bluuebunny/crossref_metadata_2025 huggingface dataset:
Extensive Metabolizers of Debrisoquine Become Poor Metabolizers during Quinidine Treatment
Authors: Brøsen K. , Gram L. F. , Haghfelt T. , Bertilsson L.
Published: March 2009

Abstract: Seven male patients (age 55–75 years) were debrisoquine‐tested immediately before and after one week of treatment with quinidine sulphate (200 mg x 3‐4 day‐1). Before quinidine all patients were classified as extensive metabolizers (metabolic ratio 0.1‐3.6). During quinidine the formation of 4‐OH‐debrisoquine was practically abolished and the phenotype of the patients was altered to PM (metabolic ratio 15‐51). This is probably due to an inhibition of debrisoquine hydroxylation by quinidine. Inhibition of 4‐OH‐debrisoquine formation was associated with a disproportionate increase in debrisoquine excretion.
Malathion Induced Alterations in the Lipid Profile and the Rate of Lipid Peroxidation in Rat Brain and Spinal Cord
Authors: Haque Nilofur , Rizvi S. J. , Khan M. B.
Published: March 2009

Abstract: Malathion, known as a low toxic pesticide, is frequently used in the third world. Neurotoxic manifestations of malathion were evaluated on various lipids and lipid peroxidation in different brain areas following intraperitoneal injections (150 mg/kg body weight for 7 consecutive days) to albino rats. Clinical investigations show that malathion produced hypomotor activity and hyperthermia. Lipid components were differently affected by this pesticide, where total lipids and phospholipids were diminished in the spinal cord and brain stem, respectively. Increased contents of cholesterol were found in the cerebellum and spinal cord. Also, total lipids were increased in the cerebellum. The cholesterol/phospholipids ratio was increased in the cerebellum, brain stem and spinal cord. Rate of lipid peroxidation was found to be increased in all parts of the brain following malathion intoxication.
A Two‐Generation Reproduction‐Fertility Study of Cyanamide in the Rat
Authors: Vallès J. , Obach R. , Menargues A. , Vallès J. M. , Rives A.
Published: March 2009

Abstract:A two‐generation reproduction‐fertility study of cyanamide in the rat has been carried out. After oral administration of 2, 7 and 25 mg/kg/day of the drug, relevant changes have been noted at the highest dose level. Decreases in dam weight gain, in number of corpora lutea, in number of implantations and in number of neonates have been observed in rats of the F0generation after treatment with 25 mg/kg/day. This group showed a reduced fertility rate and decreases in the weight of several reproductive organs male rats. In contrast to the findings noted in the F0generation, changes related to cyanamide treatment have not been observed in the F1generation. Histopathology of these organs has disclosed a low incidence of bilateral testicular atrophy. Decreased fertility rate due to non‐specific toxicity associated with a diminished food intake cannot be discarded.
Differences in the Effects of Morphine on the α‐Methyl‐p‐tyrosine‐induced Depletion of Dopamine and Noradrenaline in Various Areas of the Mouse Brain
Authors: Martti L. , Attila J. , Etemadzadeh Ehsan , Ahtee Liisa
Published: March 2009

Abstract:The effect of morphine on the α‐methyl‐p‐tyrosine (αMT)‐induced depletion of dopamine (DA) and noradrenaline (NA) was studied in various brain areas of male NMRI mice, whose locomotor activity is clearly stimulated by morphine. Morphine (10 mg/kg) accelerated the αMT‐induced DA depletion in the striatum and in the area “rest of forebrain + midbrain”, which contains the limbic dopaminergic neurons, but did not clearly alter it in the hypothalamus. The effects were blocked by naloxone. The enhancement of the striatal DA depletion was attenuated when morphine was given after αMT or when morphine dose was increased to 30 mg/kg. The smallest dose of morphine to enhance the αMT‐induced NA depletion in the forebrain + midbrain area was 3 mg/kg, and in the hypothalamus and the lower brain stem 10 mg/kg. The enhancement of the NA depletion was dose‐dependent, occurred whether morphine was given before or after αMT, and was blocked by naloxone. Our findings suggest that morphine alters the αMT‐induced depletion of cerebral DA in mice similarly to what has been reported to occur in rats. In contrast its effects on cerebral NA depletion in mice are clearly different from its effects in rats. The substantial activation of cerebral noradrenergic systems, especially of those in the forebrain + midbrain area, in mice could underly the fact that morphine's predominant behavioural effect in mice is stimulation of motor activity.
Influence of Prostaglandins and Ketoprofen on Contractile Responses of Human and Pig Detrusor and Trigone Muscles in Vitro
Authors: Klarskov Peter
Published: March 2009

Abstract: Detrusor and trigone smooth muscle from pig and man were investigated in vitro. The strips were adjusted to a tension of 1 g. During the first hour detrusor strips relaxed and had to be lengthened repeatedly to maintain tension. The tension of strips from the trigone increased spontaneously during this initial period of recovery and accommodation. Detrusor contractions evoked by transmural electric field stimulation, carbachol, histamine and Ca++ were reduced by ketoprofen (an inhibitor of prostaglandin synthesis), while contractions evoked in trigone strips were augmented by ketoprofen. PGE2 10 nM reversed the effect of prostaglandin synthesis antagonism, augmenting the reduced detrusor response and reducing the augmented trigone response. PGF2α augmented evoked contractions in strips from all regions. Activation of endogenous prostaglandin production can not explain the strip behavior during recovery. After recovery, synthesis of the E‐type of prostaglandins seem to dominate over the F‐type of prostaglandins, since annulment of the E‐type of prostaglandins explains best the alterations of evoked contractions following prostaglandin synthesis antagonism.
3,3′,4,4′‐Tetrachlorobiphenyl in Pregnant Mice: Embryotoxicity, Teratogenicity, and Toxic Effects on the Cultured Embryonic Thymus
Authors: D'Argy R. , Dencker L. , Klasson‐Wehler E. , Bergman Å. , Darnerud P. O. , Brandt I.
Published: March 2009

Abstract:3,3′,4,4′‐Tetrachlorobiphenyl (TCB) is a known ligand of theAh‐receptor. When TCB was given toAh‐responsive C57BL/6 mice at gestation day 11, 12 or 13, a pattern of embryotoxic effects similar to those of TCDD was produced. This pattern included death and resorptions of the conceptus (peak sensitivity at day 11), as well as characteristic malformations such as cleft palate, dilated kidney pelvis (peak sensitivity day 12), and thymus hypoplasia (peak sensitivity day 13). The ED50 for cleft palate induction was found to be about 100 mg/kg, as compared to 30 μg/kg for TCDD (earlier results). The binding affinity of TCB for theAh‐receptor has been reported to be two orders of magnitude lower than that of TCDD. When TCB was introduced into a thymus organ culture (thymi taken from day‐14 embryos), the lymphoid cell development was inhibited with an approximate EC50 of 5 × 10‐8M. This is approximately 100 times higher than that of TCDD and in good agreement with the receptor binding affinities of both compounds. The difference inin vivotoxicity between TCB and TCDD can be explained by a more rapid metabolism and excretion of TCB.
The Effect of 2,5‐Hexanedione on Newly Formed Collagen in Granulation Tissue
Authors: Brændgaard Hans , Jørgensen Peter Holmberg , Andreassen Troels T.
Published: March 2009

Abstract: The mechanical strength of newly formed collagen in granulation tissue was investigated by implantation of cellulose sponges into rats intoxicated with 2,5‐hexanedione (2,5‐HD) and control rats. Intoxication with 2,5‐HD caused a significant decrease in mechanical strength after 20 days of implantation. No differences were found between 2,5‐HD intoxicated and control groups in the amount of collagen formed in the sponges. The mechanical strength of granulation tissue depends on formation and cross‐linking of the newly formed collagen fibrils. 2,5‐HD is known to react with ε‐amino groups of lysine and it is therefore able to interfere with both fibril aggregation and cross‐linking of the collagen. On the other hand, 2,5‐HD induces the formation of cross‐links in intact tendon collagen. Therefore, we stress that it is essential to distinguish between intact and newly formed fibrils when evaluating the effect of 2,5‐HD on fibillary proteins.
Kinetics of Radioiodine Released from Prelabelled Thyroid Gland in Vivo: Influence of Propylthiouracil
Authors: Ahrén Bo , Rerup Claus
Published: March 2009

Abstract: The kinetics of free and hormone bound blood iodine after stimulation with endogenous thyroid stimulating hormone (TSH) are not satisfactorily characterized. We studied these kinetics in mice injected with 125I and thyroxine. In control mice, the injected 125I is organified within the thyroid and incorporated into thyroid hormones, whereas in mice treated with the thyreostatic drug propylthiouracil (PTU), most 125I remains inorganic, since the thyroperoxidase activity is inhibited by PTU. We found that during blockade of TSH secretion by means of thyroxine, blood 125I activity was significantly higher in PTU‐treated animals than in controls, indicating that PTU impaired thyroidal uptake of 125I. On the fourth day after the thyroxine load, the blockade of TSH secretion vanished. This caused the blood 125I activity to increase markedly. The increase of blood 125I was as high in PTU‐treated animals as in controls. After the peak, blood 125I was cleared according to first order kinetics, with a half‐time of 0.72 days (= 17.3 hours) in PTU‐treated animals and of 6.3 days in controls (P<0.001). It is suggested (1) that PTU impairs thyroidal uptake of iodide, (2) that endogenous TSH stimulates release from the thyroid of inorganic iodide as well as of thyroid hormones, and (3) that inorganic iodide released by the thyroid has a much shorter biological half‐life than hormone‐bound iodine.
Placental and Blood‐CSF Transfer of Orally Administered Diazepam in the same Person
Authors: Kanto Jussi , Scheinin Mika
Published: March 2009

Abstract: Both placental and blood‐lumbar CSF transfer of diazepam (5 mg orally) and its two metabolites, N‐desmethyldiazepam and unconjugated oxazepam, was measured (by GLC) in 15 patients undergoing Caesarean section under spinal analgesia. Differing from our earlier studies with atropine (Virtanen et al. 1982; Kanto et al. 1981 & 1987), a reasonably fast penetration of diazepam and its two metabolites through the two biological membranes was found. Diazepam, N‐desmethyldiazepam and to a lesser extent unconjugated oxazepam accumulated on the foetal side of the placenta, apparently due to a higher degree of plasma protein binding in the foetus. No accumulation was found in CSF, probably due to the lack of binding proteins in this tissue compartment. Concerning atropine, lumbar CSF with an incomplete drug penetration was found to be a “deeper” compartment than amniotic fluid, but in the present study with diazepam there was no clear difference between these two tissue compartments.
The Actions of Nifedipine and Nisoldipine on the Contractile Activity of Human Coronary Arteries and Human Cardiac Tissuein Vitro
Authors: Godfraind Théophile , Eglème Cécile , Finet Michel , Jaumin Pierre
Published: March 2009

Abstract:We have studied the action of nifedipine and nisoldipine on the contractile activity of human isolated coronary arteries and human isolated auricular and ventricular muscles. Nisoldipine depressed dose dependently the spontaneous rhythmic contractions displayed by the coronary artery preparations and at 1 nM abolished these contractions. Nisoldipine was twenty times more potent than nifedipine as an inhibitor of increase in tone induced by depolarization (100 mM K+). The rhythmic activity induced by serotonin (10 μM) was about five times more sensitive to nisoldipine than to nifedipine. In both auricular and ventricular preparations, isoprenaline evoked an increase in the rate of force development and in the rate of relaxation. Nifedipine was five times (ventricular muscles) and ten times (auricular muscles) more potent than nisoldipine as an negative inotropic agent. The present observations in human isolated preparations indicate that nisoldipine shows a higher vascular selectivity than nifedipine.
Resistance to Acute Nephrotoxicity Induced by Cadmium‐Metallothionein Dependence on Pretreatment with Cadmium Chloride
Authors: Jin Taiyi , Nordberg Gunnar F. , Nordberg Monica
Published: March 2009

Abstract:Three groups of rats (B‐D) were given various daily doses of CdCl2(0.5–2 mg Cd/kg) continously or in intervals during time periods of 1–8 weeks. Another group of animals (A) were kept untreated. At the end of the period, selected subgroups of groups A‐D were given a single subcutaneous injection of109Cd‐metallothionein (109CdMT) 0.05 or 0.4 mg Cd/kg (“challenge dose”). Subsequently, urinary creatinine, protein, Cd,109Cd and MT and kidney cortex Cd,109Cd and MT were determined. In group A (no long term pretreatment), an increased proteinuria was observed after the rats had received the lower of the challenge doses of109CdMT, and an even greater increase after the higher challenge dose of109CdMT. No such increase appeared in group B, C and D (repeatedly pretreated with CdCl2) at either of the challenge doses. Higher metallothionein concentrations in kidney cortex observed in the pretreated groups constitute a plausible explanation of the protective effects of pretreatment against the development of increased proteinuria after challenge dosing. It is likely that increasing Cd concentrations, gradually accumulating in the renal cortex (22–226 μg/g wet wt.) as a result of the pretreatment, served to induce the synthesis of metallothionein in the renal cortical cells, thus making them resistant to the challenge from109CdMT.
Effect of Corticosteroids on Muscarinic Receptors on Cultured Myocardial Cells
Authors: Ransnäs Lennart , Hjalmarson Åke , Sabler Eva , Jacobsson Bo
Published: March 2009

Abstract:Rat myocardial cells in tissue culture were utilized to investigate modulation by corticosteroids on muscarinic receptor affinity. Competition binding experiments between tritiated quinuclidinyl benzilate and carbachol were performed on the muscarinic receptor both on whole cells and on a crude membrane preparation from cultured myocardial cells. Hydrocortisone was shown to promote a transition of the high affinity site of the muscarinic receptor towards super‐high affinity. This was analogous with the effect of divalent ions. The affinity shift was detectable after 6 hr exposure to 0.1 μg/ml of hydrocortisone in the tissue culture dishes but was abolished by concomitant incubation with a protein synthesis inhibitor (10 μM puromycin). The response on agonist binding of Gpp(NH)p in the presence of manganese ions was altered indicating that the adenylate cyclase‐coupled muscarinic receptor nucleotide binding protein was modulated. No effects of corticosteroid exposure were noted on phosphatidyl inositol turnover.
The Effect of Isosorbide Dinitrate on the Arterial Vascular Bed: A Dose Response Study in Dogs
Authors: Aldershvile Jan , Abildgaard Ulrik , Eliasen Per , Amtorp Ole
Published: March 2009

Abstract:Isosorbide dinitrate (ISDN) was infused stepwise intraarterially into the left hindlimb (5.7–364.8 μg/kg/min.) into six dogs. The mean local vascular resistance was decreased by 32% in the left hindlimb after a dose of up to 91.2 μg/kg/min. corresponding to a 1.6‐fold increase in the left femoral artery blood flow, without significant changes in the control limb or central haemodynamics. The muscular blood flow in the adductor magnus muscle obtained by the Xenon washout technique remained unchanged in 6 of 7 other dogs at ISDN infusion rates of 91.2 μg/kg/min., indicating that the increase in femoral artery blood flow was not a consequence of increased muscular blood flow. The arterio‐venous extraction fraction of radioactive microspheres was lower in the experimental leg during ISDN infusion when compared with the control leg, suggesting that AV‐shunts are opened during ISDN infusion. In addition to the well‐known effect on preload, the present results confirm that ISDN also acts on afterload. Thus, ISDN may be classified as a mixed agent acting on both pre‐ and afterload which is in agreement with some previous studies.
Interaction of Dihydropyridine Calcium Channel Agonists and Antagonists with Adenosine Receptors
Authors: Hu Ping‐Sheng , Lindgren Eva , Jacobson Kenneth A. , Fredholm Bertil B.
Published: March 2009

Abstract:We have confirmed our previous (Fredholmet al.1986a) finding that the dihydropyridine calcium channel agonist Bay K 8644 can displace [3H]‐R‐PIA from its binding site, the adenosine A1‐receptor. Bay K 8644 had an apparent Kiof 5.2 × 10‐6M. The effect was shared by the two dihydropyridine calcium channel antagonists nifedipine and felodipine (Ki4.2 and 8.7 × 10‐6M, respectively). By contrast, two non‐dihydropyridine calcium channel antagonists, verapamil and diltiazem, did not affect binding. Bay K 8644 displaced [3H]‐R‐PIA from its binding sites in a solubilized preparation. [3H]‐XAC, a novel, potent A1‐receptor antagonist ligand, was also displaced by the dihydropyridine compounds with a similar or slightly higher potency as the displacement of R‐PIA. This suggests a direct interaction with the adenosine receptor rather than an effect on regulatory GTP‐binding proteins. However, at 1 μmol/l neither Bay K 8644 nor nifedipine significantly attenuated cyclic AMP accumulation in rat hippocampi or the R‐PIA‐mediated adenylate cyclase inhibition. The results show that dihydropyridine compounds that act as agonists or antagonists on L‐type calcium channels can also affect adenosine receptors. The potency of the compounds for this effect is much lower than their potency as calcium channel agonists or antagonists. The results may therefore be of more experimental than clinical significance.
Trichloroethylene Inhibits Uptake of3H‐5‐Hydroxytryptamine but not Uptake of3H‐Zimeldine or3H‐Propranolol in Isolated Perfused Rat Lungs
Authors: Hede A. Ragnar , Berglund Bengt G. , Post Claes
Published: March 2009

Abstract:Pulmonary uptake of 5‐hydroxytryptamine (5‐HT), zimeldine and propranolol were studied using the isolated perfused rat lung model. The 5‐HT uptake was found to be attenuated by approximately 50 per cent in comparison to the control, when the lungs were ventilated with air containing 5,000 p.p.m. trichloroethylene. In experiments in which the active uptake of 5‐HT was blocked with the selective 5‐HT uptake inhibitor zimeldine (5 × 10‐6M), the uptake of 5‐HT decreased by 70$pL1.7 per cent (mean$pLS.E.M.). When trichloroethylene (5,000 p.p.m. and 18,000 p.p.m.) was added, no further decrease in uptake was noted. The uptake of3H‐zimeldine (10‐6M) and3H‐propranolol (10‐6M) was unaffected by ventilating the lungs with trichloroethylene. It is concluded that trichloroethylene inhibits the active uptake of 5‐HT from the pulmonary circulation, but that it has no effect on the uptake of zimeldine or propranolol, which are taken up predominantly by passive diffusion.
A New Device to Measure Drug‐Induced Changes on Reactive and Coordinative Skills of Human Performance
Authors: Linnavuo M. , Ylilääkkölä P. , Mattila M. J. , Mäki M. , Seppälä T.
Published: March 2009

Abstract: A computerized device for simultaneous measurement of coordinative and reactive skills related to driving was developed and tested in two consecutive trials of psychoactive agents in healthy volunteers. The test system comprises a vehicle, a driving computer (Sinclair QL), and the programming and measurement computer (IBM‐PC). The computerized driving programme projects to the colour ‐ TV screen a winding road, and the driver has to keep the car on the road by turning the steering wheel. The driving proceedes at a fixed, fairly rapid rate for 5 min., and the numbers of tracking errors (deviations from the road) as well as the tracking percentage (relative length of the track driven off the road) were computed separately for both halves of the track. During the latter half of the track 60 visual or/and sound stimuli were given in random order, and the driver had to respond or not respond to them by pressing a button or by pushing a foot pedal. The number of reaction errors and the cumulative reaction time were recorded. The programme also provides a histogramme that relates the number of deviations from the road to their duration, enabling a visual judgement of the severity of errors. Matched versions (mirror image, reverse direction) of tracks of varying severity were offered to reduce learning effect during the trial. When testing the device in two placebo‐controlled double‐blind and cross‐over trials, a considerable practice effect on tracking and reaction strategies took place, but after proper training the baselines remained reasonably stable. In spite of the practice effect an impairment of coordinative skills by lorazepam 2.5 mg or by diazepam 15 mg was demonstrated whereas ethyl alcohol 0.8 g/kg impaired reactive skills more than eye to hand coordination. Additive drug‐drug and drug‐alcohol combined effects were found.
Preferential Localization of 3H‐Pentosanpolysulphate to the Urinary Tract in Rats
Authors: Odlind B. , Dencker L. , Tengblad A.
Published: March 2009

Abstract: Endogenous glycosaminoglycans probably have a protective effect in the urinary tract, e.g. against stone formation. The synthetic sulphated polysaccharide pentosanpolysulphate (PPS) has been suggested to exert a similar protective effect e.g. by inhibition of crystallization and bacterial anti‐adhesion. We have studied the distribution in rats of tritium‐labelled PPS. Chromatography showed this material to contain two distinct peaks with approximate molecular weight around 2.700 (60–70%) and 1.000 (30–40%) daltons. PPS was administered orally and intavenously (5 mg/kg b.wt.) to Sprague‐Dawley rats, which were killed 1 and 4 hours later, respectively, and subjected to whole‐body autoradiography. Autoradiograms of sections from intravenously injected rats showed an extensive distribution of radioactivity in the whole animal, with a notable labelling of connective tissues, while bone and cartilage had low activity. There was upper intestine activity, suggesting some hepatic excretion. The most conspicuous finding, however, was the high concentration in urine and a preferential localization of activity corresponding to the lining of the urinary tract (pelvis, ureter, and bladder). The distribution was similar, but the activity lower after oral administration. In one experiment, PPS was applied intravesically under anaesthesia, with and without epithelial destruction caused by instillation of 0.4 M HCl. After vigorous rinsing, with saline, the radioactivity was still retained in the bladder wall. In other intravenous experiments, the bladder was extirpated, everted and rinsed in saline or urea of increased osmolality. High amount of radioactivity could be rinsed off by 0.5 M saline. Chromatography of the rinsing solution showed presence of both fractions of PPS previously found in the injection solution. No other peak of activity was found. Thus, some of the injected material could be recovered unchanged from the bladder wall, where it seems to be bound ionically with moderate strength. Since PPS of molecular weight 2.700 and 1.000 is preferentially located to the surface epithelium of the urinary tract in rats, the effects of PPS in urinary tract diseases could depend on surface coating of the epithelium and/or urinary concentrations of PPS.
Monoamine Metabolite Levels in Rat CSF: Kinetic Studies
Authors: Scheinin Harry , Scheinin Mika
Published: March 2009

Abstract:The kinetics of monoamine metabolites, 3‐methoxy‐4‐hydroxyphenylglycol (MHPG), 5‐hydroxyindoleacetic acid (5‐HIAA) and homovanillic acid (HVA), in cisternal CSF were determined after monoamine oxidase (MAO) inhibition (pargyline, 100 mg/kg) and tyrosine hydroxylase inhibition (α‐methyl‐p‐tyrosine, α‐MPT, 250 mg/kg) in awake rats. In addition, the possibility of a peripheral contribution to CSF MHPG levels was investigated by infusing large amounts of the metabolite into vena jugularis. Pargyline induced an exponential decrease of CSF MHPG, 5‐HIAA and HVA, with respective half‐lives of 51, 86 and 46 min. α‐MPT caused a slower decline of MHPG and HVA, while 5‐HIAA was unaffected. Results from the MHPG‐infusion experiments indicate minor peripheral contribution to CSF MHPG levels in acute pharmacological studies. The present paper gives further support for the validity of our new animal model in detecting acute changes in central monoaminergic activity.
Study on Adrenergic Function after Development of Tolerance to Ethylene Glycol Dinitrate (EGDN) in Rats
Authors: Johansson Pehr , Ehrenström Fredrik , Ungell Anna‐Lena
Published: March 2009

Abstract:The effects of sustained exposure to ethylene glycol dinitrate (EGDN; 50 mg·kg‐1·2, 10 days) on heart rate (HR) and mean arterial blood pressure (MAP), isolated strips from aorta and vena cava, catecholamine (CA) and DOPAC levels in brain, heart, adrenals and plasma, and synaptosomal uptake of noradrenaline (NA) have been investigated in rats. Aortic strips showed a decreased responsiveness to EGDN and were more sensitive to NA than were control strips 2, 24 and 96 hrs after cessation of EGDN. Acute cumulative doses of EGDN induced a decrease in MAP at all time intervals but 2 hrs after cessation of chronic EGDN‐treatment, while NA induced a dose‐dependent increase in MAP. MAP was lower 2 hrs after cessation of EGDN, than in the control rats, while HR was higher. After 24 hrs, MAP was slightly higher than in the controls and HR was still elevated. EGDN induced a decrease in the accumulation of L‐DOPA and DOPAC in all brain structures measured, which was especially prominent 2 hrs after cessation of EGDN. The levels of CA's and DOPAC in peripheral tissues did generally not change significantly, although there was a tendency to a decrease. L‐DOPA, NA and adrenaline (A) in plasma decreased significantly, while DOPAC and dopamine (DA) increased. No consistent effects on uptake of NA into synaptosomes could be distinguished. However, the amount of protein was generally lower at all times after cessation of EGDN. It is suggested that prolonged exposure to EGDN not only induces tolerance at the cellular level, but also interferes with arterial smooth muscle sensitivity to NA and with resetting of MAP and HR. The decrease in the synthesis and turnover of CA's and DOPAC in the brain indicated a decrease in nervous activity, which is reflected by a corresponding decrease of NA and A levels in plasma.
Characteristics of Analgesia Induced by Adenosine Triphosphate
Authors: Gomaa Adel A.
Published: March 2009

Abstract:Adenosine triphosphate (ATP) injected intravenously in mice was found to have dose‐dependent analgesic activity in the hot plate and phenylquinone‐induced stretching assays. ATP prolonged the hot plate latency (ED50 value of 1 (0.7–1.4) mg/kg) and inhibited phenylquinone‐induced writhing (ED50 value of 0.4 (0.31–0.52) mg/kg). Low doses of ATP produced a potent antinociceptive effect without any significant depression of locomotor activity. Treatment of mice for either 4 days or 14 days with ATP did not result in development of physical dependence on or tolerance to ATP. The analgesic action of ATP was not antagonized by naloxone at 1 and 5 mg/kg. ATP analgesia was antagonized, in a dose‐related fashion, by Ca++ion injected intracerbroventricularly which may indicate that Ca++plays a role in ATP‐induced antinociception.
Shaking Behaviour Induced by Putrescine in Naive Rats: A Pharmacological and Histological Study
Authors: Genedani S. , Bernardi M. , Tagliavini S. , Botticelli A. , Bertolini A.
Published: March 2009

Abstract: In untreated rats, the intraperitoneal injection of putrescine evoked a typical wet‐dog shake response, that was maximal at a dose of 300 mg/kg and at room temperature (22°) (number of shakes: 84.00$pL17.90/hr). In a hot environment (30°) the number of shakes was markedly reduced (29.60$pL5.19/hr). The putrescine‐induced shaking behaviour was unaffected by atropine, bicuculline, chlorpheniramine, cimetidine, methysergide, naloxone and noradrenaline, but was markedly antagonized by morphine. Naloxone pretreatment nullified the antagonistic activity of morphine. Histological studies showed marked alterations in brain vascular permeability, which was increased by putrescine. Morphine completely prevented this putrescine‐induced vascular effect. These results suggest a correlation between WDS produced by putrescine and increase in brain vascular permeability. Furthermore they show that morphine can affect brain vascular permeability.
Transport of p‐Aminohippuric Acid (3H‐PAH), Inulin and Dextran Out of the Cranial Cavity: A Methodological Study Using Intraventricular Injection and Sample Combustion
Authors: Jakobson Åke M.
Published: March 2009

Abstract:Material injected into the cerebral ventricles can leave the cerebrospinal fluid (CSF) but remain in the cranial cavity. To analyze the disappearance of3H‐ and of14C‐labelled material from the cranial cavity, such material was injected into the lateral ventricles together with a bulk flow marker, labelled with the other radionuclide. In the present pilot study3H‐PAH and14C‐inulin were used. Five μl of a mixture was injected into each lateral cerebral ventricles in rats, which were killed at various intervals. The whole skull was analyzed without opening the CSF space after homogenization in the deep‐frozen state. The samples were combusted and analyzed by liquid scintillation counting. Probenecid, injected intraperitoneally, inhibited the removal of3H‐PAH from the skull cavity, as anticipated. Immediately after the intraventricular injection, however,3H‐PAH was transiently retained, probably by uptake into actively transporting tissue. After injection of probenecid, this delay in removal was reduced. The difference in disappearance rate between3H‐PAH and4C‐inulin was estimated by comparing the3H/14C ratio in the skulls with that in the injected solution, which appeared to be a better method than comparing the recovery of each compound.
Species Differences in the Intestinal Excretion of Emepronium
Authors: Hallén Bengt , Räf Lars
Published: March 2009

Abstract:A substantial proportion of a parenteral dose of emepronium given to dogs is excreted via the gastrointestinal tract by biliary excretion and by excretion through the intestinal mucosa (Hallénet al.1979). In the present paper the different routes of elimination were further investigated in mouse and man and compared to the dog. The disposition of emepronium‐derived radioactivity (14C) in the three species showed that about 45% was excreted via urine and 55% via faeces. The proportion of the faecal excretion of14C that could be referred to the intestinal route differed between the species and was about 20% in man, 60% in the mouse and most pronounced, 80%, in the dog.
Effects of Halothane and Other Chlorinated Hydrocarbons on α2‐Adrenoceptors in the Mouse Cortex
Authors: Wikberg J. E. S. , Hede A. R. , Post C.
Published: March 2009

Abstract:A number of general anaesthetics and organic solvents were tested for their ability to inhibit the binding of3H‐clonidine to α2‐adrenoceptors in mouse cerebral cortex membranes. The order of potency of the tested agents was: chloroform>halothane>trichloroethylene>carbon tetrachloride>dichloromethane. Of these agents halothane was tested further. When saturation curves of3H‐clonidine were constructed, halothane (25 mmol/l added directly to the assay) was found to induce a proportionally greater inhibition at low3H‐clonidine concentrations than at high. Computer modelling these saturation curves indicated that halothane reduced the apparent affinity of3H‐clonidine; Kd= 4.2 nmol/l in the absence of halothane and Kd= 6.0 nmol/l in its presence Gassing the cortex membranes with 3% halothane induced a practically identical reduction in the affinity for3H‐clonidine; Kd= 4.6 nmol/l for the control versus Kd= 10.7 nmol/l for halothane. The effects of halothane was compared to that of the non‐hydrolyzable GTP analog Gpp(NH)p. Gpp(NH)p in the concentration range 10‐8‐10‐3mol/l dose‐dependently reduced the binding of 1 nmol/l3H‐clonidine, the effect being essentially maximal at 10‐4mol/l. Computer modelling of saturation curves of3H‐clonidine indicated that 0.1 mmol/l Gpp(NH)p reduced the apparent affinity of 3H‐clonidine; Kd= 5.4 nmol/l in the absence of Gpp(NH)p and Kd= 9.3 nmol/l in its presence. In addition Gpp(NH)p caused some reduction in the apparent number of3H‐clonidine binding sites. The effect of halothane on3H‐clonidine binding was tested both in the absence and presence of 0.1 mmol/l Gpp(NH)p. During these conditions halothane was slightly more potent in the presence of Gpp(NH)p (IC50 of halothane = 17 mmol/l) than in its absence (IC50 = 41 mmol/l). The data suggest that halothane induces a direct conformational change in the ligand binding subunit of the α2‐adrenoceptor that decreases its affinity for3H‐clonidine. The results are discussed with respect to possible mechanisms of action of general anaesthetics.
Proadifen‐sensitive High Affinity Binding of3H‐Alaproclate to Liver Membranes
Authors: Ross Svante B.
Published: March 2009

Abstract:3H‐Alaproclate, a selective 5‐hydroxytryptamine uptake inhibitor, was found to bind to microsomal membranes from the rat liver with high affinity (KD= 3 nM) and large capacity (Bmaxabout 2 nmol/g liver). This binding was stereoselective since S‐(‐)‐alaproclate was 30 times more potent than the R‐(+)‐enantiomer to displace the3H‐labelled racemate. Proadifen (SKF 525A), an inhibitor of cytochrome P‐450, displaced the3H‐alaproclate binding with the same, high affinity (Ki= 3 nM) as alaproclate itself. Repeated treatment with phenobarbital sodium (5 × 75 mg/kg intraperitoneally) increased the number of alaproclate binding sites 7–8 times without changing the affinity. However, most of the phenobarbital induced3H‐alaproclate binding was not displaceable by proadifen, showing the presence of at least two different high affinity binding sites. The possible involvement of cytochrome P‐450 in the alaproclate binding is discussed.
Stereoselective High‐Affinity Binding of3H‐Alaproclate to Membranes from Rat Cerebral Cortex
Authors: Ross Svante B. , Gawell Lars , Hall Håkan
Published: March 2009

Abstract:The binding of3H‐alaproclate, a selective 5‐hydroxytryptamine uptake inhibitor, to membranes prepared from the rat cerebral cortex was investigated by a filtration technique. It was found that3H‐alaproclate bound with high affinity to three or four different sites and to one low affinity site. The binding to two of these sites was displaceable by 1 μM proadifen (SKF 525A), an inhibitor of drug metabolism. From iterative nonlinear regression analysis the KD‐values of these sites were calculated to about 1 and 28 nM and the Bmaxvalues 1.5 and 19 pmol/g wet tissue, respectively. The high affinity binding that was not displaceable by proadifen but by 10 μM alaproclate had KD‐values of 1 nM and 6 nM and Bmax‐values of 0.4 and 2 pmol/g wet tissue. The low affinity binding that was not displaceable by proadifen had a KD‐value of about 200 nM and a Bmax‐value of about 90 pmol/g tissue. The possible relationship between the proadifen sensitive high affinity binding of3H‐alaproclate and the brain cytochrome P‐450 is discussed.
Oral Verapamil and Calcium Infusion in Patients with Sick Sinus Syndrome
Authors: Midtbø Kjell
Published: March 2009

Abstract: Electrophysiologic and circulatory effects of a single oral dose of verapamil (120 mg) were evaluated in 8 patients with symptomatic sick sinus syndrome. Ninety min. after verapamil, calcium gluconate (1375 mg) was infused in an attempt to reverse the depressor actions of the drug. Verapamil significantly increased sinus node recovery time (P<0.05) and atrioventricular conduction time (P<0.01), and decreased both systolic (P<0.01) and diastolic blood pressure (P<0.05) and spontaneous heart rate (P<0.01). Intravenous calcium significantly reversed blood pressure reduction (P<0.001) and further lowered heart rate (P<0.05) without affecting sinus node recovery time and atrioventricular conduction significantly. There was no significant correlation between plasma verapamil concentrations and any of the cardiovascular parameters. These data confirm that verapamil is principly contraindicated in patients with sinus node dysfunction and demonstrate that the actual calcium dose, although partly reversing blood pressure reduction, cannot reverse the depressant action of the drug on the sinus and atrioventricular node in such patients.
Calcium Uptake in Brain Synaptosomes from Rats Exposed to Daily Toluene for up to 80 Weeks
Authors: Edelfors Sven , Ravn‐Jonsen André
Published: March 2009

Abstract: Rats were exposed to toluene, 500 p.p.m., for 12 hrs/day for up to 80 weeks. The brains were removed and the synaptosomes were prepared. Potassium‐stimulated and unstimulated synaptosomes were incubated with 45Ca2+ for 1/2, 2, 4, 8, and 16 min. Toluene exposure for 4 and 12 weeks caused a significant, approximately 20%, increase in 45Ca2+ uptake into unstimulated synaptosomes. The effect was of moderate quantity and transient, since it was not significant after 30 and 80 weeks of exposure. It seems doubtful whether the demonstrated change in calcium uptake should have any relevance in connection with the “organic solvent neurotoxicity syndrome”.
Low Sensitivity of Cultured Human Young Adult and Adult Gingival Fibroblasts to Fluoride. I. Relation to Doubling Time
Authors: Sato Tsutomu , Yagori Akihiko , Niwa Motoo
Published: March 2009

Abstract: Sensitivity to fluoride of human gingival fibroblasts derived from six different normal tissues (donor age; 17–36 years, male and female) and a foetal tissue were studied by measuring cell growth and protein synthesis in vitro. Fibroblasts derived from four different human foetal lungs were also studied in order to compare them with the gingival cells. Two cell lines of gingival and lung fibroblasts were derived from the same foetus. All of the young adult and adult gingival cells grew slowly in the medium containing 1.32 mM fluoride, while foetal cell growth, including the foetal gingival cells, was completely inhibited. Both foetal cultures had faster cell replication rates and greater protein synthesis rates than those of the young adult or adult cultures. The fluoride sensitivity was lower in all young adult and adult gingival fibroblasts than in the foetal cells. However, “aged” foetal cultures obtained by serial passage showed lower fluoride sensitivity. These “aged” cells also had prolonged generation times. These findings indicate that although the mechanism is unclear, the low fluoride sensitivity of the young adult and adult gingival fibroblasts observed in this study are likely to be related to their slower rate of cell growth.
The Effect of in Vitro and in Vivo Toluene Exposure on Rat Erythrocyte and Synaptosome Membrane Integral Enzymes
Authors: Korpela M. , Tähti H.
Published: March 2009

Abstract: The mechanism of the anaesthetic effect of toluene on the central nervous system (CNS) was studied by using rat erythrocyte and synaptosome membranes as nerve cell models both in vitro and in vivo. The activities of the membrane‐bound integral enzymes acetylcholinesterase (AChE), total adenosine triphosphatase (total ATPase) and magnesium‐activated adenosine triphosphatase (Mg2+‐ATPase) were determined. A short‐term exposure to 2000 p.p.m. of toluene had an inhibitory effect on the enzyme activities studied. The degree of inhibition in erythrocyte membranes in vitro and in vivo, and in synaptosome membranes in vitro were in good correlation. In in vivo conditions, the synaptosome‐bound enzymes were, however, significantly more inhibited by toluene, which indicates that membranes in vivo are even more vulnerable to the toxic effects of organic solvents than they are as isolated membranes in vitro. However, our results show that in vitro experiments can be used to predict the toxic nerve cell membrane effects of organic solvents. Toluene caused similar enzyme inhibitions both in neural cell membranes and in erythrocyte membranes. Thus, even peripheral non‐excitable cell membranes, like erythrocytes, can be used as nerve cell membrane models in studies on the mechanism of the anaesthesia caused by solvents.
β2‐Mediated Changes in Central Haemodynamics, Coronary Circulation and Myocardial Metabolism in Canine
Authors: Bo Hansen Peter , Waldorff Stig , Hjelms Erik , Steiness Eva , Diamant Bertil
Published: March 2009

Abstract:The combined effect of terbutaline on systemic and coronary circulation was investigated in dogs to clarify its influence on myocardial oxygen supply and lactate balance. The dogs were anaesthetized and the chest opened. Coronary sinus blood flow and cardiac output were monitored by thermodilution, aortic pressure was measured by tip‐transducer and heart rate by RR‐interval on ECG, coronary sinus blood were analyzed for lactate, oxygen and carbon dioxide. Terbutaline caused a substantial systemic vasodilation and an increased heart rate, the total external cardiac work increased to a minor degree. Terbutaline increased arterial lactate concentration. Coronary vascular resistance was reduced after terbutaline. Even if myocardial perfusion pressure was reduced and an increased external cardiac work was present, no signs of myocardial distress was observed in lactate metabolism or coronary sinus oxygen content. In fact a tendency to increased myocardial aerobic metabolism was observed, as myocardial lactate consumption increased after terbutaline. Terbutaline seems to be a coronary vasodilator in dogs. However, the demand for oxygen secondary to both an increase in cardiac work and aerobic metabolism can be harzardous to the potentially ischaemic myocardium.
Cholecystokinin (CCK)‐33 Stimulates Insulin Secretion from the Perfused Rat Pancreas: Studies on the Structure‐Activity Relationship
Authors: Sandberg Elvi , Ahrén Bo , Tendler Deborah , Efendic Suad
Published: March 2009

Abstract: Cholecystokinin (CCK)‐33 is known to stimulate insulin secretion. Presently, using the perfused rat pancreas, we have characterized the active site in the CCK‐33 molecule that is responsible for this effect by the use of different CCK fragments. We found that CCK‐33, CCK‐8 and CCK‐7 (1 nM) all significantly stimulated insulin secretion in the presence of 4.4 mM or 6.7 mM glucose. However, CCK‐7 was much less potent than the longer forms. In contrast, CCK‐4, CCK‐6 and CCK‐33 (1–21) had no effect on insulin secretion. We conclude that the shortest CCK‐form that stimulates insulin secretion at 1 nM is the C‐terminal heptapeptide CCK‐7. However, CCK‐8 is much more potent than CCK‐7 in this respect.
Neonatal Treatment with Monoamine Uptake Inhibitors Alters Later Response in Behavioural ‘Despair’ Test to β and GABA‐B Receptor Agonists
Authors: Hilakivi L. A. , Taira T. , Hilakivi I. , Loikas P.
Published: March 2009

Abstract:The administration of monoamine uptake‐inhibiting antidepressant drugs to rats during the early postnatal period was previously shown to lengthen the duration of subsequent immobility in Porsolt's swim test, hence suggesting increased behavioural ‘despair’ in these animals. Because the mechanism of the antidepressant action may be related to changes in the cerebral monoamine or γ‐aminobutyric acid (GABA) function, the present study was carried out to examine the response in the swim test to a β‐receptor agonist salbutamol, or to the GABA‐B receptor agonists progabide and baclofen in rats treated with antidepressant drugs during the second and third postnatal week: either desipramine 5 mg/kg, nomifensine 10 mg/kg or zimeldine 25 mg/kg. When tested a month later i.e. at the age of two months these rats were immobile in water for a longer period than the controls. Salbutamol 10 mg/kg and progabide 100 mg/kg increased the immobility time in the control rats but neither drug affected the rats treated with desipramine, nomifensine or zimeldine. When the animals were 5 months of age, salbutamol 10 mg/kg and baclofen 10 mg/kg shortened the immobility time in the desipramine‐treated rats. The control rats and those treated with zimeldine were not affected by the drugs. The results indicate that in the rats which were neonatally treated with antidepressants, the immobility time in water is lengthened in adulthood. Moreover, the response to β‐receptor and GABA‐B receptor agonists is increased from the response observed in the control rats.
Binding of Toremifene to Human Serum Proteins
Authors: Sipilä Hannu , Näntö Veikko , Kangas Lauri , Anttila Markku , Halme Tapio
Published: March 2009

Abstract: The in vitro protein binding of toremifene in human serum was measured by ultracentrifugation using 3H‐toremifene together with unlabeled toremifene, 50, 500, and 5000 ng/ml. Of the total radioactivity 99.7 per cent was bound to the proteins independent of the concentration of the unlabeled drug. Binding of toremifene to different protein fractions was studied by adding 3H‐toremifene and 500 ng/ml of cold toremifene to normal serum. The serum samples were exposed to agarose gel electrophoresis to fractionate different proteins. The radioactivity was localized using a position‐sensitive proportional counter. After that the proteins were visualized by staining. Of the total protein bound radioactivity 92 per cent was bound to albumin, about 6 per cent to β1 globulin fraction and about 2 per cent to a fraction between albumin and α1 globulins, part of this probably to α1 acid glycoprotein.
Neuroinhibition of Xylazine Induced Emesis
Authors: Zabara Jacob
Published: March 2009

Abstract:Xylazine produces retching and vomiting presumably by activation of the chemoreceptor trigger zone (CTZ). The purpose of this project was to investigate whether neuroinhibition can prevent xylazine vomiting. Inhibitory neurons in the cervical vagus nerve of cats were stimulated with implanted cuff electrodes. Female cats, weighing from 3 to 4 kg, were anaesthetized with pentobarbital for surgical implantation of electrodes. After full recovery from surgery, animals were tested in weekly sessions. Stimulation was via a pulse generator connected to photon coupled linear isolator supplying constant current. Videotape was used to record observations. The range of effective stimulation was 1–10 ma, 4–100 Hz and 0.3–0.6 msec. Stimulation was initiated thirty sec. after subcutaneous injection of xylazine, 0.66 mg/kg. Stimulation of the inhibitory nerve group of the cervical vagus was effective in preventing vomiting in over 85% of the experimental trials. In addition to preventing emesis during stimulation, the latency of xylazine emesis was increased over control values. Repeated experimental trials of stimulation coupled with xylazine injection could result in the complete absence of emesis.
Computerized Evaluation of Drug‐Induced Changes in Guinea‐Pig Epicardial Monophasic Action Potentials
Authors: Duker G. , Almgren O. , Axenborg J.
Published: March 2009

Abstract:The monophasic action potential (MAP) has been widely used for the study of drug effects on cardiac repolarizationin vivo.There is, however, no study of drug‐induced effects on MAP depolarization, i.e. effects on MAP Vmax and/or MAP rise‐time. For this study, we developed a method in the anaesthetized open chest guinea‐pig. MAP signals were recorded and subjected to on‐line computerized analysis, in which parameters describing both depolarization and repolarization were calculated. With the MAP electrode kept at the same epicardial position the MAP rise‐time did not vary with time. If the influences of heart rate were eliminated, the intra‐ and interindividual variation in the MAP duration was very low. Sotalol significantly and dose‐dependently prolonged MAP duration, but did not affect rise‐time, whereas tocainide significantly and dose‐dependently shortened MAP duration and increased rise‐time. The effect of tocainide on rise‐time is most likely secondary to a reduction in conduction velocity due to a decrease in Vmax in the single cell action potential. These results suggest that monophasic action potential recordings coupled with an on‐line computerized analysis may be used for rapid and simple evaluation of drug effects, both on cardiac depolarization and repolarization.