bluuebunny/crossref_metadata_2025 huggingface dataset:
The Hypertensive Response to Soman and its Relation to Brain Acetylcholinesterase Inhibition
Authors: Brezenoff Henry E. , McGee John , Knight Valerie
Published: July 2010

Abstract:Intravenous injection of soman in the rat produced a rapid and dose related increase in blood pressure. The dose response curve was very steep, threshold responses occuring after intravenous injection of 10 μg/kg, and maximum increases of about 50 mmHg occuring after 40 μg/kg. Heart rate also generally increased. An increase in blood pressure also followed injection of soman subcutaneously, intramuscularly, intraperitoneally and into the cerebral ventricles, although the onset was slower and higher doses were required. The magnitude of the pressor response was correlated with the degree of AChE activity in the cortex, hypothalamus and brain stem, but not in the striatum. The pressor response was aborted or prevented by atropine, but not by methylatropine. It also was prevented by phenoxybenzamine. Atropine increased survival following an LD50 dose of soman; phenoxybenzamine prevented the pressor response but did not alter the survival rate.
Adenosine Analogues Stimulate Cyclic AMP‐Accumulation in Cultured Neuroblastoma and Glioma Cells
Authors: Elfman L. , Lindgren E. , Walum E. , Fredholm B. B.
Published: July 2010

Abstract:The effect of three stable adenosine analogues, L‐phenylisopropyl‐adenosine (L‐PIA), 2‐chloroadenosine, and adenosine 5′‐ethylcarboxamide (NECA), on cyclic AMP accumulation was studied in five different cell lines derived from the nervous system. In N18‐neuroblastoma cells, with cholinergic properties, all three analogues caused an increased accumulation of cyclic AMP with the following relative order of potency: NECA > 2‐chloroadenosine > L‐PIA. The half maximal effect of NECA was obtained at close to 10‐8M concentration. In the two other neuroblastoma cell lines, 41A3 with cholinergic and NIE115 with adrenergic properties, the two analogues NECA and PIA had similar effects. In glioma C6 and 138 MG cells NECA was also found to be more potent that PIA in elevating cyclic AMP levels. However, the absolute potency of NECA in these cell lines was almost 100 times lower. Phosphodiesterase (PDE) activity in crude homogenates of the five cell lines showed essentially similar Kmand Vmax, with the exception that the three neuroblastoma cell lines showed biphasic, the glial cell lines monophasic Eadie‐Hofstee plots. Theophylline was equally potent as an inhibitor of PDE in all cell lines, but the non‐xanthine, inhibitor rolipram, was more potent against neuroblastoma than glial cell PDE. These results indicate that all five cell lines have adenosine receptors of the A2‐subtype. However, the apparent affinity of the adenosine analogues to these receptors was markedly different between the neuroblastoma and glial cell lines. The absolute potency of adenosine analogues may be a poor criterion to classify adenosine receptors, into A1 and A2 subtypes, especially when intact cells are used.
Kinetics of White Spirit in Human Fat and Blood During Short‐term Experimental Exposure
Authors: Pedersen Lisbet Milling , Larsen Kjeld , Cohr Karl‐Heinz
Published: July 2010

Abstract: Seven volunteers were exposed to 100 p.p.m. white spirit (99% paraffins C8‐C12) 6 hrs daily in 5 days. The mean concentration of white spirit after 5 days of exposure was 41.1 mg/kg fat (Friday afternoon). On the following Monday morning, the concentration was 31.7 mg/kg, i.e. only 23% had been eliminated during the exposure‐free weekend. The estimated mean and median half‐life was 7 and 8 days, respectively, elimination rate constant 0.0039 and 0.0036 hrs1, time to reach steady state 5 to 8 weeks, maximal and minimal steady state concentration 85 and 66 mg/kg and 66 and 52 mg/kg, respectively. The concentration of white spirit in fat found each afternoon correlated significantly with the total dose. The concentration of white spirit/kg fat correlated positively with serum triglyceride and inversely with the percentage body fat (not significantly). The concentration of white spirit in the brain at steady state was estimated to maximum 11 mg/kg, while the half‐life in the brain was estimated to maximum 18–19 hours. Minor differences occurred in the spectrometrical pattern produced by the in vivo biopsy evaporate as compared to in vitro specimens and white spirit vapours per se, thus indicating that the white spirit was slightly biotransformed or that the approximately 200 constituents of white spirit were absorbed differently. Thus, during exposure at the threshold limit value level, white spirit is accumulated in depot fat over weekends and in brain over working days. However, white spirit is almost eliminated from the brain during weekends.
Biochemical Pattern in Experimental Exposure of Humans to White Spirit. I. The Effects of a 6 Hours Single Dose
Authors: Pedersen Lisbet Milling , Cohr Karl‐Heinz
Published: July 2010

Abstract: The effect of 6 hrs single exposure to white spirit on the concentration of S‐α‐amylase, S‐cholesterol, S‐triglyceride, S‐sodium, S‐potassium, S‐creatine kinase, S‐orosomucoid, S‐urate, and S‐glucose was analysed in 12 volunteers 6 and 48 hrs after start of exposure. After exposure to 0 p.p.m. and 100 p.p.m. of each of three white spirits containing 99% paraffins or 52% paraffins and 48% naphthenes, or 57% paraffins, 25% naphthenes and 18% aromatics, respectively, the only significant changes were a decrease in S‐α‐amylase concentration and S‐Potassium concentration by 9% (P < 0.05) 48 hrs after exposure to the white spirit high in naphthenes. This type also caused the highest blood concentration. In a subsequent study on exposure to 0, 50, 100, and 200 p.p.m. of the spirit high in naphthenes the only significant dose‐response relationsship was that the concentration of S‐α‐amylase decreased 7% (P<0.05) after 6 hrs, and S‐urate decreased 4% (P<0.05%) after 48 hrs as the doses increased. No changes in subjective symptoms were found. Thus, even at low levels, white spirit high in naphthenes appears to result in subtle biological effects prior to the appearance of symptoms of poisoning.
In Vivo Absorption of Theophylline and Salicylic Acid from Rat Small Intestine
Authors: Johansson Ö. , Lindberg T. , Melander A.
Published: July 2010

Abstract: In vivo absorption of theophylline and salicylic acid from the rat small intestine was studied by a closed segment technique. The drugs were administered at 1 and 4 mM in dissolved form, both in the presence and absence of phlorizin (0.01 mM). Drug concentrations were measured by high‐pressure liquid chromatography. Phlorizin inhibited the absorption of theophylline (pKa = 8.6) at 4 mM but not at 1 mM. In contrast, the absorption of salicylic acid (pKa = 3) both at I and 4 mM was unaffected by phlorizin. This suggests that an active transport system, sensitive to phlorizin, is involved in the rat intestinal absorption of theophylline, but not in that of salicylic acid. Apart from differences in drug structure, differences in the degree of ionization may influence the access of acidic drugs to this transport system.
Physical Dependence on Ethanol During Multiple Intoxication and Withdrawal Episodes in the Rat: Evidence of a Potentiation
Authors: Clemmesen Lars , Hemmingsen Ralf
Published: July 2010

Abstract:An animal model of repeated alcohol intoxication‐withdrawal episodes consisting in a 2‐day period of intoxication followed by 5 days abstinence in a 17 week period of study is presented. Gastric intubation was used. As a group the animals presented a statistically significant increase of convulsive withdrawal phenomena which during the 10th and 17th episode was comparable to the withdrawal reaction in abstinent 4‐day alcohol‐intoxicated animals. It is suggested that the present model may represent a paradigm for the study of effects of multiple ethanol withdrawal episodes.
The Postjunctional α‐Adrenoceptors of the Human Saphenous Vein
Authors: Steen Stig , Sjöberg Trygve , Skärby Tor , Norgren Lars , Andersson Karl‐Erik
Published: July 2010

Abstract:The postjunctional α‐adrenoceptors in human long saphenous vein were characterized using α‐adrenoceptor subtype selective agonists and antagonists. The order of potency for the α‐adrenoceptor agonists used was: Clonidine (α2) > BHT‐920 (α2) > naphazoline (α2) > guanfacine (α2) > cirazoline (α1) > phenylephrine (α1) > ST 587 (α1) > BHT‐933 (α2). Clonidine had the same potency as noradrenaline (NA), but was 52 times more potent than phenylephrine (pEC50 7.09 and 5.37, respectively). Phenylephrine and guanfacine had intrinsic activities that did not differ from that of NA, whereas the intrinsic activities of the other agonists were significantly lower. The highly selective α1‐adrenoceptor antagonist prazosin in concentrations 10‐9‐10‐7M was unable to cause a significant shift of the NA concentration response (cr) curve to the right. However, the α2‐adrenoceptor antagonists yohimbine and rauwolscine in concentrations 10‐8‐10‐6M shifted the NA cr‐curve towards higher concentrations. No concentration of any antagonist used significantly attenuated the maximum contraction. The slope of the regression line in the Schild plot differed significantly from unity for rauwolscine but not for yohimbine, and the pA2‐values were 9.00 and 8.27, respectively. These results suggest that the contraction mediating α‐adrenoceptors in the human saphenous vein are mainly of the α2‐type. However, the low slope value of the Schild plot for rauwolscine may indicate the presence of a small population of α1‐adrenoceptors.
The Binding of Cadmium Ions to the Smooth Muscle of Guinea‐Pig Taenia Coli
Authors: Nasu Tetsuyuki
Published: July 2010

Abstract:Taenia coli was used to study the property of binding of Cd2+. The Scatchard plots of cadmium uptake showed that two qualitative Cd2+binding sites (high and low affinity binding sites) exist in taenia coli. Decrease in Ca2+concentration in the medium did increase the cadmium binding. The Scatchard analysis of Cd2+binding in taenia coli at 4° indicated a single class of binding sites (only high affinity binding sites). These findings suggest that the greater number of high affinity Cd2+binding sites in taenia coli may relate to the binding to cell membrane. Further, it was postulated that some of low affinity binding sites in taenia coli may reflect intracellular accumulation, indicating the action on the contractile system.
The Citalopram/5‐HTP‐induced Head Shake Syndrome is Correlated to 5‐HT2 Receptor Affinity and also Influenced by other Transmitters
Authors: Arnt Jørn , Hyttel John , Larsen Jens‐Jørgen
Published: July 2010

Abstract: Combination of the 5‐HT‐uptake inhibitor, citalopram, with 1–5‐HTP induced a characteristic head shake syndrome in rats. This was blocked by a range of 5‐HT antagonists, including the selective 5‐HT2 antagonists, ketanserin and pirenperone and was also blocked by the α1‐adrenoceptor antagonists, prazosin and WB 4101, and the α2‐adrenoceptor agonist, clonidine. 1–5‐HTP‐antagonistic effect was also recorded for 26 neuroleptic drugs. Their inhibitory potencies showed close correlation to 5‐HT2‐receptor affinity in vitro and, slightly weaker, to α1‐adrenoceptor affinity. In contrast, no correlation to dopamine D‐2 receptor affinity was found, indicating that the cataleptogenic and motility‐inhibitory properties of neuroleptics did not unspecifically influence 1–5‐HTP‐induced head shakes. These were not influenced by a histaminic antagonist, muscarinic antagonist or α2‐adrenoceptor antagonist, but were inhibited by β‐adrenoceptor blockers, GABA agonists, a benzodiazepine and morphine. The results indicate that 1–5‐HTP‐induced head shakes are most sensitive to 5‐HT2 antagonists, but that the syndrome is influenced by other neuronal systems. Since 5‐HT2 affinity and α1‐adrenoceptor affinity of many compounds is found concomitantly, caution is needed to evaluate the relative importance of these properties for 1–5‐HTP antagonism.
The Effects in Myometrial Preparations of D2343, a β2‐Adrenoceptor Agonist Possessing α1‐Receptor Blocking Qualities
Authors: Olsson O. A. T. , Ahlquist B. , Gustafsson B. , Persson G.
Published: July 2010

Abstract:D2343 is a compound with about the same β2‐adrenoceptor‐agonistic effect as terbutaline and exhibiting in addition an α1‐receptor inhibitory activity. D2343 has been compared to the β2‐agonist terbutaline on oestrogenized uterine preparations from rat and rabbit (in vitroandin vivo) and in myometrial strips from homo. Generally, D2343 has shown an ability to relax the uterine muscles to the same degree as terbutaline or even more, especially when the two drugs were comparedin vitroin preparations from rabbit and rat.
Ethanol‐inducible Cytochrome P‐450 is more Susceptible toin VitroCarbon Tetrachloride‐mediated Destruction than Phenobarbital‐inducible and β‐Naphtoflavone‐inducible Cytochromes P‐450
Authors: Gadeholt Gaut
Published: July 2010

Abstract:Liver microsomes were incubated aerobicallyin vitrowith NADPH and carbon tetrachloride in the presence of 1.5 mM EDTA. The resulting losses of haemoproteins and monooxygenase activities were evaluated after washing. Microsomes from ethanol‐pretreated rats lost about 66% of their cytochrome P‐450 measured as such, together with 94% of their ethoxycoumarin 0‐deethylase activity. Microsomes from control and phenobarbital‐pretreated rats lost between 30 and 35% of their cytochrome P‐450 and between 65 and 50% of the ethoxycoumarin 0‐deethylase activity. Microsomes from β‐naphtoflavone‐pretreated rats lost about 10% of their cytochrome P‐450 and 13% of their ethoxycoumarin 0‐deethylase activity. The inhibition with tetrahydrofuran, metyrapone and α‐naphtoflavone were also changed after incubation, suggesting selective destruction of isoenzymes with high affinity for tetrahydrofuran and selective sparing of others. Studies of 4‐nitroanisole O‐demethylation indicated selective destruction of enzymes with high affinity for the 4‐nitroanisole and sparing of enzymes with lower affinity. The properties that were destroyed after incubation with carbon tetrachloride were those that were elevated after chronic ethanol feeding. The destructive action of carbon tetrachloride in microsomes from ethanol‐pretreated rats was found to be different from those of allyl alcohol and 2‐isopropyl 4‐pentenamide. The findings may have relevance to the enhancement of chronic ethanol feeding on the hepatotoxicity of carbon tetrachloride.
Chapter 2: METABOLISM OF CARCINOGENS, POSSIBILITIES FOR MODULATION
Authors: Oesch Franz
Published: July 2010

Abstract:One of the structural elements which are widely occurring in very many chemical mutagens and carcinogens are aromatic and olefinic moieties. These can be transformed into epoxides by microsomal monooxygenases. Such epoxides may spontaneously react with nucleophilic centers in the cell and thereby covalently bind to DNA, RNA and protein. Such a reaction may lead to cytotoxicity, allergy, mutagenicity and/or carcinogenicity, depending on the properties of the epoxide in question. An important contributing factor is the presence of enzymes controlling the concentration of such epoxides. There are several microsomal monooxygenases which differ in activity and substrate specificity. With large substrates, some monooxygenases preferentially attack at one specific site different from that attacked by others. Some of these pathways lead to reactive products, others are detoxification pathways. Also important are the enzymes which metabolize epoxides, such as epoxide hydrolases and glutathione transferases. Such enzymes can act as inactivating and in some specific cases also as co‐activating enzymes. Moreover, precursor‐sequestering enzymes such as dihydrodiol dehydrogenase, glucuronosyl transferases and sulphotransferases are important for the control of reactive epoxides. These enzymes themselves are subject to control by many endogenous and exogenous factors. By virtue of their contribution to the control of carcinogenic metabolites such modulators can act as modifiers of tumorigenesis and can be used experimentally to study the role of the various individual enzymes.
Chapter 4: THE ROLE OF GENOTOXIC CARCINOGENS AND OF PROMOTERS IN CARCINOGENESIS AND IN HUMAN CANCER CAUSATION
Authors: Weisburger John H. , Wynder E. L.
Published: July 2010

Abstract: The majority of human cancers have multifactorial environmental causes stemming mainly from lifestyle factors such as use of tobacco products through cigarette smoking, snuff dipping, or chewing, and specific nutritional elements and dietary practices. The mechanisms of these lifestyle factors can be analyzed in terms of specific genotoxic carcinogens, and of epigenetic agents or promoting factors. Tobacco and tobacco smoke contain not only genotoxic carcinogens but also, with a more important ultimate effect, cocarcinogens and promoters. Alcohol acts as a cocarcinogen with tobacco, possibly by modifying the metabolism of carcinogens in select organs. Genotoxic carcinogens as nutritional factors may be found in pickled, salted, and smoked foods and may be responsible for gastric cancer. Vitamins C and E and other antioxidants are effective inhibitors. Other types of genotoxic carcinogens are mutagenic chemicals found in broiled and fried foods, and these may be involved in cancer of the colon, breast, and prostate. Promoting effects derive from a high level of dietary fat, which has been linked epidemiologically and through laboratory studies to a higher risk for these cancers. Possible mechanisms by which fat exerts its effects are an increased concentration of bile acids in the stool, as related to colon cancer, and which may be countered by a high cereal fiber diet, to increase stool bulk. In relation to breast or prostate cancer, fat may exert its effect on complex hormonal balances, and also on membrane composition. These promoting effects, whether associated with tobacco smoke or nutrition, are highly dose‐dependent, and provided the insult is not too far advanced, reversible. Thus, lowering the dosage, or eliminating the effect as in smoking cessation should have an appreciable effect in reducing overt disease development, and do so fairly promptly. This may apply also to a reduction of second disease in cases where a first occurrence has been successfully treated by conventional means.
Chapter 8: MODIFICATION OF CARCINOGENESIS BY ANTIOXIDANTS AND OTHER COMPOUNDS
Authors: Tsuda Hiroyuki , Fukushima Shoji , Imaida Katsumi , Sakata Takao , Ito Nobuyuki
Published: July 2010

Abstract: Studies were made on the effects of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium L‐ascorbate (SA), ethoxyquin (EQ) and acetaminophen (AAF) on the induction of neoplastic lesions in the liver, kidney or urinary bladder of rats initiated by N‐ethyl‐N‐hydroxyethylnitrosamine (EHEN), diethylnitrosamine (DEN) or N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN). The number and area of histochemical γ‐glutamyltranspeptidase‐positive (γ‐GT+) foci per unit area of liver section in rats given BHA, BHT, EQ or AAP, but not SA, were significantly less than in rats given EHEN or DEN alone. Similarly, the number of hyperplastic nodules (HN) in groups given BHA or AAP and their area in groups given BHA, EQ or AAP were significantly less than in control groups. Induction of hepatocellular carcinoma (HCC) was also clearly inhibited by these three chemicals. In contrast, the incidence and quantitative values of preneoplastic lesions and renal cell adenoma in the group given EHEN were significantly increased in groups given BHA, EQ or AAP administration. For assesing the influence of BHA and BHT on urinary bladder carcinogenesis, rats received BHA or BHT after treatment with BBN. The incidences and the number per unit length of basement membrane of papilloma and carcinomas were significantly increased in rats given BHA. BHT also showed significant increase but values were less than with BHA. These results clearly demonstrated that BHA, BHT, EQ and AAP inhibit the development of γ‐GT+ foci, or HN and HCC, whereas BHA, EQ and AAP enhance the appearance of preneoplastic and neoplastic lesions in the kidney, BHA and BHT also enhancing urinary bladder carcinogenesis.
Hemodynamic effects of diuretic therapy in hypertension
Authors: Danielson Mats
Published: July 2010

Abstract:The antihypertensive effect of diuretics is well documented. At least some preserved kidney function seems to be necessary to achieve a demon‐strable effect. The importance of fluid volume reduction for the antihypertensive effect of these drugs during long‐term treatment is however uncertain. The effects on central hemodynamics vary according to the literature, but the blood pressure reduction in responders (Δ MAP > 10 %) may primarily be explained by a reduction of the total peripheral vascular resistance. The peripheral circulation is influenced in the same way. Sometimes a flow reduction is observed, and sometimes a resistance reduction. In spite of a lasting blood pressure reduction after treatment with diuretics, the structural hypertensive vascular changes do not seem to be influenced.
The use of diuretics in modern antihypertensive therapy
Authors: Andersson Ove
Published: July 2010

Abstract:A review is made to sum up the indications when diuretics may be the drug of choice in the treatment of hypertension. Advantages from the combined treatment of thiazide diuretics and other antihypertensive agents are also emphasized. Adverse effects from diuretic treatment, i. e. hypokalemia, hyperuricemia, impaired glucose tolerance and risks associated with unfavourable serum lipoprotein patterns are discussed. It is concluded that from a hemodynamic point of view thiazide diuretics can be a good therapeutic alternative for most patients, excepting those with hyperkinetic circulation. It is recommended to use lower doses of thiazide diuretics than previously and the monitoring of S‐potassium is necessary in all patients.
Hyponatremia in congestive heart failure treated with diuretics
Authors: Orinius Erik
Published: July 2010

Abstract: In this brief review of the literature on hyponatremia in congestive heart failure treated with diuretics, different mechanisms and various treatments are presented. The hyponatremia is usually of the dilutional type. Therapeutical alternatives to the traditional water restriction are discussed.
Magnesium infusion in decompensated hypomagnesemic patients
Authors: Johansson Bengt W.
Published: July 2010

Abstract:I ive patients with severe cardiac decompensation, NYHA classes III and IV, and with hypomagnesemia were given 25 mmol magnesium sulphate i.v. daily for a week. Biochemical parameters were followed as shown in Table 2. The slight decrease in serum calcium, urate and blood glucose observed indicates that magnesium deficiency may be a contributing factor for the development of side effects often seen during treatment with diuretics. Leg cramps in one patient improved after the magnesium infusion.
Effect of General Anaesthetics and Organic Solvents on α1–Adrenoceptors in the Myometrium
Authors: Wikberg J. E. S. , Hede A. R. , Lindahl M.
Published: July 2010

Abstract:The α1selective radioligand3H–prazosin was used to assay α1receptors in membranes prepared from the rabbit myometrium.3H–Prazosin was found to bind to a single high affinity site in these membranes which was the presumed α1receptor. A series of general anaesthetics and organic solvents were tested for their ability to inhibit3H–prazosin binding. The order of potency of the tested agents to inhibit the binding was: chloroform = halothane = trichloroethylene > carbon tetrachloride > dichloromethane. The depression of3H–prazosin binding seemed to be induced on the α1receptor since non–specific radioligand binding was not affected as revealed by a saturation experiment with3H–prazosin where halothane was used as inhibiting agent. Computer analysis of the latter experiment also showed that halothane depressed mainly the affinity of3H–prazosin for the α1receptor. The ability of the general anaesthetics and organic solvents to inhibit contractions elicited by α1stimulation with phenylephrine in the rabbit uterus was also investigated. In these tests the order of potency for the inhibition of the contractile response was: carbon tetrachloride ≥ halothane = chloroform > trichloroethylene > dichloromethane. The mechanism of action for α1receptor and myometrial depression is discussed
Comparative Metabolism of Debrisoquine, 7–Ethoxyresorufin and Benzo(a)pyrene in Liver Microsomes from Humans, and from Rats Treated with Cytochrome P–450 Inducers
Authors: Birgersson Carol , Blanck Agneta , Woodhouse Ken , Mellström Britt , von Bahr Christer
Published: July 2010

Abstract:The metabolism of debrisoquine, 7–ethoxyresorufin and benzo(α)pyrene has been studied in human liver microsomes. There was a significant correlation (r = 0.70, P < 0.05) between debrisoquine hydroxylation and 7–ethoxyresorufin 0–deethylation among various livers, and debrisoquine inhibited 7–ethoxyresorufin deethylation competitively. These results suggest that debrisoquine and 7–ethoxyresorufin may be metabolised by a common P–450 form in human liver. The effect of cytochrome P–450 inducers on the metabolismofthe three substrates was also examined in rat liver. Debrisoquine hydroxylation was not enhanced by phenobarbitone, β–naphthoflavone or isosafrole
Complete Blockade and Attenuation of 5–Hydroxytryptamine Induced Analgesia Following NA Depletion in Rats and Mice
Authors: Archer Trevor , Arweström Ewa , Jonsson* Gösta , Minor Bruce G. , Post Claes
Published: July 2010

Abstract:The effect of pretreatment with the noradrenaline neurotoxin, N–2–chloroethyl–N–ethyl–2–bromobenzylamine (DSP4), upon the analgesia induced by various doses of 5–hydroxytryptamine (5–HT) was examined in rats and mice. DSP4 treatment (2 × 50 mg/kg, intraperitoneally) of rats caused a complete blockade of 5–HT induced analgesia in the tail–flick, hot–plate and shock titration tests. DSP4 treatment (1 × 50 mg/kg, intraperitoneally) of mice caused a partial blockade of 5–HT induced analgesia in the hot–plate test, but no significant blockade in the tail–flick test. These results are discussed with regard to serotonergicnoradrenergic interactions and the species discrepancy in nociceptive testing
Effect of a Homologous Series of Halogenated Methanes on Pulmonary Uptake of 5–Hydroxytryptamine in Isolated Perfused Rat Lung
Authors: Hede A. Ragnar , Andersson Lennart , Post Claes
Published: July 2010

Abstract:The potency of halogenated methanes to inhibit uptake of 5–hydroxytryptamine (5–HT) from the pulmonary circulation was studied using an isolated, perfused and ventilated rat lung preparation. The agents were vaporized and mixed with the inlet air. The results indicate that the degree of chlorination is the most important factor for potency of the methanes to inhibit lung uptake of 5–HT. When hydrogen was substituted with fluorine the potency was decreased dramatically. Bromine seemed to have the opposite effect. The data also suggested that the degree of chlorination was more important rather than hydrophobic/ hydrophilic balance of the solvent molecule. These effects seem to be correlated with the narcotic effects of the substances studied
Comparative Genotoxicity and Nephrotoxicity Studies of the Two Halogenated Flame Retardants Tris(1,3‐Dichloro‐2‐propyl)phosphate and Tris(2,3‐Dibromopropyl)phosphate
Authors: Sederlund Erik J. , Dybing Erik , Holme Jern A. , Hongslo Jan K. , Rivedal Edgar , Sanner Tore , Nelson Sidney D.
Published: July 2010

Tris(1,3‐dichloro‐2‐propyl)phosphate (Tris‐CP) was metabolized to products which were mutagenic forSalmonella typhimuriwnTA100 in the presence of liver microsomes from phenobarbital (PB)‐pretreated rats and NADPH. Effects of various inhibitors and inducers of cytochrome P‐450 on Tris‐CP mutagenicity were in accordance with PB‐inducible forms of this enzyme system being responsible for the formation of mutagenic product(s). A comparison was made between the toxic potential of the two halogenated flame retardants Tris‐CP and tris(2,3‐dibromopropyl)phosphate (Tris‐BP) in 5in vitrotests. Tris‐CP was much less potent than Tris‐BP with respect to bacterial (Salmonella/microsome orSalmonella/hepatocyte assay) and mammalian (V79 cells) mutagenicity, as well as DNA repair synthesis in hepatocytes. On the other hand, Tris‐CP and Tris‐BP were both equally effective in transforming Syrian hamster embryo cellsin vitro.Tris‐CP was not nephrotoxic to rats after a single dose of 500 mg/kg intraperitoneally, whereas Tris‐BP caused extensive tubular necrosis accompanied by elevated levels of plasma urea and creatinine.
Kinetics of Di‐(2‐ethylhexyl) Phthalate in Immature and Mature Rats and Effect on Testis
Authors: Sjöberg P. , Bondesson U. , Kjellen L. , Lindquist N.‐G. , Montin G. , Plöen L.
Published: July 2010

The testicular response of di‐(2‐ethylhexyl) phthalate (DEHP), as well as the kinetics of DEHP and its primary metabolite mono‐(2‐ethylhexyl) phtalate (MEHP), were studied in immature and mature rats. After 14 daily oral doses of 1.0 g DEHP/kg body weight to 25, 40 and 60‐day‐old rats, testicular damage was observed in the youngest age group only. DEHP was not found to any significant extent in the peripheral plasma after an oral dose of 1.0 g DEHP/kg body weight. High plasma levels of MEHP were found, with maximal plasma concentrations ranging from 48 to 152 μg/ml. Thein vitroplasma protein binding of MEHP was extensive, approximately 98%, in all age groups and no age‐related difference in the elimination half‐life was observed. The amount of DEHP‐derived material excreted in urine was twice as high in 25 as in 60‐day‐old rats. The mean area under the plasma concentration‐time curve of MEHP was also significantly larger in 25 than in 40 and 60‐day‐old rats. These observations suggest that the extent of absorption, and hence total exposure to MEHP and its metabolites, is higher in young than in more mature rats after oral administration of DEHP. It seems probable that this finding is relevant to the age‐related difference in the toxic effects on the testis.
Intrathecal Morphine Induces Myoclonic Seizures in the Rat
Authors: Shohami Esther , Evron Shmuel
Published: July 2010

The development of myoclonic activity as a toxic effect of morphine application into the intrathecal space in rats is described. This syndrome resembled the human syndrome of action myoclonus by its spontaneous onset and its augmentation by initiation of movement or by an acoustic stimulus. It was not reversed or prevented by naloxone. This effect of morphine was associated with an increase in serotonergic activity in the spinal cord and was reduced by pretreatment with parachlorophenylalanine in doses which reduced spinal 5‐HT by ∼60%. The dose which produced this syndrome was about ten times higher than the analgesic dose applied by the same route. Other commonly used opiates such as: methadone (0.5–2 mg/kg), pethidine (2‐10 mg/kg), fentanyl (2–10 μg/kg) and ketamine (2–10 mg/kg) did not produce myoclonic‐like activity, but methadone and pethidine at the highest doses caused respiratory arrest. Fentanyl appeared to be the safest of the drugs tested since a relatively high dose, administered into the intrathecal space did not cause any side effects, while morphine was least safe of the five drugs since it produced myoclonic activity in addition to the widely documented respiratory depression. We suggest that the production of the myoclonic activity is mediated by spinal serotonergic systems.
Effect of Intracerebroventricular Clonidine on some Renal Functions in Rats
Authors: Puri V. N. , Sur R. N.
Published: July 2010

In male Charles Foster rats, intracerebroventricular clonidine (0.2, 1.0, 10 mmol/l) caused dose dependent increase in the urine output and sodium excretion (P < 0.01). Urinary creatinine excretion was decreased to a significant level (P < 0.02). Urinary potassium excretion was increased but was not dose dependent. Maximal increase in the urine volume occured during first hour of clonidine administration. Intraperitoneal administration of clonidine in similar molar concentration failed to produce changes in the urine volume. The results indicate that clonidine‐induced diuresis is centrogenic and is attributed to the inhibition of the release of vasopressin from central hypothalamoneurohypophyseal axis.
Cellular Calcium and the Contraction Induced by Prostaglandin F2αin Feline Cerebral Arteries
Authors: Uski Tore K.
Published: July 2010

The influences of different calcium‐entry blockers, sialidase and caffeine on the biphasic contraction induced by prostaglandin (PG) F2αin the feline basilar artery (BA) were studied in calcium‐free medium. After incubation in calcium‐free solution, PGF2αinduced a contraction of the BA amounting to 87% of the contraction in calcium‐containing solution. The response was biphasic in 41 out of 42 vessel segments. PGF2α‐induced contractions were markedly attenuated in TRIS‐buffered solutions as compared to contractions in Krebs solution. PGF2αfailed to induce a biphasic contraction (8 out of 9 preparations) in calcium‐free HEPES‐buffered solution. Calcium entry blockade with 1 mM manganese or 10−5M diltiazem abolished the second and major phase of the PGF2α‐induced contraction in calcium‐free Krebs solution. The second contraction phase was also eliminated in four out of five preparations pretreated with sialidase (1 unit/ml for 30 min.), but was unaffected by a brief exposure to 20 mM caffeine in calcium‐free medium. The present findings strongly support previous suggestions that a major part of the PGF2α‐induced contraction in calcium‐free medium is mediated via the release of calcium bound to the exterior aspect of the cell membrane.
Ethanol Dependent Interaction between Prostaglandins and Lipoxygenase Products in Human Peripheral Lymphocytes
Authors: Lanefelt Fred , Martinsson Arne
Published: July 2010

The effect of lipoxygenase products, 12‐L‐HETE and 15‐L‐HPETE, on cyclic AMP levels in human peripheral lymphocytes was examined in the absence and in the presence of a prostaglandin of the E‐type (0.6–3.0 μM) or isoprenaline (33 μM). The studies were performed either in the absence or in the presence of 6 per cent ethanol. For comparison the effect of arachidonic acid and linolenic acid were studied. In the absence of ethanol 12‐L‐HETE and 15‐L‐HPETE had no significant effect on cyclic AMP accumulation. However, in the presence of ethanol 12‐L‐HETE (above 1 μM) inhibited prostaglandin E1but not isoprenaline induced cyclic AMP accumulation. 15‐L‐HPETE had a biphasic effect on prostaglandin E2induced cyclic AMP accumulation. Concentrations below 1 μM stimulated, those above inhibited. Virtually complete inhibition was seen at 15 μM. The two other fatty acids inhibited both prostaglandin E2and isoprenaline induced cyclic AMP accumulation in the presence, but not in the absence of ethanol. The results show that lipoxygenase products have little or no effect on cyclic AMP accumulation in human peripheral lymphocytes unless ethanol is present. In the presence of ethanol both 12‐L‐HETE and 15‐L‐HPETE appeared to selectively affect the cyclic AMP accumulation stimulated by PGE.
Propyl Ether. I. Interaction with the Sensory Irritant Receptor
Authors: Nielsen G. D. , Olsen J. , Bakbo J. C. , Holst E.
Published: July 2010

The sensory irritating response of propyl ether, measured as a decrease in respiratory rate in mice, faded within one minute. The threshold was 620 p.p.m., calculated from the concentration‐response curve, which had a low slope. The sensory irritating level depressing the respiratory rate to 50 per cent (RD‐50 = 89,000 p.p.m.) could not be reached with saturated vapour at 20°. The thermodynamic activity corresponding to the RD‐50 was about 0.6, a rather high value. The low slope and high thermodynamic activity may be explained by steric hindrance of the oxygen atom and thereby decreasing the receptor‐activating capacity and/or the stability of the active receptor conformation. A specific effect beyond the receptor offers another explanation.
Effects of Retinylacetate on the Kinetics of Rat Liver Guanylate Cyclase: Possible Interaction with Sulfhydryl Groups
Authors: Rydell Ewa L. , Axelsson Krister L. , Wikberg Jarl E. S.
Published: July 2010

The effect of retinylacetate (RA) was investigated on rat liver guanylate cyclase stimulated by nitroprusside (NP). The stimulated enzyme seemed to adhere to Michaëlis‐Menten kinetics with an apparent Kmfor MnGTP of 0.10 mM and a Vmax, of 410 pmol cGMP/min. × mg prot. RA (0.1–1mM) dose‐dependently inhibited the enzyme stimulated by NP (0.1–10 mM). In the presence of 1 mM RA the activity was only 10% of the control activity. The inhibitory action of RA seemed to be non‐competitive since it depressed Vmaxwithout affecting the Kmfor MnGTP. In contrast, however, RA was instead found to stimulate the enzyme when low concentrations of NP (0.01–0.1 mM) were used. The concentration‐activity curve for NP was bell‐shaped showing an optimum at 0.5 mM. The inhibition induced by RA could not be surmounted by increasing the NP concentration indicating that RA did not compete with NP. A bell‐shaped activity curve was also seen when the enzyme activity was measured in the presence of increasing Mn2+concentrations and during these conditions RA also caused inhibition. In the presence of the sulphydryl reductant dithiothreitol (DTT), the NP concentration needed for optimal enzyme activation was about 100‐fold less than in the absence of DTT. The maximal enzyme activity was also slightly increased. In the presence of DTT, RA was much less effective to induce inhibition of the stimulated enzyme, than when DTT was absent. (In the presence of DTT 1 mM RA caused only 30% inhibition compared to 90% inhibition in its absence). These results suggest that sulphydryl groups are of crucial importance in regulating guanylate cyclase activity and that the inhibitory effect of RA on the enzyme might be dependent on the interaction with these sulphydryl groups.
Human Platelet 5‐Hydroxytryptamine Concentration as a Tool in Prediction of Solvent Induced Neurotoxic Effects
Authors: Lam Henrik R. , Tarding Finn , Stokholm Jens , Gyntelberg Finn
Published: July 2010

Many organic solvents are lipophilic and concentrate in lipid rich tissues e.g. nervous tissue, where they are known to induce toxic effects in humans, especially in the central nervous system. Changes in the presynaptic neurotransmitter metabolism may play a role in these effects. The platelet is proposed as an alternative human model for this complex in the investigation of such changes, especially regarding 5‐hydroxytryptamine (5‐HT). The platelet 5‐HT concentration was measured in platelets isolated from exposed persons with diagnosed neurointoxication caused by exposure to organic solvents and compared to controls. No difference in the concentration was found. Instead of using the platelet 5‐HT concentration in the prediction of neurotoxic effects, the platelet 5‐HT uptake rate may be an alternative parameter. A specific and sensitive double isotope derivative technique for 5‐HT measurements is described. A solvent induced reduction in the number of platelets/ml platelet rich plasma was found and is discussed.
Plasma and Urinary Levels of Zearalenone and α‐Zearalenol in a Prepubertal Gilt Fed Zearalenone
Authors: Olsen M. , Malmlöf K. , Pettersson H. , Sandholm K. , Kiessling K.‐H.
Published: July 2010

One prepubertal gilt, fed 192 μg zearalenone/kg body weight/day for 4 days, showed plasma concentrations of α‐zearalenol 3–4 times higher than of the parent compound during the treatment. Zearalenone and α‐zearalenol could be traced in plasma until the 5th day and in urine until the 4th day of the posttreatment period. A maximum circulating amount of zearalenone plus α‐zearalenol, 10.4 ng/ml plasma, was found on the 4th day of treatment followed by an urinary excretion of 305 ng/ml urine. All zearalenone and α‐zearalenol in plasma and urine were bound to glucuronic acid. On the second day of treatment the animal showed oedema and reddening of the vulva which became more pronounced during the treatment. Hormone analysis, however, showed that the animal had no oestrus cycle during the 3 week experimental period.
The Effects of Aerosols of Carbamylcholine, Serotonin and Propranolol on the Ventilatory Response to CO2 in Guinea Pigs and Comparison with the Effects of Histamine and Sulfuric Acid
Authors: Schaper Michelle , Alarie Yves
Published: July 2010

A new method is introduced to recognize the acute pulmonary effect of airborne contaminants in guinea pigs. The method avoids anaesthesia and invasive techniques and requires minimal restraint of the animal. To recognize the acute pulmonary effect, the inspiratory volume of the animal was increased by continuous inhalation of a mixture containing 10% CO2 in 18% O2 and 72% N2 . Once a plateau increase in inspiratory volume was reached, the aerosol to be studied was added to this mixture and its effect in reducing inspiratory volume measured. By exposing the animals to different exposure concentrations of carbamylcholine, serotonin and propranolol aerosols, concentration‐response relationships were obtained which permitted comparison of their potency. Comparisons were also made with histamine and sulfuric acid aerosols previously studied.
Blood and Brainn‐Pentanol in Inhalation Exposure
Authors: Savolainen H. , Pfäffli Pirkko , Elovaara Eivor
Published: July 2010

Male Wistar rats exposed to 100, 300 or 600 p.p.m.n‐pentanol vapour for 7 to 14 weeks during five days weekly and 6 hrs daily showed a dose‐dependent bloodn‐pentanol concentration. The brainn‐pentanol content was linearly related to the blood pentanol concentrations although this relationship changed after 14 weeks because the brainn‐pentanol was significantly smaller than the respective values at 7 weeks. Valeraldehyde, the primary metabolite ofn‐pentanol, was only found in the brain at the highest vapour dose level. The livern‐pentanol dehydrogenase and 7‐ethoxycoumarinO‐deethylase activities remained unchanged while kidney ethoxycoumarin deethylase activity was enhanced in a dose‐dependent manner at both time points. Brain and muscle acetylcholinesterase activities were increased by the exposure dose‐dependently after 7 weeks although this effect ameliorated after 14 weeks. Moderaten‐pentanol vapour exposure seems to cause metabolic and functional adaptation in its target organs.
Changes in Liver Histology during Methotrexate Therapy of Psoriasis Correlated to the Concentration of Methotrexate and Folate in Erythrocytes
Authors: Hendel J. , Poulsen H. , Nyfors B. , Nyfors A.
Published: July 2010

To investigate, whether an assessment of the folate and methotrexate concentrations in erythrocytes could be used to indicate incipient histological liver changes, these 2 parameters were related to liver histology in series of liver biopsies (means 4.3 biopsies) from 31 long‐term methotrexate‐treated psoriasis patients. Logistic regression analysis showed that the probability of changes in liver histology during methotrexate therapy increased significantly with increasing erythrocyte methotrexate concentrations and with decreasing erythrocyte folate concentration. The application of these variables as a decisive criterion when to institute liver biopsy surveillance needs further studies, but can probably help reduce the number of liver biopsies to be taken during long‐term methotrexate therapy considerably.
Psychomotor Effects of Alprazolam and Diazepam during Acute and Subacute Treatment, and during the Follow‐up Phase
Authors: Aranko K. , Mattila M. J. , Bordignon D.
Published: July 2010

Psychomotor effects of alprazolam (AZ) and diazepam (DZ) were compared in a controlled double‐blind and cross‐over trial in 24 student volunteers, who received, three times daily, placebo for the first 4 days, then an active drug (AZ) 0.25 mg or DZ 5 mg) for 7 days, and again placebo for 3 days. After a 3 week wash‐out period the procedure was repeated with the comparative drug. Objective and subjective measurements were made on day 3 (placebo), on days 4 and 10 (active drug) and on days 11, 12 and 13 (follow‐up placebo). Baseline levels were measured in the morning, a capsule was taken, and the tests were repeated 2 hours and 8 hours later. Blood samples were taken in the afternoon of day 10 for the bioassay of serum benzodiazepine concentrations. Single doses of both AZ 0.25 mg and DZ 5 mg showed similar degree of impairment in several objective tests. At the end of the 7‐day maintenance DZ (15 mg daily) proved significantly more sedative and impaired more psychomotor performance than AZ (0.75 mg daily) did. Improvement of the complex test performances (a learning effect) was counteracted by DZ more than by AZ. No actual development of tolerance was demonstrated after either drug. During the follow‐up placebo phase, DZ showed more objective residual effects than AZ. The Maddox wing test (exophoria) showed a significant DZ effect to be still present on the third post‐treatment day. However, during the follow‐up period subjects reported subjectively more sedation and clumsiness after AZ than after DZ, but this was not associated with impairment of objective skills.
Role of Glutathione and Hepatic Glutathione S‐transferase in the Biliary Excretion of Methyl Mercury, Cadmium and Zinc: A Study with Enzyme Inducers and Glutathione Depletors
Authors: Gregus Zoltán , Varga Ferenc
Published: July 2010

The effect of hepatic glutathione (GSH) depletion and enzyme induction on hepatic glutathione S‐transferase (GST) activity, biliary excretion of GSH, methyl mercury, cadmium and zinc was studied in rats. The GSH depletors, methyl iodide and diethyl maleate, did not influence hepatic GST activity but, depending on the substrate used, benzo(a)pyrene, phenobarbital, pregnenolone‐16α‐carbonitrile (PCN) andtrans‐stilbene oxide (TSO) increased it by 16–33, 44–89, 53–97 and 208–279%, respectively. GSH depletors decreased (‐ 88%), benzo(a)pyrene and TSO did not affect, phenobarbital and PCN increased (+113 and + 149%) the transport of GSH into bile. The biliary excretion of methyl mercury, cadmium and zinc was reduced by GSH depletors (‐97, ‐74 and ‐93%), and enhanced by phenobarbital (+139, +280 and + 220%) and PCN (+150, +121 and +160%). Treatment with benzo(a)pyrene and TSO did not affect the excretion of methyl mercury and zinc into bile, but decreased that of cadmium. These results do not provide evidence for the role of hepatic GST but strongly support the importance of biliary GSH excretion in the hepatobiliary transport of methyl mercury, cadmium and zinc. It is assumed that phenobarbital and PCN enhance the biliary excretion of these metals by increasing the transport of GSH, the carrier molecule, from liver to bile.
The Effect of D2343 in Transmurally Stimulated Rabbit Isthmus Muscle
Authors: Olsson O. A. T. , Gustafsson B.
Published: July 2010

Inin vitroexperiments spirally cut isthmic preparations from oestrogenized rabbits have been contracted by transmural stimulation. The β2‐agonistic and α1‐antagonistic drug D2343 (for chemical structure, see fig. 1 inOlssonet al.1984) inhibits the evoked contractions in a concentration related fashion with 50% effect at 9.6 × 10−6mol/l. The α1‐antagonist prazosin has an inhibiting action in the same concentration range (EC50 = 14.0 × 10−6mol/l). To inhibit the contractile response to the same degree by the β2‐agonist terbutaline the concentration has to be > 10−3mol/l. From received results the β (β2)‐adrenoceptor mediated effects seem to be of minor importance compared to the α (α1)‐receptor dominance in the isthmus muscle during oesterus.