bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical Cerebral Blood Flow is Enhanced by Hornet Venom
Authors: Kaspi Thalia , Ishay Jacob S.
Published: March 2009

This study examined the effect of Oriental hornet venom sac extract (VSE) on the rate of local blood flow in the cerebral cortex of rats. Sublethal doses of VSE in isotonic saline solution were injected into the femoral vein of anaesthetised rats and the rate of blood flow was assessed by the hydrogen clearance technique both before the envenomation as well as during the following 150 min. The injection of VSE was found to induce a prolonged elevation of blood flow in the cerebral cortex. The time of occurrence of this elevation varied in different rats and so also the intensity of the elevation, ranging between 47–212% of the basal values. No exceptional or toxic phenomena were recorded in the course of this investigation. It would seem that the factor(s) responsible for boosting the blood flow is probably one or more of the water soluble components of the hornet venom.
Relaxation of Bovine Mesenteric Arteries by Glyceryl Trinitrate and Other Nitro‐Compounds: Evidence for Partly Different Mechanisms of Action
Authors: Torfgård Kristina , Ahlner Johan , Axelsson Krister L.
Published: March 2009

The effect of pertussis toxin (PTX) and the cyclic GMP lowering agent LY83583 on the relaxatory response induced by glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide‐5‐mononitrate (IS‐5‐MN) and sodium nitroprusside (SNP) in bovine mesenteric artery (BMA) was investigated. Pretreatment with PTX (100 ng/ml; 2 hr induced a 100‐fold right shift of the concentration‐effect curve for GTN, while no effect on the relaxatory response elicited by ISDN, IS‐5‐MN or SNP was seen. The relaxatory effect of all the substances tested was markedly reduced by LY83583 (10 μM). The basal cGMP level as well as the GTN induced increase in cGMP were markedly reduced when BMA was exposed to LY83583. The substance also reduced the activation of soluble guanylate cyclase by SNP. Based on the different sensitivity towards PTX it is suggested that GTN induces vascular smooth muscle relaxation by a partly different mechanism than ISDN, IS‐5‐MN and SNP. As far as the GTN induced relaxation is concerned the sensitivity towards PTX indicates the involvement of regulatory component, possibly a G‐protein. However, cyclic GMP seems to play a crucial role in mediating the relaxatory response of all the substances tested since the cGMP‐lowering agent LY83583 markedly inhibited the relaxant response induced by all the vascular relaxant agents investigated.
Fate of Ethion in Goats after Intravenous, Oral and Dermal Administration
Authors: Mosha Resto D. , Gyrd‐Hansen N. , Nielsen Poul
Published: March 2009

Toxicokinetic parameters and cumulative excretion were studied in goats after intravenous, oral and dermal administration of unlabelled and14C‐ethion. Plasma concentration‐time data was subjected to non‐compartmental analysis. IV injection studies showed an effective half‐life (t1/2) of 2 hr, a total body clearance (C1T) of 3.21 · kg‐1· hr‐1and a volume of distribution (Vd(SS)) of 9.4 1kg‐1. Plasma levels of14C‐ethion (ethion + metabolites) were much higher and more persistent than those of unchanged ethion. Cumulative excretion of14C‐ethion was 78% of the dose with 66% in urine, 8% in faeces and 4% in milk. Oral administration resulted in low plasma levels of unchanged ethion, an absorption half‐life (t1/2 abs) of 10 hr and a bioavailability of less than 5%. Cumulative excretion was 80% of the dose with 64% in urine, 14% in faeces and 1.7% in milk. Dermal application showed a t1/2 absof 85 hr and a bioavailability of 20%. Only 0.05% of the dose was excreted unchanged in milk. It is concluded that (1) orally administered ethion is extensively metabolized in the GIT, (2) dermal application results in prolonged and limited absorption and (3) absorbed ethion is rapidly eliminated through metabolism.
Immunologic Protection against VX Intoxication in Experimental Animals
Authors: Rong K.‐T. , Zhang L.‐J.
Published: March 2009

Rabbits immunized with an artificial VX‐antigen could survive 1 × LD95 of VX challenge on the 7th day and the 31st day after the last immunization. One hundred μl of rabbit anti‐VX antiserum given intravenously immediately before 1 × LD95 of VX or 200 μl of antiserum intraperitoneally 1–10 days before 1 × LD95 VX protected all the tested mice from death. The antiserum could prevent the in vitro inhibition of Torpedo AChE activity by VX and reduced its effect on brain AChE activity in vivo. No protective effect of the antiserum was observed on the Torpedo AChE activity inhibited by sarin and soman.
Changes in Rat Brain Monoamines, Monoamine Metabolites and Histamine after a Single Administration of 2,3,7,8‐Tetraclilorodibenzo‐p‐dioxin (TCDD)
Authors: Tuomisto Jouko , Pohjanvirta Raimo , MacDonald Ewen , Tuomisto Leena
Published: March 2009

Male Long‐Evans rats were given 50 μg/kg 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) intraperitoneally and after 1, 4, 28 or 76 hr, noradrenaline, dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5‐hydroxytryptamine (5‐HT), 5‐hydroxyindoleacetic acid (5‐HIAA), tryptophan and histamine were measured in the brain (dissected into ten parts) as well as in the pituitary gland. Several slight but significant changes were observed, e.g. in the hypothalamus where HVA and 5‐HIAA were decreased after 4 hr, noradrenaline was decreased after 76 hr and histamine increased after 28 hr. Several late changes were also found, conspicuously tryptophan was increased in most brain areas after 76 hr and in some cases earlier; these changes may be due to starvation after hypophagia rather than TCDD directly. The results demonstrate that TCDD causes changes in brain neurotransmitter systems, but the changes are minor and it is not likely that aminergic systems are the key mediators in TCDD‐induced hypophagia.
Short Term Inhalation of Bromobenzene: Methodology and Absorption Characteristics in Mouse, Rat and Rabbit
Authors: Aarstad Kjell , Becker Rune , Dahl Jon , Dybing Erik , Nilsen Odd G.
Published: March 2009

In a dynamic inhalation system, mice, rats and rabbits were exposed to bromobenzene vapour (250–3400 p.p.m.) for 4 hr. Blood concentrations of bromobenzene were determined by head‐space gas chromatography. After inhalation of 1000 p.p.m. for 4 hr, concentrations of 153, 102 and 47 μg bromobenzene/ml blood were found in mice, rats and rabbits, respectively.In vitroexperiments showed a blood/air partition coefficient at 37° of approximately 200, which was reflected by a linear uptake of bromobenzene up to an air concentration of 2500 p.p.m. Compared with results obtained previously by intraperitoneal bromobenzene administration inhalation resulted in higher blood concentrations.
Radioreceptor Assay for Pharmacokinetic Studies of Glycopyrrolate
Authors: Kaila T. , Ali‐Melkkilä T. , Iisalo E. , Kanto J.
Published: March 2009

A sensitive radioreceptor assay for the determination of glycopyrrolate concentrations in human plasma, urine and cerebrospinal fluid (CSF) is described. The applicability of the assay for kinetic studies in humans was studied by determining the plasma concentrations and the renal excretion in three gynaecological surgical patients, who received 8 μg/kg of glycopyrrolate as a premedication intramuscularly. Tritiated N‐methyl scopolamine was used to label the muscarinic cholinergic receptors in the membrane preparation obtained from the rat brain. The limit of detection of the assay was 70 ng/1 in plasma, 2 μg/1 in urine and 140 ng/1 in CSF. There was no evidence of cross‐reactivity of glycopyrrolate derivatives in clinical concentrations. A very rapid absorption was found with a mean maximum plasma concentration (Cmax) of 14.26 (range 12.02–16.97) μg/1 and mean Tmax (time to Cmax) of 13.3 (range 10–15) min. and almost 50% of the dose administered was excreted into the urine within 3 hr. The CSF levels of glycopyrrolate were under detection limit. It is concluded that the sensitivity of the method is sufficient for pharmacokinetic studies of glycopyrrolate after therapeutic dosing.
Hepatotoxicity of Diethyldithiocarbamate in Rats
Authors: Ishiyama Hironobu , Ogino Keiki , Shimomura Yuichi , Kanbe Toshimi , Hobara Tatsuya
Published: March 2009

Hepatotoxicity of diethyldithiocarbamate (DDC) was investigated in rats. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were markedly elevated 24 hr after subcutaneous administration of DDC and histologically, the liver showed submassive necrosis. A sustained inhibition in the liver of Cu, Zn‐superoxide dismutase (Cu‐SOD) activity was observed following DDC treatment. DDC produced a significant loss in liver reduced glutathione (GSH) level after 1 hr, but the nadir was observed later than that of Cu‐SOD. Catalase activity decreased gradually from 7 hr. Thiobarbituric acid reactive substances (TBARS) in the liver were significantly increased from 15 hr. Hepatic haemodynamics were scarcely changed up to 15 hr. Desferrioxamine (a chelator of iron) and piperonyl butoxide (an inhibitor of cytochrome P‐450) prevented DDC‐induced increases of both ALT and TBARS, but GSH did not. DDC hepatotoxicity was not changed by phenobarbital induction. Thus, we have shown that subcutaneous dose of DDC caused hepatotoxicity in rats. Although the exact sequence of its hepatotoxic factors is unproven, it seems likely that lipid peroxidation through the dysfunction of antioxidant defence factors and a toxic metabolite contribute to the formation of this liver injury.
Difference in Effect of Sodium Selenite on Mercury Distributions after Duodenal Administration of Mercuric Chloride and Mercuric Oxide
Authors: Endo Tetsuya , Nakaya Shozou , Kimura Ryohei
Published: March 2009

To obtain evidence for difference in the absorptive forms of HgCl2 and HgO from duodenum, the Hg distributions after the duodenal administration of HgCl2 and HgO and the effect of Na2SeO3 on their Hg distributions were compared. The Hg concentrations in erythrocytes and liver 2 hr after the administration of HgCl2 were significantly lower and higher than those of HgO, respectively, but their Hg distributions at 3.5 or 5 hr became identical. The administration of Na2SeO3 (intravenously) 2 hr after the administration of HgCl2 and HgO resulted in significant differences in their Hg concentrations in plasma, erythrocytes and kidney at 3.5 or 5 hr. These results suggest that the absorptive form of HgCl2 from the duodenum differs from that of HgO and this difference is a cause for the marked difference in effect of Na2SeO3 on the Hg distributions of HgCl2 and HgO.
Accumulation and Distribution of Aliphatic (n‐Nonane), Aromatic (1,2,4‐Trimethylbenzene) and Naphthenic (1,2,4‐Trimethylcyclohexane) Hydrocarbons in the Rat after Repeated Inhalation
Authors: Zahlsen K. , Nilsen A. M. , Eide I. , Nilsen O. G.
Published: March 2009

The concentrations of the C9 hydrocarbons n‐nonane, 1,2,4‐trimethylbenzene and 1,2,4‐trimethylcyclohexane were measured in rat blood, brain and perirenal fat after exposures to 1000 p.p.m. of the individual compounds. Measurements were made by head space gas chromatography at the end of 12 hr exposures on days 1, 3, 7, 10 and 14 of the exposure periods. The relative concentrations of hydrocarbons in each organ were, brain: n‐nonane »trimethylcyclohexane ∼ trimethylbenzene, blood: trimethylbenzene »n‐C9 > trimethylcyclohexane and perirenal fat: trimethylbenzene > n‐nonane > trimethylcyclohexane, showing the widely different distribution properties of the different hydrocarbons. Brain/blood ratios of 11.4, 2.0 and 11.4, and fat/blood ratios of 113, 63 and 135 were found for n‐nonane, trimethylbenzene and trimethylcyclohexane, respectively. A marked decrease in biological concentrations of trimethylbenzene and trimethylcyclohexane during the initial phase of exposure indicate that these hydrocarbons are capable of inducing their own metabolic conversion resulting in lower steady state levels. A special attention was made to n‐nonane showing the highest concentration in brain concomitantly with a low blood concentration. This observation demonstrate that biological monitoring of occupational exposure by blood measurements not should be performed without knowledge of the distribution properties of the compounds investigated.
Inhibition of Cell Growth and DNA, RNA, and Protein Synthesis in Vitro by Fentanyl, Sufentanil, and Opiate Analgesics
Authors: Nassiri M. Reza , Flynn Gordon L. , Shipman Charles
Published: March 2009

Abstract: We have studied the cytotoxic nature of two groups of narcotic analgesics. Group I consists of the opioids, morphine, codeine, hydromorphone, thebaine, and etorphine. Group II contains but two phenylpiperidine‐type narcotics, fentanyl and sufentanil. To measure cytotoxicity, three different bioassays were employed using an established line of human cells. Specifically, the effects of narcotic analgesics on DNA, RNA, and protein synthesis were measured by following the uptake and incorporation of radiolabeled thymidine, uridine, and amino acids, respectively. Inhibition of cell growth also was studied by measuring population doubling times of logarithmically growing cells in the presence (or absence) of the test compounds. Lastly, cloning efficiencies of cells were determined in the presence of both groups of compounds. Group I compounds were significantly less inhibitory than Group II compounds by all three bioassays. Moreover, flow cytometric DNA analysis of cells treated with 100 and 320 μM etorphine HC1 showed essentially no effects on cell cycle distribution. These in vitro results thus suggest that (1) fentanyl and sufentanil are inherently more cytotoxic than the opioid narcotics in Group I, and (2) the highly potent morphinoid drug etorphine HCl appears to have special promise as a transdermal narcotic to control pain.
Investigation of the Possible Dopaminergic Toxicity of 1‐Methyl‐3‐phenyl‐1,2,3,6‐tetrahydropyridine, an Isomer to the Neurotoxin MPTP
Authors: Nilsson Kristina , HaUberg Anders , Pileblad Erik , Tunek Anders
Published: March 2009

Abstract: 1‐Methyl‐3‐phenyl‐1,2,3,6‐tetrahydropyridine (M‐3‐PTP) is an analogue to the Parkinson‐producing dopaminergic toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). M‐3‐PTP, and simple analogues thereof, are versatile intermediates in organic synthesis. The present study was undertaken to investigate the possible dopaminergic toxicity of M‐3‐PTP. Male albino mice were injected with 50 mg/kg of either MPTP or M‐3‐PTP and dopamine (DA) and its metabolites were determined 2 hr and 7 days after the administration. Two hr after MPTP profound acute changes in brain DA metabolism were found, i.e. an approximately 50% reduction in the concentration of DA together with a 10‐fold increase in the level of 3‐methoxytyramine. Seven days after MPTP, DA and metabolites were markedly reduced which is consistent with a degeneration of the dopaminergic neurones. In contrast M‐3‐PTP produced no acute or long‐term alterations in the concentrations of DA and its metabolites in mouse brain. Furthermore, in vitro experiments show that M‐3‐PTP does not inhibit monoamine oxidase B. Thus, the present data show that M‐3‐PTP is devoid of dopaminergic toxicity in mouse brain and is not likely to produce Parkinson's disease in humans. The lack of toxicity is probably explained by the low affinity of M‐3‐PTP for monoamino oxidase B.
Biotransformation of Cyclophosphamide in Post‐Implantation Rat Embryo Culture Using Maternal Hepatocytes in Co‐Culture
Authors: Piersma A. H. , Van Aerts L. A. G. J. M. , Verhoef A. , Garbis‐Berkvens J. M. , Robinson J. E. , Peereboom‐Stegeman J. H. J. Copius , Peters P. W. J.
Published: March 2009

Abstract: The post‐implantation rat embryo culture technique is employed to study embryotoxic effects of xenobiotic compounds in the absence of the maternal compartment. For compounds biotransformed in vivo the embryo culture technique must be adapted in order to mimick the in vivo effects. In the present study the possibility of co‐culturing metabolically active maternal hepatocytes suspended in the standard culture system with rat serum as a medium was investigated. Cyclophosphamide (CP) was used as a model compound as it needs bioactivation to display embryotoxicity. Morphologic and histologic effects were studied. Neither hepatocytes nor CP alone affected embryo development, whereas in the presence of hepatocytes embryotoxicity was observed at 30 μg/ml CP. Embryotoxicity was decreased in the additional presence of metyrapone, a monoxygenase inhibitor. Hepatocyte suspensions prepared via slicing or perfusion of livers were equally effective. In conclusion, co‐culture of embryos and suspended hepatocytes can be performed under optimal conditions for embryo development and in the presence of biotransforming activity.
Nifedipine Increases Urinary Excretion of Prostacyclin Metabolite in Hypertensive Pregnancy
Authors: Manninen Auli , Metsä‐Ketelä Timo , Tuimala Risto , Vapaatalo Heikki
Published: March 2009

Abstract: Renal prostanoid excretion was investigated in nine hypertensive pregnant patients before and during treatment with nifedipine 10 mg orally t.i.d. Urinary excretion of prostacyclin (measured as 6‐ketoprostaglandin Fla, 6‐keto‐PGF1a) increased by 77% during nifedipine treatment (P<0.05). No changes were found in prostaglandin E2 (PGE2) and thromboxane A2 (as thromboxane B2, TXB2 excretions. A significant reduction in blood pressure did not correlate with an increase in 6‐keto‐PGFla excretion. Plasma prekallikrein and urinary kallikrein and catecholamine excretions remained unaltered. In six normotensive non‐pregnant women, increase in 6‐keto‐PGFla excretion during nifedipine treatment was not significant. No changes in PGE2 and TXB2 excretions were found, whereas plasma prekallikrein was reduced (P < 0.05) and urinary excretion of kallikrein (P<0.05) and noradrenaline (P = 0.06) increased under nifedipine. The results suggest that nifedipine enhances the renal 6‐keto‐PGF10 excretion in hypertensive pregnancy.
Distribution of 2‐Ethylhexanoic Acid in Mice and Rats after an Intraperitoneal Injection
Authors: Pennanen S. , Manninen A.
Published: March 2009

Abstract:The distribution of 2‐ethylhexanoic acid (2‐EHA), a new wood preservative agent was studied in mice and rats. 2‐14C‐EHA in rat blood, brain, liver and kidney was quantitated by liquid scintillation analysis and by wholebody autoradiography in mice. A single intraperitoneal dose of 2‐14C‐EHA was injected in both species. Animals were sacrificed 30 min., 2 and 6 hr after the administration of 2‐14C‐EHA in autoradiography experiments. The highest uptake of 2‐14C‐EHA was observed in the liver, kidney and blood of mice. In contrast, low uptake of 2‐14C‐EHA was seen in the brain. 2‐14C‐EHA was well detectable in the olfactory bulb and in the salivary gland. In rats, at 2 hr after administration the highest concentration of 2‐14C‐EHA occured in blood (0.3% of the total dose/g tissue). The radioactivity in the liver (0.2%) and kidney (0.1%) was also relatively high. The concentration of 2‐14C‐EHA was low in the brain (0.02%). By 6 hr, the radioactivity had decreased rapidly and was hardly measurable at 24 hr after the administration. The results suggest that 2‐EHA is rapidly cleared from the tissues.
Alcohol Consumption Does Not Affect Fathers but Does Affect Their Offspring in the Forced Swimming Test
Authors: Abel Ernest L.
Published: March 2009

Abstract: Male rats that had consumed alcohol for seven months did not differ significantly from controls in their immobility response in the forced swimming test. In contrast to this observation, the offspring of these males exhibited a significant dose‐related decrease in immobility. These results suggest that while alcohol's effects may not be observable in males consuming it, this does not necessarily mean that it has no important biological effects on these males. However, these effects may not be appreciated until their offspring are examined.
Biliary Excretion of the Vasopressin Analogue DDAVP after Intraduodenal, Intrajugular and Intraportal Administration in the Conscious Pig
Authors: Lundin S. , Pierzynovski S. G. , Weström B. R. , Bengtsson H.‐I.
Published: March 2009

Abstract:The biliary excretion of the vasopressin analogue 1‐deamino‐8‐D‐arginine vasopressin (dDAVP) was determined in the pig after three administration routes, intrajugular venous, intraportal venous and intraduodenal. In all cases the biliary excretion was less than 1% of the administered dose. The plasma/bile concentration ratio was less than 1:1. A significant first‐pass effect was found when the liver was exposed to a high intraportal dose of dDAVP. Possible uptake and degradation/biotransformation was evaluated by incubating [3H]dDAVP with liver tissue slices showing that [3H]dDAVP was rapidly removed from the incubation medium. The following conclusions can be drawn from these experiments: 1) The intestinal mucosa constitutes the major barrier to intestinal absorption of dDAVP. 2) dDAVP is excreted in bile in small amounts. 3) Indirect evidence suggests that the dDAVP molecule is degraded/biotransformed in the liver at its C‐terminus.
Relationship between Red Blood Cell Potassium and Plasma Digitoxin Concentrations in Intoxicated Patients
Authors: Urtizberea M. , Rochdi M. , Sabouraud A. , Bismuth C. , Scherrmann J. M.
Published: March 2009

Abstract: After severe acute self‐poisoning by cardiac glycosides, significant and persistent depletion of red blood cell K+ due to inhibition of Na+K+ ATPase is seen. Because of a delay between the time course of plasma digitalis concentrations and that of red blood cell K+ depletion, no direct relation exists between the two, and RBC K+ has hitherto not been considered useful as pronostic indicators of clinical outcome. In an effort to solve this problem, red blood cell K+ was measured by atomic absorption spectrophotometry and plasma digitoxin concentration assayed in six patients admitted to an intensive care unit after digitoxin self‐poisoning. Using the effect compartment model of Sheiner, a relationship based on a sigmoid Emax model was able to relate the digitoxin concentration at the action site to red blood cell K+ depletion. Thus the duration of red blood cell K+ depletion could be predicted from two relative simple in vitro assays. Since RBC K+ is a marker of the inhibition of Na+K+ ATPase by digitoxin, this method could be of use for the management of patients self‐poisoned with digitalis.
TRH‐Induced Tachyphylaxis: Present in the Smooth Muscle but Not in the Cardiorespiratory Effects
Authors: Järvinen Asko , Paakkari Ilari
Published: March 2009

Abstract:The development of tachyphylaxis to the pressor, tachycardiac, ventilatory and smooth muscle effects of thyrotropin‐releasing hormone (TRH) was studied. Subsequent administrations of increasing doses of TRH (0.1‐1000 nmol/kg intracerebroventicularly), at 20 min. intervals in urethane‐anesthetized rats dose‐dependently increased the mean arterial blood pressure, heart rate and minute ventilation volume. At all doses the effect on mean arterial blood pressure was apparent at least 20 min. after each injection whereas at low doses (0.1‐1 nmol/kg) the duration of the effects on heart rate or minute ventilation volume were shorter. The cardiorespiratory effects of TRH 10 nmol/kg intracerebroventricularly did not subside completely within an observation period of 1 hr. However, a repeated administration of TRH at 1 hr resulted in the levels of mean arterial blood pressure, heart rate and minute ventilation volume not statistically different from the peak levels of the first injection. While the cardiorespiratory effects of TRH were long‐lasting, the TRH induced inhibition of the contractions of the rat duodenal smooth muscle lasted only 12‐18 sec. The TRH‐treated duodenal preparation responded normally to noradrenaline but remained unresponsive to further administrations of TRH until washed extensively. When the medium after cessation of the TRH response was transferred into another chamber with an untreated preparation, a full response was resulted. Inhibitors of TRH metabolism, bacitracin, EDTA and iodoacetamide, did not prolong nor enhance the response. Likewise, a stable TRH‐analogue MK‐771 did not produce any longer response than TRH. It is concluded that no tachyphylaxis was produced to the neurally mediated pressor, tachycardiac or ventilatory effects of TRH. However, the duodenal smooth muscle effect of TRH was attenuated due to rapid homologous tachyphylaxis not related to breakdown of TRH.
Adsorption of Atrial Natriuretic Peptide to Different Materials: A Factor Influencing Results of in Vitro Experiments?
Authors: Lindberg B. Fredrik , Andersson Karl‐Erik
Published: March 2009

Abstract: Studies on atrial natriuretic peptide (ANP) in ex vivo situations, include a risk of adsorption to surrounding materials. In order to investigate this potential source of error, known concentrations of ANP in Krebs solution were prepared in test tubes of different materials. The solutions were analyzed for ANP‐concentration by radioimmunoassay (RIA), using a standard‐curve of ANP in phosphate buffer supplemented with 0.1% human serum albumin (HSA) and 0.1% Triton X100. A considerable adsorption was seen to the different materials tested, also to siliconized glass and polypropylene. With 1 ml ANP‐solution in concentrations from 1 × 10−9 to 1 × 10−5M an adsorption varying between 10 and 31% was seen to a 15 cm2 polystyrene‐surface, corresponding to a conventional test tube. With 1 ml of ANP 120 pM in Krebs solution serially dispensed into six empty polystyrene test tubes, 73% of the initial peptide amount was lost due to adsorption. The adsorption could be prevented or partly reversed by adding HSA or Triton X100 to the solutions. These findings indicate that adsorption entails a risk of disturbing the results of in vitro experiments in studies on ANP.
Theophylline Effects on Phasic Tension and Slow Inward Current of Isolated Frog Atrial Fibres: Influence on the Action of Isoprenaline
Authors: Gauthier C. , Soustre H.
Published: March 2009

Abstract:The action of theophylline on phasic tension and slow inward current (Isi) was investigated on isolated voltaged‐clamped frog atrial fibres. The action of theophylline was both dose‐ and time‐dependent; the most effective dose was 2.10−3M. Theophylline induced a rapid positive inotropic effect which cannot be attributed to a β‐adrenoceptor stimulation or to an adenosine antagonism; this effect was closely related to an increase in slow inward current (Isi), probably due to an inhibition of phosphodiesterase activity and a subsequent increase in cAMP content. The decline of the positive inotropic effect of theophylline was discussed in terms of additional effects of the drug. Theophylline, consistently with its phosphodiesterase inhibitory action, was shown to potentiate the effects of isoprenaline on phasic tension and Isi; however no potentiation was observed after reserpine‐induced depletion of endogenous catecholamines. It might be thought that non‐specific effects of reserpine on some steps of cardiac excitation‐contraction coupling couteract the effects of theophylline.
Acute Haemodynamic Effects of Felodipine, Verapamil and Hydralazine in the Anaesthetized Dog
Authors: Björkman Jan‐Arne , Ek Lars , Gustafsson David , Ljung Bengt , Nordlander Margareta
Published: March 2009

Abstract: Felodipine, a potent dihydropyridine calcium antagonist with a pronounced vascular selectivity, was given intravenously (0.006‐0.025 μmol kg−1) to anaesthetized, open‐chest dogs with denervated hearts. The result was a dose‐dependent decrease in mean arterial pressure (MAP) and total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and left ventricular end‐diastolic pressure remained relatively unchanged. Cardiac tension work (TTI) and oxygen consumption (MVO2) were reduced, probably due to the decrease in afterload. The relative reduction of the coronary vascular resistance (CVR) was greater than that of TPR. The hypotensive effect of verapamil (0.05‐0.20 μmol kg−1) was small and MAP decreased mainly via a decrease in HR and SV. Higher doses of verapamil which induced vasodilatation could not be given without the development of complete atrio‐ventricular dissociation. Hydralazine (11‐45 μmol kg−1) decreased TPR and CVR in parallel but the decrease in MAP was partly counteracted by a powerful increase in HR, SV and cardiac inotropy which was associated with elevated catecholamine levels in plasma. When MAP and HR were maintained constant by means of aortic balloon inflation and atrial pacing, felodipine markedly increased coronary blood flow and coronary sinus oxygen saturation while SV, TTI, inotropy and MVO2 remained relatively unchanged. It is concluded that felodipine markedly dilates peripheral resistance vessels, and in particular those in the coronary vascular bed, without any cardiodepressant effects.
Assessment of the Sedative Effects of Dexmedetomidine, an α2‐Adrenoceptor Agonist, with Analysis of Saccadic Eye Movements
Authors: Aantaa Riku
Published: March 2009

Abstract:Single intravenous doses (0.5 μg/kg and 1.0 μg/kg) of dexmedetomidine (4(5)‐(1‐(2,3‐dimethylphenyl)ethyl)imidazole), a selective α2‐adrenoceptor agonist, and saline placebo were administered to six healthy volunteers (4 males and 2 females) in a double‐blind, placebo‐controlled cross‐over study. The effects on vigilance were assessed using both subjective estimation (visual analogue scale, VAS) and objective tests (critical flicker fusion frequency, CFF; the Maddox wing; saccadic eye movement analysis). Dose‐dependent subjective sedation was seen in VAS measurements, and impairment of vigilance was observed in CFF, Maddox wing and peak saccadic velocity, while saccade latency was not influenced by dexmedetomidine. The changes in vigilance were concurrent with moderate reductions in blood pressure and heart rate. CFF, the Maddox wing and peak saccadic velocity all proved sensitive in the assessment of sedation induced by dexmedetomidine.
Effect of Aspartame and Protein, Administered in Phenylalanine‐Equivalent Doses, on Plasma Neutral Amino Acids, Aspartate, Insulin and Glucose in Man
Authors: Møller Svend E.
Published: March 2009

Abstract: Six human males each received 0.56 g phenylalanine (Phe) in the form of 1.0 g aspartame or 12.2 g bovine albumin in 200 ml water or water alone. Venous blood samples collected before consumption and during the following 4 hr were assayed for plasma levels of large, neutral amino acids (LNAA), aspartate, insulin and glucose. The area under the curve for plasma Phe was 40% greater, although not significant, after aspartame compared with albumin intake. The indicated increased clearance rate of plasma Phe after albumin may be caused by the significant increase of insulin, on which aspartame had no effect. There was a significant main effect of aspartame for plasma tyrosine but not for tryptophan, valine, isoleucine or leucine. Plasma aspartate was significantly increased at 0.25 hr after the aspartame intake. The percentage Phe/LNAA decreased slightly in response to albumin but increased 55% after aspartame and remained significantly increased for 2 hr. Tyrosine/LNAA increased and tryptophan/LNAA decreased modestly after aspartame intake. The study showed that the intake of aspartame in a not unrealistically high dose produced a marked and persistent increase of the availability of Phe to the brain, which was not observed after protein intake. The study indicated, furthermore, that Phe was cleared faster from the plasma after consumption of protein compared with aspartame.
Effect of Organic and Inorganic Mercury on Human Sperm Motility
Authors: Ernst Erik , Lauritsen Jørgen Glenn
Published: March 2009

Abstract:The effects of mercuric chloride and methyl mercuric chloride on the motility of human spermatozoain vitrowere investigated. Organic as well as inorganic mercury compounds decreased the percentage of motile spermatozoa. After 15 min. incubation with 40 μM mercuric chloride a significant decrease in sperm motility was observed. Less than 5% of spermatozoa were motile after 30 min. of exposure to 20 μM methyl mercuric chloride. These effects could not be attenuated by addition of 5 μM sodium selenite. The ultrastructural localization of mercury was demonstrated by autometallography. Silver‐enhanced mercury deposits could be demonstrated only in spermatozoa exposed to inorganic mercury. In these cells mercury grains were most abundant in membranes of midpiece and tail.
Effect of Trimethyltin on Amino Acid Concentrations in Different Regions of the Mouse Brain
Authors: Lipe George W. , Ali Syed F. , Newport Glenn D. , Scallet Andrew C. , Slikker William
Published: March 2009

Abstract: Trimethyltin (TMT) is a neurotoxic compound known to cause marked alterations in brain chemistry. We have previously demonstrated that a single oral dose of TMT produced a dose‐dependent decrease in muscarinic cholinergic receptors in mouse brain and significantly elevated glutamine in several regions of the rat brain. This study was designed to determine if TMT produced dose‐ and time‐related alterations in amino acid concentrations in the adult male C57BL/6N mouse brain and in peripheral organs and plasma. In the dose‐response study, TMT was administered orally as a single dose of 0, 0.5, 1.0, 3.0 or 5.0 mg/kg and animals were sacrificed 24 hr after treatment. In the time‐course study, mice were dosed with TMT at 3.0 mg/kg and sacrificed 4, 12, 24, 48 or 96 hr after dosing. Amino acid concentrations were quantified by HPLC/EC following precolumn derivatization with o‐phthalaldehyde‐tert‐butylthiol. TMT produced dose‐dependent increases in aspartate, glutamine and glycine in the caudate nucleus (CN), frontal cortex (FC) and hippocampus (HIP) at 3.0 and 5.0 mg/kg. TMT at 3.0 mg/kg produced significant increases of aspartate in FC and HIP after 48 hr. Glutamine concentrations were significantly increased at 24 and 48 hr in HIP and at 48 hr in CN. Glycine and GABA concentrations were significantly increased at 48 and 96 hr respectively in the HIP. Glutamine was increased in plasma at 4 and 12 hr and in liver at 24 hr. Hyperammonemia occurred in plasma after 8 hr and continued through 24 hr and was accompanied by an increase in serum urea nitrogen. These data demonstrate that a single dose of TMT produces significant alterations in amino acid concentrations in several brain regions and in peripheral systems in a dose‐and time‐dependent manner. The dose‐ and time‐dependency of the alterations reported here in the mouse, and previously in the rat, suggest that alterations in amino acid and ammonia concentrations can be used as a multispecies biomarker for TMT neurotoxicity.
Possible Role of Glutathione in Chromium(VI) Metabolism and Toxicity in Rats
Authors: Standeven Andrew M. , Wetterhahn Karen E.
Published: March 2009

Abstract:The effect of Cr(VI) on liver, kidney, and lung glutathione (GSH) levels and the effect of GSH depletion on Cr(VI)‐induced nephrotoxicity were studied in male Sprague‐Dawley rats (150‐200 g). GSH levels, measured as nonprotein sulfhydryls, were determined between 0.5 and 26 hr after intraperitoneal injection of the maximum non‐toxic dose of sodium dichromate (10 mg/kg). While Cr(VI) at this dose did not significantly change hepatic, renal, or pulmonary GSH levels, there appeared to be an initial decrease of hepatic GSH followed by an increase to ~120% of control between 5 and 12.5 hr after Cr(VI) treatment. The increase in hepatic GSH levels was significant 5 hr after treatment with 20 mg/kg sodium dichromate, was manifested as an increase in both non‐protein sulfhydryls and total glutathione, and was prevented by L‐buthionine sulfoximine (BSO) pretreatment. In rats pretreated with 4.0 mmol/kg BSO to deplete GSH, subsequent treatment with Cr(VI) further reduced hepatic GSH levels 2 hr after Cr(VI) treatment and inhibited weight gain in the first 24 hr after treatment. Intraperitoneal injection of Cr(VI) did not inhibit hepatic glutathione reductase activity, even at toxic doses. Depletion of renal GSH to ~25% of control with BSO potentiated the acute nephrotoxicity of 30 mg/kg sodium dichromate as measured by serum urea nitrogen levels and relative kidney weight. However, GSH depletion with BSO did not appear to affect the incidence of glucosuria, haematuria, or lysozymuria over a range of Cr(VI) doses, nor did it affect renal uptake of Cr. Taken together, these data show that GSH protects against the acute nephrotoxicity of Cr(VI), although it is not clear whether GSH is directly involved in the intracellular metabolism of Cr(VI) at non‐toxic doses.
Kinetics of Lead in Bone and Blood after End of Occupational Exposure
Authors: Nilsson U. , Attewell R. , Christoffersson J.‐O. , Schütz A. , Ahlgren L. , Skerfving S. , Mattsson S.
Published: March 2009

Abstract: In 14 retired lead workers, followed for over 18 years after end of exposure, repeated analyses of lead levels in finger bone by an in vivo X‐ray fluorescence method revealed a decrease of lead concentration. The data were analysed using an exponential retention model. For the whole group the biological half‐time was 16 (asymptotic 95% confidence interval, CI 12,23) years. The median of the estimated bone lead levels at the end of exposure was 85 μg·g−1 above the “background” (3 μg·g−1). A simultaneous follow‐up of blood lead levels displayed a decrease, which could be described by a tri‐exponential retention model with group half‐times of 34 (CI 29,41) days, 1.2 (CI 0.9,1.8) years, and 13 (CI 10,18) years, respectively. The median of the estimated blood lead levels at the end of exposure for the three components were 0.49, 0.61, and 1.1 μmol·l−1 above the “background” (0.38‐0.56 μmol·l−1), respectively. The well‐documented decrease of lead exposure in the general population over the years, urged the use of a decreasing “background” of blood lead during the time of the study. The slowest of the three components represented the skeleton (probably mainly cortical bone), as did mainly probably also the intermediate one (trabecular bone). The data show the rather slow turnover of lead in the skeleton, the usefulnes of in vivo skeletal lead measurements as a long‐term exposure index, and the importance of bone as a source of “endogenous” lead exposure.
Cadmium and Zinc Kinetics in Fish: Studies on Water‐Borne 109Cd and 65Zn Turnover and Intracellular Distribution in Minnows, Phoxinus phoxinus
Authors: Glynn Anders Wicklund
Published: March 2009

Abstract: This study investigates the short‐ and long‐term turnover of zinc and cadmium in fish. Juvenile minnows, Phoxinus phoxinus, were exposed to water‐borne 109Cd and 65Zn for 24 hr. Tracer uptake, redistribution, elimination, and intracellular tracer distribution were studied for 60 days in tracer‐free water. The influx of 65Zn from the water to the internal organs was more rapid than the influx of 109Cd, and the 65Zn turnover in the liver and kidney was considerably faster than the turnover of 109Cd. Moreover, in the gills and kidney, intracellular 65Zn was more mobile between intracellular compartments than 109Cd. The liver and kidney accumulated the major part of the 109Cd originating from the gills, whereas the head and skin, and muscle and bone‐fractions retained the majority of the 65Zn. This indicates that the metals have different pathways in the fish body, after entering the body from the water. The cadmium levels in the gills, liver and kidney increased drastically because of the cadmium exposure, but the zinc levels in the organs were not markedly affected by a fifteen‐fold increase in external zinc concentration, indicating a homeostatic control of zinc in the minnow.
Long‐Term (Imprinting) Effects of Transplacental Treatment of Mice with 3‐Methylcholanthrene or β‐Naphthoflavone on Hepatic Metabolism of 3‐Methylcholanthrene
Authors: Anderson Lucy M. , Jones Ann B. , Riggs Charles W.
Published: March 2009

Abstract:Foetal mice of genotype AhbAhd(responsive to induction of metabolism of polycyclic aromatic hydrocarbons [PAH]) or AhdAhd(non‐responsive) were exposed transplacentally on gestation day 17 to a single dose of 3‐methylcholanth‐rene (MC, 5–17. mg/kg) with or without prior treatment on day 15 with β‐naphthoflavone (βNF, 150 mg/kg). The mothers were themselves either induction‐responsive [(C57BL/6 x DBA/2)F1] or non‐responsive (DBA/2). Metabolism of [14C]MC by homogenates of livers from the transplacentally‐exposed offspring was quantified at 9 months of age (first experiment) or 13 months (second experiment) with or without prior inducing treatment with MC. The foetal exposure to MC had a permanent effect on MC metabolism by the adult hepatic homogenates in both experiments. In most instances the effect was positive in direction and small in magnitude (15‐30%). It was dose‐dependent with regard to transplacental MC, occurred in both induced (AhbAhd) and non‐induced (AhdAhd) individuals, and was significant only when the mother and/or the foetus was inducible. βNF itself did not have a positive imprinting effect. In some cases it either reduced or potentiated the long‐term imprinting effect of MC, depending on the MC dose and the phenotype of the mother. These results confirm that transplacental exposure to a carcinogenic PAH may permanently alter metabolism of the chemical in later life, and indicate that this imprinting action is dependent on induced metabolism of the chemical in the mother and/or foetus.
Comparative Effects of Medetomidine Enantiomers on in vitro and in vivo Microsomal Drug Metabolism
Authors: Pelkonen Olavi , Puurunen Juhani , Arvela Pentti , Lammintausta Risto
Published: March 2009

Abstract:The effects of dexmedetomidine, a selective α2‐adrenoceptor agonist, and its levo enantiomer (MPV‐1441), onin vitromicrosomal P450‐dependent drug‐metabolizing activities as well as onin vivoaminopyrine elimination and hexobarbital sleeping time were studied. Both enantiomers inhibited the oxidative metabolism of several model substrates and testosterone in rat liver microsomal incubations. Microsomal activities derived from control animals or rats pretreated with phenobarbital were more sensitive to inhibitory effects of dexmedetomidine than those from rats treated with 3‐methylcholanthrene. Enzyme activities in human liver microsomes were also inhibited by dexmedetomidine. Retardation of the elimination of aminopyrine was dose‐dependent; elimination was marginally retarded with doses up to 100 μg/kg (from 17 to 23 min.; both enantiomers). Higher doses of the levo enantiomer prolonged aminopyrine half‐life to 78 (1 mg/kg) and 162 min. (10 mg/kg). The hexobarbital sleeping time was prolonged by the dose of 1 mg/kg of the levo enantiomer (128 min. versus 20 min. in controls), while the dose of 0.1 mg/kg had no effect (23 versus 20 min.). These studies indicate that both enantiomers of medetomidine are inhibitors of microsomal drug metabolismin vitro, but significant effects on aminopyrine elimination or hexobarbital sleeping time are apparent only at doses, which do not allow the use of dexmedetomidine because of excessive sedative effect.
Dipyridamole and RA‐642 Inhibit the Production of Superoxide Anion and Free Radical Damage to Rat Lens
Authors: De La Cruz J. P. , Sintas A. , Moreno A. , Garcia‐Campos J. , De La Cuesta F. Sanchez
Published: March 2009

Abstract:We studied the effects of dipyridamole and RA‐642 on the production of superoxide anions and on oxygen radicals‐induced lipid peroxidation in lens tissue homogenates from normal rats and rats given dipyridamole or RA‐642 intraperitoneally. Superoxide production was evaluated by phenazine methosulphate (PMS)‐induced nitroblue tetrazolium (NBT) reduction and lipid peroxidation by ferrous sulfate and ascorbic acid (FeAs)‐induced malondialdehyde (MDA) production. Dipyridamole and RA‐642 showed an inhibitory effect on both assays in the experiments with lens tissue homogenates from untreated or treated rats. The extent of inhibition, however, was significantly higher in pyrimidopyrimi‐dinic‐treated rats (range of inhibition at different times of incubation was 18% versus 23–57. for dipyridamole and 14% versus 73–80. for RA‐642 in the assay of MDA production, and 10% versus 33–37. for dipyridamole and 2.5% versus 11–32. for RA‐642 in the assay of NBT reduction). Concentrations of dipyridamole and RA‐642 in lens tissue from treated animals could not be determined (< 0.001 μg/mg of tissue). Although both compounds inhibited lipid peroxidation induced by oxygen free radicals, the mechanism of action might include the role of adenosine as a mediator.
Effect of Opioid Agonists Selective for Three Subclasses of Opioid Receptors and One σ Receptor Agonist on Dopamine Stimulated Adenylate Cyclase in Rat Caudate Nucleus
Authors: Grynne B. Hougens , Holmen Aa. T. , Enger M. , Maurset A. R.
Published: March 2009

Abstract:The adenylate cyclase in rat caudate nucleus homogenate could be stimulated by dopamine and less potently by the dopamine D1receptor specific agonist SKF38393. Agonists selective for μ[D‐Ala2, MePhe4Gly(o1)5]enkephalin (DAGO) and δ opioid receptors [D‐Pen2, D‐Pen5]enkephalin (dPen‐dPen), inhibited the dopamine but not the dopamine D1stimulated adenylate cyclase. The opioid agonist, U69593, had no effect, probably due to low kappa receptor contents in rat caudate nucleus. 10−4M of the σ receptor specific agonist, 1,3‐di‐o‐tolylguanidine (DTG), potentiated the dopamine as well as the dopamine D1stimulated adenylate cyclase while lower concentrations of DTG had no effect.
Microdialysis of Lipophilic Compounds: A Methodological Study
Authors: Carneheim Claes , Ståhle Lars
Published: March 2009

Abstract: The influence of perfusion medium on in vitro recovery of 14C‐oleate to microdialysis probes was investigated. Four perfusion media were investigated: water, 4% bovine serum albumine (BSA) in Ringer solution, 2.25% glycerol in water and a 20% soybeanoil/eggphospholipid emulsion (Intralipid®). The following order of recovery was found (highest recovery first): BSA = Intralipid® > glycerol > water. The recoveries at 0.5 μl/min. perfusion rate of the dialysis probe were 4.8%, 4.4%, 2.6% and 1.2% respectively. It was attempted to measure 14C‐oleate after intravenous infusion. The samples were extracted with hexane/isopropylalcohol in order to separate the free fatty acid from products of oxidation which are hydrophilic. Dialysis probes were implanted in interscapular adipose tissue, epididymal fat, muscle, liver and jugular vein of rats. We were not able to detect unbound fatty acids, neither basally nor after stimulation with 1 mg/kg norepinephrine intraperitoneally. However, products of oxidation from the infused oleate were released in response to norepinephrine stimulation. It is concluded that the recovery of lipophilic compounds in microdialysis devices can be improved by means of a lipophilic perfusion medium or by means of e.g. BSA to which the compound binds. The free fatty acid levels were too small to be measureable in vivo in the present study.
Purification and Characterization of Hepatic Microsomal Cytochrome P‐450 in Phenobarbital‐ and β‐Naphthoflavone‐Treated Pigs
Authors: Thomsen Mads Krogsgaard , Friis Christian , Nielsen Poul
Published: March 2009

Abstract:Different cytochrome P‐450 isoenzymes from hepatic microsomes of phenobarbital (PB) and β‐naphthoflavone (β‐NF) treated pigs and rats were isolated, purified, and characterized. The physico‐chemical properties of the porcine isoenzymes were similar to properties of forms isolated from other species. The molecular sizes ranged from 52.5 to 59.5 kD and, in the ferrous‐carbonyl state, the isoenzymes had absorbance maxima between 447 and 451 nm. Antigenic similarities were found between the isoenzymes present in PB‐induced pigs, and between the isoenzymes present in β‐NF‐induced pigs. Cross‐reactivity was not observed between PB‐ and β‐NF‐inducible isoenzymes, but β‐NF‐inducible isoenzymes in pigs and rats possessed antigenic similarities.