motility, such as velocity, linearity and amplitude of the track. Thus, the pattern of response considering the motion variables was not the same with the different phthalates. With regard to the effects on sperm motion di‐n‐octyl phthalate seemed to be the least toxic, followed by dibutyl phthalate. The initial effects of diesel particulate extracts were moderate and mainly restricted to percent motile sperm but upon exposure for 18 hr the effects became more pronounced for all the movement variables.
Different Effects of the K+Channel Blockers 4‐Aminopyridine and Charybdotoxin on Sensory Nerves in Guinea‐pig Lung
Authors: Lou Ya‐Ping , Lundberg Jan M.
Published: March 2009

Abstract:In the isolated guinea‐pig bronchus, the potassium channel blocking agent 4‐aminopyridine (10‐4M) caused a contraction which was abolished by capsaicin tachyphylaxis, suggesting involvement of sensory neuropeptides. Charybdotoxin (10‐8, 5 × 10‐8M), which is a potent blocker of the high‐conductance Ca2+‐activated K+channel in smooth muscle, caused slowly developing and long lasting bronchoconstriction, which was resistant to capsaicin tachyphylaxis. Neither 4‐aminopyridine (10‐3, 10‐4M) nor charybdotoxin (10‐8, 5 × 10‐8M) had any significant effect on the bronchoconstriction induced by electrical field stimulation. Furthermore, charybdotoxin had no significant influence on the inhibitory effect of the α2‐adrenoceptor agonist SKF 35886 (5 × 10‐7M) on the bronchoconstriction induced by electrical field stimulation. In the isolated perfused guinea‐pig lung, 4‐aminopyridine (3 × 10‐5‐10‐3M) caused bronchoconstriction and enhanced both basal and (at 3 × 10‐5M) vagal nerve stimulation‐evoked calcitonin gene‐related peptide outflow from pulmonary sensory nerves. In conclusion, 4‐aminopyridine stimulated capsaicin‐sensitive sensory neurons and enhanced the sensory activation induced by vagal nerve stimulation in guinea‐pig lung. Charybdotoxin, on the other hand, caused bronchial contraction independently of capsaicin‐sensitive nerves.
Effects of Post‐Training Administration of (−)‐Baclofen and Chlordiazepoxide on Memory Retention in ICRC Swiss Mice: Interactions with GABAAand GABABReceptor Antagonists
Authors: Saha Nilanjan , Chugh Yati , Sankaranaryanan Alangudi , Sharma Pyare Lal
Published: March 2009

Abstract:The effects of post‐training administration of chlordiazepoxide and (−)‐badofen on memory retention was studied in ICRC Swiss mice by measuring the retest stepdown latency 24 hr after foot‐shock in a passive avoidance task. Chlordiazepoxide 20 mg/kg impaired memory retention and a similar effect was produced by 10 mg/kg of diazepam. The effect of chlordiazepoxide was antagonised when combined with picrotoxin but not by the addition of a specific GABABantagonist CGP 35348. The effect of chlordiazepoxide on memory retention seems to be mediated by action at the GABAA‐benzodiazepine receptor complex. (−) Baclofen, the active isomer of the GABABagonist enhanced memory in ICRC mice and this effect was antagonised by CGP 35348 at a dose of 10 mg/kg. The inactive isomer of baclofen, (+)‐baclofen did not produce any effect. This indicates that GABABreceptors contribute to the effects of (−)‐baclofen on memory.
The cGMP Modulator, LY83583 Alters Oxygen Metabolites Differently in Cultured Endothelial Cells and Isolated Neutrophilic Granulocytes
Authors: Sundqvist T. , Axelsson K. L.
Published: March 2009

Abstract:The present study was designed to assess the effect of LY83583 on H2O2/O2‐production from endothelial cells and neturophils, as determined by chemiluminiscence generationin vitro. We found that LY83583 increased H2O2/O2‐production from endothelial cells, but inhibited the H2O2/O2‐production from phorbol myristate acetate‐stimulated neutrophils. Furthermore, LY83583 consumed NADPH under certain conditions. Since neutrophils generate superoxide anion radicals via an NADPH‐oxidase, we suggest that the reduction of chemiluminiscence, seen after addition of LY83583 to phorbol myristate acetate‐stimulated neutrophils, is due to increased consumption of NADPH. In endothelial cells, NADPH is required as a co‐factor in the generation of nitric oxide, which may interact with superoxide anion. A consumption in NAPDH would therefore be expected to decrease the production of nitric oxide and increase H2O2/O2‐generation. The consumption of NADPH in endothelial cells could also cause reduced scavenger functions of the glutathion system, resulting in a further increase in H2O2release.