bluuebunny/crossref_metadata_2025 huggingface dataset:
Exposure to Carbachol Induces Several Changes in Muscarinic Cholinergic Parameters in N1E‐115 Mouse Neuroblastoma Cells
Authors: Hedlund Britta , Lorentz Maud , Reintam Anne‐Christine , Sydbom Anita
Published: March 2009

Abstract:Mouse N1E‐115 neuroblastoma cells were used to study carbachol induced changes in muscarinic cholinergic parameters. Cells were treated with carbachol (1 mM) for up to 96 hours. The number of muscarinic receptors, measured in3H‐3‐quinuclidinyl benzilate binding experiments, decreased approximately 50% after 4 hours exposure to carbachol. This was followed by an increase in binding sites, and after 24 hours the number of binding sites was the same as in control cells. The changes observed in the choline esterase activity followed the same pattern. The increase in number of binding sites was not dependent on protein synthesis, while the increase in choline esterase activity was. The muscarinic receptor‐stimulated uptake of45Ca2+showed an initial decrease, which was followed by a significantly increased basal uptake of45Ca2+. It is suggested that all these changes are adaptations of long time exposure to carbachol.
The Influence of Magnesium on the Release of Calcium from Intracellular Depots in Vascular Smooth Muscle Cells
Authors: Sjögren Anders , Edvinsson Lars
Published: March 2009

Abstract:Vasoconstrictor responses to prostaglandin F2a and noradrenaline were investigated in ring segments of feline femoral, coronary and cerebral arteries incubated in calcium‐free solutions containing different concentrations of magnesium (1.2, 4.4 and 13.2 mM). Contractions produced by prostaglandin F2a and noradrenaline were depressed when calcium was omitted from the incubation solution. The presence of raised concentrations of magnesium (4.4 or 13.2 mM) in the tissue bath further depressed the prostaglandin f2a and noradrenaline contractions in calcium‐free medium. In a separate set of experiments the vessel wall contents of cAMP and cGMP were measured before and after the additions of 4.4 or 13.2 mM magnesium; stable relaxations by magnesium were noted but there was no parallel change in the vessel content of cAMP or cGMP. The results indicate that magnesium may interfere with the release of calcium from intracellular depots, and that neither adenylate cyclase, nor guanylate cyclase are involved in the dilator activity of magnesium in isolated arteries.
Influence of Endothelium on the Response to Calcium Agonists, Calcium, Potassium and Noradrenaline in Rat Aorta
Authors: Mikkelsen E. O. , Costa G. , Nyborg N. C. B.
Published: March 2009

Abstract:We have studied the influence of endothelium on BAY K 8644, CGP 28392, potassium, noradrenaline and calcium induced responses in isolated thoracic aorta from rats. In aortic preparations with intact endothelium BAY K 8466 and CGP 28392 (10‐9‐10‐5M) had a concentration dependent contractile effect, but BAY K 8644 was more effective in contracting the vessels than CGP 28932. Removal of endothelium increased the contractile response to both substances without affecting the difference in contractile effect between the two calcium agonists. In high concentrations (10‐4M) BAY K 8644 and CGP 28392 had an equal relaxing effect on potassium precontracted preparations, which was unaffected by removal of endothelium. Removal of endothelium caused a shift to the left of the potassium and noradrenaline concentration response curves without any change in maximal contractile response. The contractile response to calcium in BAY K 8644 and potassium activated vessels was unaffected by removal of endothelium. We conclude that endothelium derived factor(s) depress the contractile response to calcium agonists, potassium, and noradrenaline but has no influence on the relaxant effect of BAY K 8644 and CGP 28392 in rat aorta. The influence of endothelium on the contractile effect on BAY K 8644 and potassium seems not to be due to a direct effect on calcium influx but rather to an influence on the membrane potential of the smooth muscle cells.
Estimating Chemical Developmental Hazard in a Chicken Embryo Limb Bud Micromass System
Authors: Wiger Richard , Støttum Anne , Brunborg Gunnar
Published: March 2009

Abstract: A chicken limb bud micromass system measuring the production of cartilage proteoglycans and the incorporation of radiolabeled thymidine and leucine was used to calculate potential developmental hazard. This hazard index was based upon the 50% inhibitory concentration (IC50) for these parameters and enabled classification of substances according to their intrinsic ability to inhibit differentiation at concentrations which were not cytotoxic. All‐trans‐retinoic acid, a potent teratogen, inhibited cartilage proteoglycan synthesis at a concentration which was more than 100 times lower than those affecting the incorporation of 14C‐thymidine and 14C‐leucine. On the other hand, sodium valproate, salicylate and isoniazid inhibited cartilage proteoglycan synthesis only near concentrations which were also cytotoxic. The results from testing with chicken limb bud micromass compared favorably, both with respect to effective concentrations and ratios describing developmental hazard to those from rodent micromass systems.
Comparison of Desipramine, Amitriptyline, Zimeldine and Alaproclate in Six Animal Models Used to Investigate Antidepressant Drugs
Authors: Danysz Wojciech , Plaznik Adam , Kostowski Wojciech , Malatynska Ewa , Járbe Torbjörn U. C. , Hiltunen Arto J. , Archer Trevor
Published: March 2009

Abstract:In the present paper the acute actions primarily of the tricyclic antidepressants amitriptyline and desipramine, the atypical antidepressant zimeldine and the potential antidepressant alaproclate were evaluated in six models used for studying antidepressant agents. These included the forced swim test, a modified learned helplessness procedure, the clonidine hypothermia test, the social dominance test (using the interaction with clonidine), a differential‐reinforcement‐of‐low‐rates (DRL‐72s) schedule and conditioned avoidance response. The results showed desipramine to be effective in all the tests employed. Zimeldine was effective in the learned helplessness, DRL‐72s and domination tests, but also caused notable deficits in two‐way active avoidance response. Alaproclate was effective in all the tests except the domination paradigm. Amitriptyline was effective in all tests employed. The results are discussed in relation to the possible mechanism of action of these compounds in the test models employed.
Effects of Antiparkinsonian Drugs on Muscarinic Receptor Binding in Rat Brain, Heart and Lung
Authors: Syvälahti E. K. G. , Kunelios R. , Laurén L.
Published: March 2009

Abstract: The anticholinergic antiparkinsonian drugs biperiden, benztropine, trihexyphenidyl, methixene, and procyclidine were compared with atropine and pirenzepine, as well as with orphenadrine, amantadine and some standard antidepressives and neuroleptics in their ability to inhibit the binding of tritiated quinuclidinyl benzilate (QNB) to the muscarinic receptors in rat brain cortical tissue. Most of the antiparkinsonian drugs studied were potent inhibitors of (‐)3H‐QNB binding, when compared to atropine (ICSO‐value=0.22 μM), the IC5O‐values ranging from 0.0084 μM (biperiden) to 0.07 μM (procyclidine). Orphenadrine had a low and amantadine no evident affinity for muscarinic receptors. With the exception of pirenzepine and biperiden the inhibition curves were steep and parallel, giving linear Hill plots with coefficients close to unity. The binding profile of atropine, pirenzepine, and biperiden was further studied in heart and lung tissues, atropine showing only small divergences in its binding to the different tissues, but biperiden and pirenzepine having five to ten times lower affinity in the peripheral tissues than in the brain. The results confirm the high affinity of most of the antiparkinsonian drugs for brain muscarinic receptors. The dissociation constants agree with the average clinical doses of the drugs. It must be remembered, however, that the binding data may represent multiple events at receptor sites because most of the drugs used are mixtures of stereoisomers. Thus further studies using individual enantiomers are needed to compare more directly binding data between the compounds.
Effect of the Antioxidant N,N1=Diphenyl=p phenylenediamine (DPPD) on Bromobenzene Metabolism and Toxicity in Isolated Hepatocytes
Authors: Qunnguan Jlang , Moldéus Peter
Published: March 2009

Abstract:Bromobenzene induced cytotoxicity in isolated hepatocytes was partly prevented by the antioxidant DPPD (N,N′‐diphenyl‐p‐phenylenediamine). This protection did not appear to be a result of an inhibition of lipid peroxidation but rather to an inhibition of the metabolic activation of bromobenzene. The extent of DPPD dependent inhibition of cytochrome P‐450 catalyzed reactions appears to depend on the substrate being metabolized. Thus, whereas cytochrome P‐450 catalyzed metabolism of bromobenzene and harmine was inhibited by DPPD, the N‐dealkylation of aminopyrine was not. The results presented in this paper indicate the importance of evaluating the effect of antioxidants such as DPPD as inhibitors of bioactivation prior to drawing definitive conclusions regarding involvement of lipid peroxidation in drug induced cytotoxicity.
An Experimental Study on Ethanol Elimination at Subphysiological Temperatures
Authors: Normann Per Tygve , Olsen Harald , Aune Håkon , Sakshaug Johan , Ripel Åse , Merland Jørg
Published: March 2009

Abstract:Hepatocytes isolated from fed and fasted rats have been used to study the rate of ethanol elimination at different incubation temperatures. In the presence of exogenous pyruvate, hepatocytes from fed and 42 hr fasted rats, eliminated ethanol at 37$dG by a rate of 11.6 ±3.4 and 6.4 ± 0.8 nmol/min./mg of cell protein (±S.D.;n= 5), respectively, which are comparable to the rates obtainedin vivo.The ethanol oxidation rate in cells from rats of both nutritional states correlated linearily to the incubation temperature (t = 24‐37$dG) with a temperature coefficient (Q10) of 1.8‐2.3. (Q10, (= temperature coefficient) is the factor by which the enzyme activity is increased on raising the temperature 10$dG). These findings indicate that the oxidation is not controlled by processes which involve membrane transitions in the temperature range 24‐37$dG. Our results indicate that a hypothermic individual with a body temperature of 27$dG would have a 40‐50 per cent inhibition of the ethanol elimination rate. Thus, the observed dependency of the ethanol oxidation on the body temperature has to be regarded in back‐calculations of blood ethanol concentrations in forensic toxicology.
Pharmacokinetics and Dynamic Effects of Diltiazem in the Isolated Guinea‐Pig Heart
Authors: Jensen Henrik Kjærulf , Nielsen‐Kudsk Folmer
Published: March 2009

Abstract:Myocardial pharmacokinetics of diltiazem showed two‐compartment characteristics in the isolated, spontaneously beating guinea‐pig heart. Half‐times of initial and terminal drug accumulation phases were about 2.1 and 14.4 rain., respectively. At 1 μg ml‐1(2.4 μM) in the perfusion liquid the average concentration of diltiazem in the myocardium at steady state was about 16 μg g‐1(38.6 μM) with 17% referable to the deepest, possibly intracellular compartment. Increasing diltiazem concentrations from 13 to 889 ng ml‐1(31–214. nM) produced a progressive increase in coronary flowrate from 100 to 174%. The computed Em‐ and EC50‐values were 73.2% and 187 nM, resepctively. Oxygen consumption decreased to 27.6% showing Em=106% and IC50 = 1536 nM. Amplitude and velocity of myocardial contraction decreased to about 6% and 2%; Em= 101% and 104%, IC50=266 and 186 nM, respectively. Heart beating frequency decreased to 63% exhibiting Em= 58% and IC50=2015 nM. The PQ‐ and QRS‐intervals increased to 133% and 112%, respectively. The frequency‐corrected QT‐interval decreased to 81.6%. Our findings demonstrate a relatively rapid and moderate accumulation of diltiazem in the guinea‐pig heart accompanied by a marked increase in coronary flow, progressive and pronounced negative inotropic and chronotropic effects and a less than proportional decrease in oxygen consumption.
Studies on the Acute and Long‐Term Changes in Dopamine and Noradrenaline Metabolism in Mouse Brain Following Administration of 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)
Authors: Pileblad Erik , Carlsson Arvid
Published: March 2009

Abstract:Previous studies from these laboratories have revealed that 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) induced acute profound release of dopamine together with a marked reduction in dopamine synthesis. The present study was undertaken in an attempt to further elucidate these acute alterations. MPTP produced dose‐dependent marked reductions in the concentrations of dopamine and noradrenaline in mouse brain 2 hours as well as 7 days after the administration. Both the acute and long‐term reductions in dopamine were most pronounced in the striatum, whereas the reductions in noradrenaline (acute and long‐term) were most pronounced in the cortical region. Contemporaneous with the acute reduction in the catecholamines, MPTP increased the levels of the dopamine metabolites 3‐methoxytyramine and homovanillic acid (HVA), and the noradrenaline metabolite normetanephrine. In contrast, the levels of the dopamine metabolite 3,4‐dihydroxyphenylacetic acid (DOPAC) were reduced. These data are indicative of a profound release of both dopamine and noradrenaline from the storage sites into the extraneuronal space. Pretreatment with the monoamine oxidase inhibitor pargyline totally prevented the acute reduction in dopamine and partially also the reduction in noradrenaline produced by MPTP. However, MPTP increased the levels of 3‐methoxytyramine and normetanephrine also in pargyline treated mice. The selective dopamine uptake inhibitor GBR 13098 antagonized the MPTP‐induced reduction in dopamine and increase in 3‐methoxytyramine, but had no effect on the MPTP‐induced reduction in noradrenaline. MPTP produced a marked acute reduction in tyrosine hydroxylation in the dopamine predominated areas striatum and limbic region, whereas a slight increase in tyrosine hydroxylation was noted in the noradrenaline predominated cortical region. Similar effects of MPTP were observed in reserpine pretreated animals. Pargyline prevented the MPTP‐induced reduction in dopamine synthesis. Recentin vitroobservations indicate that MPP+, the toxic metabolite of MPTP, is capable of inhibiting the electron‐transport carrier, an action which may account for the neurotoxicity of the compound. It appears possible that this effect of MPP+could explain the currently observed acute changes in catecholamine metabolism.
Toxicity of n‐C9 to n‐C13 Alkanes in the Rat on Short Term Inhalation
Authors: Nilsen Odd G. , Haugen Olav A. , Zahlsen Kolbjørn , Halgunset Jostein , Helseth Are , Aarset Harald , Eide Ingvar
Published: March 2009

Abstract: Male Sprague Dawley rats were exposed to inhalation of n‐C9 to n‐CI3 alkanes close to air saturation at 20$dG (4438, 1369, 442, 142 and 41 p.p.m., respectively) for 8 hours and observed for the following 14 days. In addition, exposure to higher and lower concentrations of n‐C9 was performed. The concentration of alkane in the brain after exposure exceeded that of blood for the lower alkanes, while the higher alkanes possessed a brain/blood ratio equal to or less than unity. Gross ataxia, general and focal seizure and spasms were observed in animals exposed to n‐C9 in the range from 5280 to 3560 p.p.m. No toxic effects were observed in animals exposed to 2414 p.p.m. of n‐C9 or to the other alkanes. An LC50 value for n‐C9 of 4467±189 p.p.m. was estimated. Despite the clinical improvement in animals surviving the n‐C9 exposure of 4438 p.p.m. (6/10), severe cerebellar damages were found at autopsy at the end of the observation period, with a loss of Purkinje cells as the most prominent feature. Immediate post mortem examination (4/ 10) showed marked vascular congestion of the liver as well as slight fatty degeneration but no cerebellar damage. No abnormalities were observed in animals exposed to the other alkanes. The significant distribution in the brain of the n‐C9 alkane, the clinical signs of cerebellar dysfunction and the damage of cerebellar neurons would suggest CNS to be a possible target organ for the toxic effects of the n‐C9 alkane.
Class III Antiarrhythrnic Action Linked with Positive Inotropy: Effects of the d‐ and 1‐Isomer of Sotalol on Isolated Rat Atria at Threshold and Suprathreshold Stimulation
Authors: Tande Pål M. , Refsum Helge
Published: March 2009

Abstract:The β‐adrenoceptor blocker sotalol has been shown to possess class III antiarrhythmic action. The present study was designed to test the hypothesis that class III antiarrhythmic action and positive inotropy may be linked. Since d, 1‐sotalol has previously been reported to have variable inotropic effect, we studied direct effects of the d‐ and 1‐stereoisomer of sotalol on refractoriness and inotropy of isolated rat atria at different strengths of electrical stimulation. Both the d‐ and I‐stereoisomer of sotalol (7.5 × 10‐5M) increased the effective refractory period, and to the same extent. However, d‐sotalol increased isometric contractile force by 10%, while 1‐sotalol had no significant effect, when the atria were stimulated at close to threshold values (10 ± 1 mA). Probably due to release of noradrenaline within the myocardium, contractile force increased when the atria were stimulated at suprathreshold values (40 mA). At suprathreshold stimulation, however, d‐sotalol induced a 10% decrease and 1‐sotalol a 20% decrease, in contractile force. In conclusion, the class III antiarrhythmic action of sotalol is linked with positive inotropy. In the presence of neurotransmitter release, negative inotropic effect of d‐ and in particular 1‐sotalol, may occur due to β‐adrenoceptor blocking activity,
Elimination Kinetics and Urinary Excretion of Disopyramide in Human Healthy Volunteers
Authors: Bonde Jan , Jensen Niels Melchior , Pedersen Lars E. , Graudal Niels A. , Angelo Helle R. , Kampmann Jens P.
Published: March 2009

Abstract:Elimination kinetics and the renal handling of disopyram5de was examined in 8 healthy volunteers. Approximately 50% of the administered disopyramide undergoes hepatic metabolism (metabolic clearance = 116.1 ± 42.2 ml/min.), while the rest is excreted by the kidneys (renal clearance= 101.9 ± 21.6 ml/min.). Total renal excretion rate of disopyramide was 0.676 ± 0.188 μmol/min. and 0.258 ± 0.029 μmol/min. was excreted by glomerular filtration leaving anettubular secretion of 60% of the total renal elimination. A significant positive correlation was observed between total serum concentrations and renal clearance values of disopyramide while no significant correlation could be obtained between serum concentrations of the unbound drug and renal clearance values of disopyramide, implying a constant value of unbound renal clearance. Hepatic blood flow was significantly (P < 0.005) decreased following disopyramide infusion.
Studies on Vascular Smooth Muscle Tolerance to Different cGMP‐Mediated Vasodilators and Cross‐Tolerance to Glyceryl Trinitrate
Authors: Ljusegren Marie Ekstam , Ahlner Johan , Axelsson Krister L.
Published: March 2009

Abstract:In the present study the possible existence of cross‐tolerance between GTN, atrial natriuretic peptide and the endothelium‐dependent vasodilators acetylcholine and calcium ionophore A23187 was investigated. Pretreatment of bovine mesenteric arteries (BMA) with GTN (0.44 mM) for 2 hrs caused a significant (P< O.OOl) right‐shift of the concentration‐effect curve for GTN as compared to controls (pD2= 6.96 ±0.208 and 4.57±0.148 in controls and GTN treated vessels, respectively), thus indicating the development of tolerance. Cross‐tolerance between GTN and the endothelium‐dependent vasodilators acetylcholine and calcium ionophore A23187 was found as judged from cumulative concentration‐effect curves. The cGMP response evoked by 1 μM GTN was markedly blunted in the GTN‐pretreated vessels (P=O.O056). Similarly the cGMP elevation induced by 10 μM acetylcholine and 0.1 μM calcium ionophore A 23187 was significantly reduced in GTN‐pretreated muscle specimens (P = 0.0475 and P = 0.0103, respectively). No cross‐tolerance between GTN and atrial natriuretic peptide (ANP) could be established from tension studies. Furthermore, the cGMP response induced by atrial natriuretic peptide was not significantly different in GTN‐tolerant vessels as compared to in controls (P=0.2097). BMA specimens were also incubated with acetylcholine and ANP (2 hrs and 6 hrs, respectively) and the vessels were thereafter tested for their responsiveness to acetylcholine, ANP and GTN. Preincubation with acetylcholine (10 μM) for 2 hrs did not affect the relaxant response to a subsequent challenge with acetylcholine or GTN. Preincubation of BMA with ANP (0.1 μM) for 6 hrs was also without effect on the responsiveness to ANP or GTN. The ANP‐evoked cGMP increase was however somewhat reduced in ANP‐incubated BMA. These results suggests the existence of a certain degree of cross‐tolerance between GTN and endothelium‐dependent vasodilators, while GTN‐pretreatment has no effect on relaxations induced by ANP in BMA.
Variable Bioavailability of Papaverine
Authors: Berg Göran , Jönsson Kjell‐Åke , Hammar Mats , Norlander Björn
Published: March 2009

Abstract:The plasma concentration curves of papaverine have been studied in nine healthy males and seven patients after administration of single intravenous (80 mg) and oral (80 mg) doses. The bioavailability of the drug was highly variable with a mean of 28% (range 5‐99%) but reproducible within the same individual (4 of the volunteers) after a repeated (80 mg) oral dose. The calculated half‐life after intravenous administration ranged between 1.2‐6.6 hours (mean 3.0). The mean apparent volume of distribution was 3.1 1/kg and the mean total plasma clearance was 836 ml/min. It is concluded that papaverine shows an unacceptable inter‐individual variation in the bioavailability after oral administration of 80 mg tablets.
Haloperidol and Metabolite Concentrations in the Rat after Concurrent Isotretinoin Administration: A Preliminary Report
Authors: Straw Gregory , Kirch Darrell , Freed William J.
Published: March 2009

Abstract:Blood and tissue haloperidol concentrations can be altered by the concurrent administration of a number of other drugs. Here we describe effects of concurrent administration of the vitamin A metabolite, isotretinoin, on haloperidol and reduced haloperidol concentrations in the rat. Isotretinoin increased the concentrations of both haloperidol and reduced haloperidol in serum, red blood cells, and brain. However, the dose dependence and degree of the effect varied significantly across tissues. Further study is called for to elucidate the interaction of neuroleptics such as haloperidol with the vitamin A acids such as isotretinoin.
Biosynthetic Human Growth Hormone: Subchronic Toxicity Studies in Rats and Monkeys
Authors: Jørgensen Karin Damm , Svendsen O. , Greenough R. J. , Kallesen T. , Goburdhun R. , Skydsgaard K. , Finch J. , Dinesen B. , Nilsson P.
Published: March 2009

Abstract: Biosynthetic human growth hormone was injected subcutaneously in rats for 90 days and in cynomolgus monkeys for 30 days. The daily doses were 0.5, 3.3 and 25 IU kg‐1 (rats) and 0.3 and 15 IU kg‐1 (monkeys). The growth hormone was tolerated well in both rats and monkeys. No drug related deaths occurred and all animals appeared to be normal and also behaved normally throughout the dosing period. Increased body weight gain, increased food utilisation and increased organ weights were seen in the rats in the high and intermediate dose groups. The higher doses of human growth hormone (3.3 and 25 IU kg‐1) caused a glandular hyperplasia of the mammary gland in male and female rats with evidence of secretory activity. In the female monkeys secretory activity was seen without any sign of mammary gland hyperplasia. Mucification of the vaginal epithelium and stress induced prostatitis was observed in the rats. Additional treatment related changes in the rats were an increased haematopoietic activity in the spleen and an increase in the amounts of calcium and phosphate excreted in urine. An increase in fasting plasma glucose levels was seen in the male monkeys on the high dose level. The changes observed during the treatment periods presumably represent exaggerated pharmacological effects of the growth hormone.
Acute Hepatocellular Effects of Erythromycin, Gentamicin, and Trospectomycin in the Perfused Rat Liver: Lack of Correlation between Lamellar Body Induction Potency and Cytotoxicity
Authors: Cox Jeffrey W. , Ulrich Roger G. , Larson Philip G. , Cramer Clay T.
Published: March 2009

Abstract:The formation of multilamellar inclusion bodies in cytoplasm is a generalized cellular response to treatment with a variety of chemical agents. The present study was conducted to determine if a correlation exists between acute lamellar body induction potency and cytotoxicity in the perfused rat liver. Livers were perfused for 3 hrs with various concentrations of erythromycin, gentamicin, sulfate, or trospectomycin sulfate, all of which are known to produce lamellar bodies in the ratin vivo.At the end of the experiments, the livers were perfusion fixed for transmission electron microscopy. Based on the bile flow rate, perfusion rate at constant pressure, and cytoplasmic enzyme release, neither gentamicin nor trospectomycin was hepatotoxic at concentrations up to 1.8 mM, whereas erythromycin was toxic at 0.1 mM. Gentamicin caused no ultrastructural changes compared to controls, but trospectomycin caused the dose‐dependent formation of lamellar bodies in hepatocytes without other cytoplasmic alterations. Erythromycin caused cellular degeneration accompanied by an increase in the number of secondary lysosomes, but these lacked lamellated inclusions. It is concluded that hepatic lamellar bodies can be induced in acuteex vivoexperiments, but that their formation does not appear to be linked with acute cytotoxicity.
Oral Absorption of Sodium Pentobarbital and Effects on Gastrointestinal Function
Authors: Curd‐Sneed Cheryl D. , Stewart John J.
Published: March 2009

Abstract:An anaesthetic dose (40 mg/kg) of sodium pentobarbital (SP) was administered intragastrically to adult, fasted male rats at total dosing volumes of 1, 2, or 3 ml. Area under the plasma concentration‐time curve did not differ for the various dosing volumes. During the initial (rapid) phase of gastric emptying all solutions containing drug appeared to empty at a faster rate than distilled water (2 ml). However, solutions containing drug emptied much more slowly than water during the terminal (slow) phase of gastric emptying. Drug solutions moved along the small intestine at approximately the same rate as distilled water. SP significantly lowered rectal temperature and slowed the propagation velocity of the migrating myoelectric complex (MMC) recorded from four serosal electrodes chronically implanted along the proximal small intestine. In addition, the drug significantly decreased the rate of MMC recurrence, extended the duration of MMC phases, and decreased slow wave frequency at all sites monitored. The results suggest that: 1) the relative oral bioavailability of sodium pentobarbital is not influenced by dosing volume within the range tested, 2) the various dosing volumes of SP tested moved through the gastrointestinal tract at an equal rate, and 3) orally administered SP significantly decreases the propagation velocity and periodicity of the MMC in the small intestine.
A Methodological Comparison of Two Formulations of Temazepam in Pharmacokinetic and Pharmacodynamic Aspects
Authors: Tuomainen P.
Published: March 2009

Abstract: In a double‐blind and cross‐over study 12 healthy subjects took temazepam 20 mg in two different formulations (soft gelatine capsule or uncoated tablet) and matched placebo at one‐week intervals. Plasma temazepam concentrations at 0.5, 1, 2, 3, 8, 12 and 24 hours after treatment were analyzed by gas chromatography. Psychomotor performance was measured objectively (digit symbol substitution, letter cancellation, Maddox wing test) and subjectively (visual analogue scales) before the drug intake and 1, 2 and 3 hours later and the plasma benzodiazepine concentrations were analyzed also by radioreceptor bioassay. The two different formulations were compared in pharmacokinetic and pharmacodynamic terms, and the gas chromatographic and radioreceptor assays were compared. The soft gelatine capsule produced higher peak plasma concentrations than the uncoated tablet. The computed AUCs and elimination half‐lives proved to be similar after either formulation. A satisfactory correlation between the bioassayed benzodiazepine concentrations and chemically assayed temazepam was shown. In pharmacodynamic terms the results suggest a shorter and somewhat smaller subjective response for the capsule than for the tablet form.
Effects of Immunosuppressive Chemicals on Lymphoid Development in Foetal Thymus Organ Cultures
Authors: D'Argy Roland , Bergman Jan , Dencker Lennart
Published: March 2009

Abstract:A murine foetal thymus organ culture system was employed to screen a number of immunotoxic chemicals for direct thymus toxicity. The toxic effects caused by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and its congeners on the system used had previously been shown to be similar to those causedin vivoon lymphoid development. The most potent compound tested was the corticosteroid fluocinolone acetonide, which caused a 50% inhibition of lymphoid development (EC50) at a concentration of 5 × 10−11M. The EC50 of TCDD was around 5 × 10−10M while that of 4 β‐phorbol 12‐myristate 13‐acetate (TPA) was ca 10−7M. TCDD and its congeners are believed to act via binding to theAhreceptor. Other known or presumed ligands of this receptor, which are potent inducers of P1‐450 (P‐448) ‐dependent polysubstrate monooxygenase activities, were considerably less toxic with EC50 levels varying between 10−5M (7,12‐dimethylbenz(α‐) antracene, α‐naphthoflavone, benzo(α)pyrene) and 10−4M (β‐naphthoflavone and 3‐methylcholantrene). Dinaphtho/2,3‐b,5,6‐b/dioxin and indolo/2,3‐b/carbazole showed toxicity at 5 × 10−6− 10−5M and 5 × 10−5M respectively. TCDD, TPA, and fluocinolone showed additive effects when added two by two in different combinations. Thus fluocinolone, known to counteract the toxicity and epidermal growth factor (EGF) cell‐surface receptor‐decreasing activity caused by TPA in other cell types, failed to decrease TPA toxicity in the thymus culture system.
Influence of Long‐Term Prenalterol Treatment on the Heart Rate and the β‐Adrenoceptor Binding‐Sites in Rat Myocardium
Authors: Ahlner Johan , Andersson Rolf G. G. , Dahlström Ulf , Nylander Eva
Published: March 2009

Abstract:The density of β‐ adrenoceptors has been determined on membranes prepared from rat myocardium. Long‐term administration of prenalterol resulted in an increase in the density of receptors, without any change in affinity. The average heart rate increase induced by intravenous prenalterol administration to denervated rats was, however, similar in the prenalterol pretreated and the control groups. We conclude that long‐term treatment with a partial β1‐adrenoceptor agonist lead to an increased β‐adrenoceptor density in the myocardium.
Parallel Decrease in the Density of Dopamine D1 and D2 Receptors in Corpus Striatum of Rats from 3 to 25 Months of Age
Authors: Hyttel John
Published: March 2009

Abstract: The density (Bmax) and apparent dissociation constant (KD) of dopamine D1 and D2 receptors in striatum was estimated in rats of different ages (from 3.5 to 25 months) using 3H‐SCH 23390 and 3H‐spiperone as ligands. The density of D1 and D2 receptors decreases with age attaining 70 and 69% of the 3.5 months' value, respectively, whereas the KD's remain constant. The decreases in density of D1 and D2 receptors are parallel. Thus, throughout life the ratio between the density of D1 and D2 receptors remains constant.
Pharmacodynamic and Pharmacokinetic Aspects on the Transport of Bronchodilator Drugs Through the Tracheal Epithelium of the Guinea‐Pig
Authors: Jeppsson A.‐B. , Roos C. , Waldeck B. , Widmark E.
Published: March 2009

Abstract:An isolated vagus nerve‐trachea tube preparation from guinea‐pig was used to study the effect kinetics of bronchodilating β‐adrenoceptor agonists. The test compounds were added either into the fluid‐filled lumen or into the external medium and they all inhibited, dose‐dependently and completely, the vagally induced contractions. The hydrophilic compounds isoprenaline, salbutamol and terbutaline were much less potent when administered intratracheally as compared with extratracheal administration indicating a slow transport through the epithelial layer. For the lipophilic compound, D2489 (the resorcinol derivative of salmeterol), this difference was less pronounced. When terbutaline was administered as its lipophilic diisobutyrate ester prodrug, ibuterol, the difference between the routes of administration was largely eliminated. The inhibitory effect of terbutaline, but not D2489, was readily reversed by washing. Measurements of terbutaline and D2489 in the tracheal tissue and in the external medium after the intratracheal administration of the compounds support the view that a hydrophilic compound slowly passes the epithelium and is not retained in the tissue, whereas a lipophilic compound rapidly passes the epithelium and is retained by the tissue. The isolated vagus nerve‐trachea tube preparation of the guinea‐pig is well suited for the concommitant study of pharmacodynamic and pharmacokinetic properties of bronchodilator drugs.
A Combined in Ovo‐in Vitro System for Studies of Volatile Compounds on Brain Development: Differential Effects of Carbon Tetrachloride on Neurones and Astrocytes
Authors: Clemedson C. , Peterson A. , Walum E.
Published: March 2009

Abstract: A method for studies of organic solvent effects on the development of neurones and astrocytes is described. Chick embryos in ovo were exposed to a low concentration of carbon tetrachloride vapours. After the exposure, primary cultures of neurones and astrocytes were prepared from the brain hemispheres of the embryos. Toxic effects of the solvent were analyzed in the cultures during the course of cellular differentiation as changes in cell growth and morphology, respiratory activity, and biochemical properties characteristic of each cell type. The development of neurones from embryos exposed from day 5 to day 8 to 25 p.p.m. of carbon tetrachloride was not affected by the exposure. On the other hand, growth rate and respiratory activity of astrocytes from embryos exposed from day 11 to day 14 to 25 p.p.m. of CCl4 were affected by the exposure, whereas no morphological changes or changes in the cyclic AMP levels could be observed. Consequently, low concentrations of carbon tetrachloride seem to affect the development of astrocytes rather than that of neurones in our experimental system.
Direct Effects of Furosemide and Amiloride on the Perfused and Ischaemic Rat Heart
Authors: Borchgrevink P. C. , Jynge P.
Published: March 2009

Abstract: The present study was undertaken in order to assess direct effects of furosemide and furosemide plus amiloride upon the perfused and ischaemic isolated rat heart. Furesemide in concentrations ranging between 4–400 mg/l in the perfusate increased coronary flow in a concentration dependent manner. There was no evidence for a negative inotropic effect of furosemide. However, very high doses of furosemide (400 mg/l) decreased the post‐ischaemic values of left ventricular developed pressure, coronary flow rate, adenosine triphosphate, creatine phosphate and potassium, and increased the myocardial content of calcium and sodium. Furosemide 4 mg/l and 40 mg/l had no effect on post‐ischaemic parameters compared to the control group except that furosemide 40 mg/l increased the recovery of coronary flow. Although amiloride 13.3 mg/l alone did not affect post‐ischaemic recovery, the addition of this dose to furesemide 400 mg/l improved the post‐ischaemic recovery of left ventricular developed pressure, coronary flow rate and adenosine triphosphate. The myocardial content of magnesium and potassium was higher indicating protection of amiloride by its magnesium‐ and potassium‐sparing properties opposing ischaemic losses aggravated by the exposure to furosemide.
Depression of the Hepatic Cytochrome P‐450 Monooxygenase System by the Neurotoxin 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)
Authors: Shahi G. S. , Moochhala S. M. , Das N. P.
Published: March 2009

Abstract:The effects of the neurotoxic compound, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) on the hepatic cytochrome P‐450 monooxygenase system were assessed using C57 BL/6J mice. Treatment with MPTP caused a marked depression of hepatic cytochrome P‐450 content, ethoxyresorufin O‐dealkylase and NADPH cytochrome C reductase activities. This effect was maximal 3 to 6 hours after treatment and was dependent on the dose of MPTP administered. Depression of spectrophotometrically measured cytochrome P‐450 content was associated with increase in cytochrome P‐420 content and lipid peroxidation.In vitrostudies showed the formation of a metabolic‐intermediate complex with cytochrome P‐450 which may partially explain the depression of cytochrome P‐450 content and activity by MPTP.
Kinetics of Reaction of cis‐Diamminedichloroplatinum(II) with DNA
Authors: Försti Asta , Leppälä Sinikka , Takala Mervi , Laatikainen Reino , Hemminki Kari
Published: March 2009

Abstract: A method based on cation exchange chromatography was developed to determine the adducts formed in the reaction of cis‐diamminedichloroplatinum(II) (cis‐Pt) with DNA. DNA was incubated with various concentrations of cis‐Pt for various periods of time, ethanol precipitated, and enzymatically digested to nucleosides and Pt‐containing oligonucleotides. The unmodified nucleosides were separated from the positively charged intra‐ and interstrand cis‐Pt‐adducts with a weak cation exchanger, CM‐Sephadex C‐25, and the adducts were further purified by HPLC. The main adduct was shown to be an intrastrand cross‐link of cis‐Pt bound to the N‐7 atoms of two neighboring guanines. The minor adducts were intra‐ and interstrand cross‐links of cis‐Pt with adenine and guanine and an interstrand cross‐link of cis‐Pt with two guanines. At low levels of DNA‐modification (cis‐Pt:nucleotide = 1:50–1:1000) the intrastrand cross‐link of cis‐Pt with two guanines consisted of 60–70% of the total platination of DNA. At higher levels of DNA‐modification (>1:20), the amount of undigested products increased, indicating shielding of DNA by cis‐Pt from nucleolytic enzymes.
Uptake of Gentamicin in Foetal and Newborn Rats after a Single Intraperitoneal Injection
Authors: Nässberger Lennart , DePierre Joseph W.
Published: March 2009

Abstract:The aim of the present investigation has been to examine 1) the placental passage and uptake of gentamicin in foetal rat tissues and 2) uptake and organ distribution of this drug in neonatal rats with special reference to the kidney. After a single intraperitoneal injection of tritium‐labelled gentamicin to the mother, we found a rapid passage of radioactivity across the rat placenta, but no pronounced tendency to accumulation in the foetus. After administration of 10 μg or 100 mg gentamicin per kg body weight to pregnant rats at day 11 or 13, respectively, of gestation, the maximal concentrations of the drug recovered in individual foetuses were 0.05 and 300 ng per mg wet weight. Ten and 90 min. after administration the uptake of gentamicin in the kidney cortex of the mother was 25 and 118 fold higher, respectively, than the corresponding uptake in the foetal kidney after 19 days of gestation. After a single intraperitoneal injection, gentamicin uptake in the kidney cortex of neonatal rats resembled that seen in adult animals, with a rapid initial phase followed by a relatively stable plateau, although the maximal uptake was only about 10% as large in the neonates.
Effects of Macromolecular Chelators on Intestinal Cadmium Absorption in Mice
Authors: Andersen Ole , Bulman Robert A. , Nielsen Jesper Bo
Published: March 2009

Abstract: Suppression of absorption by macromolecular chelators have been successful with several metals. In this paper a series of immobilized chelators ranging from DTPA to S‐containing soft bases have been syntetized and investigated for ability to suppress intestinal uptake of 109Cd2+ in mice. Dextran‐0‐ethyl‐mercaptan, xanthates derived from polysaccharides and polyvinyl alcohol, dithiocarbamates of polyethylene imine and aminoethyl cellulose, and DTPA immobilized on aminopropyl silica were all ineffective. DTPA immobilized on aminoethyl cellulose even enhanced the intestinal uptake. The macromolecular chelators were without extensive effect on organ distribution of absorbed cadmium, except for dithiocarbamate immobilized on polyethylene imine, which enhanced the deposition of cadmium in several organs including the brain. Although the results are discouraging, they indicate that design and synthesis of immobilized vicinal dithio compounds may represent an avenue for development of non‐absorbable chelators with high affinity for cadmium.
Interaction between Benzylpenicillin and Thiopental in the Central Nervous System of the Male Rat
Authors: Schliamser Silvia E. , Karlsson Kurt , Larsson Jan‐Erik , Marklund Stefan , Wahlström Göran
Published: March 2009

Abstract:The effect of benzylpenicillin (BPC) pretreatment on the kinetics and brain sensitivity for thiopental was studied in male rats using a previously developed electroencephalgrafic (EEG) threshold method. Thiopental was infused intravenously with constant infusion rate. The rats were killed by decapitation immediately after the first burst suppression of 1 sec. or more (the silent second) which was observed in the EEG‐record during the infusion. Thiopental concentration in serum and in different brain regions was determined by a high pressure liquid chromatografic method. After pretreatment with 0.9 g/kg of BPC the dose of thiopental needed to induce the silent second was significantly reduced (‐ 20 per cent) when compared with saline treated controls. The serum concentration was also reduced (‐ 30 per cent) after this BPC pretreatment but the concentrations in the different brain regions were the same in both groups. After pretreatment with 1.2 g/kg of BPC almost all animals had convulsions, the dose needed to obtain the silent second was very much reduced and there were reduced concentrations of thiopental in the different brain regions. After both doses of BPC high negative correlations were found between BPC concentrations in brain tissue and thiopental concentrations in hippocampus and brainstem indicating an interaction between the drugs. The most probable site of this interaction is the organic acid transport system out of the CNS which could be used by both substances. Lipid solubility is not the only factor involved in the distribution of thiopental in the rat brain.
Increased Thermal Stability of Collagen after 2,5‐Hexanedione Intoxication in Rats
Authors: Brændgaard Hans , Andreassen Troels T.
Published: March 2009

Abstract: The present study examined the ability of 2,5‐hexanedione (2,5‐HD) to cross‐link the fibrillary protein, collagen, in vivo. The thermal stability of collagen measured as the isometric contraction‐relaxation force was studied in tail tendons from rats, recieving 2,5‐HD intraperitoneally for 2 or 6 weeks (1 g/kg/week, divided into 3 doses). The maximum contraction force was significantly increased after 6 weeks of intoxication as compared to controls, indicating an increase in covalent cross‐linking between collagen molecules. Likewise, in vitro incubation of rat tail tendons in 2,5‐HD for 24 hr induced an increase in thermal isometric contraction force.
Methyl Mercury Uptake Across Bovine Brain Capillary Endothelial Cells in Vitro: The Role of Amino Acids
Authors: Aschner M. , Clarkson T. W.
Published: March 2009

Abstract: Previous studies in the rat in vivo have demonstrated that co‐injection of methyl mercury (MeHg) with L‐cysteine into the common carotid artery enhances brain Hg levels following a single capillary pass through the CNS vasculature. In order to elucidate the relationship between MeHg transport and the neutral amino acid transport carrier system, regulatory aspects of MeHg transport across the bovine blood‐brain barrier were investigated in isolated brain microvessel preparations. Following 1 hour co‐incubations of 203Hg‐MeHgCl with 0.1 mM L‐cysteine at 37°, 203Hg uptake by suspended microvessels was significantly increased (P<0.05) compared with controls. This enhanced capillary uptake of 203Hg was abolished by co‐incubations of microvessels with 0.1 mM L‐cysteine‐L‐methionine, or 0.1 mM L‐cysteine plus AT‐125 (alpha S, 5S)‐alpha‐amino‐3‐chloro‐4,5‐dihydro‐5‐isoxazolacetic acid), an irreversible inhibitor of gammaglutamyl‐transpeptidase. One hr co‐incubations of bovine capillaries with 203Hg‐MeHgCl and 0.1 mM D‐cysteine at 37° or 0.1 mM L‐cysteine at 0° did not increase rat of 203Hg uptake compared with controls. These results indicate that L‐cysteine enhances the rate of capillary MeHg uptake. The accumulation of 203Hg in the bovine microvessels appears to be a carrier‐mediated process. It is inhibited by L‐methionine, a competitive substrate for neutral amino acid transport, and by AT‐125. Capillary uptake of 203Hg is stereospecific to the L‐enantiomorph of cysteine, suggesting selective uptake of MeHg across the blold‐brain barrier. The data emphasize the relationship between the L‐enantiomorph neutral amino acid carrier system and MeHg transport across the capillaries.
The Electrically‐Stimulated Spinal Reflex in Pithed Rats: A Possible Test Model for Evaluating Blockade of Central Dopamine D1 and D2 Receptors
Authors: Skarsfeldt Torben
Published: March 2009

Abstract: Intravenous injection of the dopamine (DA) D1 receptor agonist SK&F 38393 (4.3 μmol/kg=1.25 mg/kg), or the DA D2 receptor agonist pergolide (3.2 μmol/kg=1.25 mg/kg), increased the electrically‐stimulated spinal reflex in pithed rats by more than 600 per cent. The specific DA D1 receptor antagonist SCH 23390 potently inhibited the SK&F 38393‐induced spinal reflex but not the pergolide‐induced reflex. The DA D2 receptor antagonists clebopride and YM 09151–2 inhibited the pergolide‐induced reflex only. Two mixed DA D1/D2 antagonists (cis(Z)‐flupentixol and zuclopenthixol) inhibited the effects of both SK&F 38393 and pergolide on the spinal reflex, while the neuroleptically inactive isomer of clopenthixol (trans(E)‐clopenthixol) was also inactive in this context. Various antagonists (prazosin (a1), idazoxan (a2), I‐ propranolol (β), bicuculline (GABA)) were inactive in the test model. The 5‐HT2 receptor antagonists altanserin and ketanserin also showed antagonistic effect. It is concluded that the electrically‐stimulated spinal reflex in pithed rats can be used as a test model to estimate the blockade of central DA D1 and DA D2 receptors without influence from a1‐adrenergic, a2‐adrenergic, β‐adrenergic and GABA‐ergic receptors. However, a serotonergic receptor antagonism does influence the specificity of the test model.