bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclic AMP as a Mediator of the Relaxing Action of Papaverine, Nitroglycerine, Diazoxide and Hydralazine in Intestinal and Vascular Smooth Muscle
Authors: Anderson Rolf
Published: July 2010

Abstract:Papaverine and nitroglycerine relaxed rabbit colon muscle. The relaxation was preceded by an increase of the cyclic AMP content of the muscle. There was a correlation between the degree of relaxation and the increase of cyclic AMP. A reduction of ATP content was obtained with these drugs; this effect was not present in the Ca++‐poor preparation in spite of the fact that the cyclic AMP level was still increased. Papaverine but not nitroglycerine reduced the phosphodiesterase activity of the intact rabbit colon. In a homogenate of colon muscle a marked inhibition of phosphodiesterase activity was obtained. The phosphodiesterase activity from different cell fractions was also studied. Phosphodiesterase from the cytoplasmic fraction was activated by papaverine and nitroglycerine, while that of a Ca++‐binding microsomal fraction like that of mitochondria was inhibited. Diazoxide and hydralazine relaxed bovine mesenteric artery but not rabbit colon. The relaxation was associated and correlated with an increase in the cyclic AMP content. A reduction in the ATP content and an activation of phosphorylaseaactivity was also obtained; the ATP reduction was Ca++‐dependent. A weak inhibitory effect on phosphodiesterase activity was observed in hornogenate of the artery after diazoxide. Hydralazine activated phosphodiesterase in a homogenate of mesenteric artery in a low concentration but inhibited it in a high concentration. It is suggested that cyclic AMP mediates, at least partly, the relaxing action of these four drugs probably by stimulating a Ca++‐binding process in the smooth muscle cell.
Distribution and Placental Transfer of14C‐Thiourea and14C‐Thiouracil in Mice Studied by Whole‐body Autoradiography
Authors: Slanina Premysl , Ullberg Sven , Hammarström Lars
Published: July 2010

Abstract:Whole‐body autoradiography of mice 5, 20, 60, 240 min. and 1 and 4 days after intravenous injection of14C‐thiourea and14C‐thiouracil showed a very similar distribution pattern for both substances. The concentration of radioactivity in the thyroid was higher than the average concentration as early as 5 min. after injection and it remained higher than in any other organ during the 4 days observation period. A high radioactivity was also found in the walls of large blood vessels, adrenal cortex, and the mammary gland as well as in the liver, lungs, and the kidney, where it persisted for as long as 24 hours. In the foetuses a very high uptake of radioactivity was found in the thyroid while the concentration in the other foetal tissues as well as in placenta did not exceed that of the blood of mother.
The Decapitated Rat as a Test Object for the study of Hypo‐ and Hyperthermic Acting Compounds*
Authors: Weis Jan
Published: July 2010

Abstract:The effects of hyper‐ and hypothermic acting compounds on the rectal and skin temperature, oxygen consumption, and heart rate were studied in the decapitated rat. Noradrenaline infusion (2 μg/kg/min.) caused thermogenesis, increased oxygen consumption, tachycardia, and vasoconstriction. 2,4‐Dinitrophenol (2 × 2.5 mg/kg intraperitoneally) and sodium salicylate (150 mg/kg intra‐peritoneally), which cause an uncoupling of the oxydative phosphorylation, caused thermogenesis and increased oxygen consumption but no significant changes in the skin temperature or heart rate. The effects of noradrenaline but not those of 2,4‐dinitrophenol and sodium salicylate could be blocked or reduced by the administration of propranolol and phentolamine. Thus the thermogenesis caused by noradrenaline could be differentiated from that caused by uncouplers of oxydative phosphorylation. The metabolic poison, iodoacetic acid reduced or prevented the noradrenaline induced thermogenesis when given as a pretreatment (30 mg/kg intraperitoneally) 60‐75 min. before the noradrenaline infusion. Chlorpromazine (10 mg/kg intraperitoneally) did not influence the noradrenaline induced thermogenesis either when given as a pretreatment or when given during the infusion. It is concluded that the decapitated rat is useful for the study of the mechanism of action of hyper‐ and hypothermic acting compounds.
Distribution and Excretion of Enibomalum (NFN) in Rats
Authors: Ravn‐Jonsen A.
Published: July 2010

Abstract:Rats were given enibomal (60 mg/kg) intravenously in a single dose. Groups of animals were then killed after 15, 30, 60, 120, 180 and 240 min. respectively, and the concentrations of enibomal determined. In the plasma, liver and muscles the concentration was reduced between 15 and 30 minutes after the injection, after which it remained at a fairly constant level until one hour after the injection. The concentration then fell again in the plasma at a rate corresponding to a half‐value period of about 2 hours. In the brain a steep fall was seen during the first hour, after which the concentration fell at a slow rate. 15 minutes after the injection the concentration was nearly the same in the plasma and fatty tissue. Thereafter it rose steeply in the fat, to four times the value in the plasma within the first hour. Finally the fat concentration fell, to reach a level of about 40 per cent of the maximum value four hours after the injection. In urine of rats collected over 72 hours the following 5‐isopropylbarbituric acid derivates (B) were detected: l‐methyl‐5‐acetonyl‐B, 5‐acetonyl‐B, and l‐methyl‐5‐(2′‐oxo‐3′‐hydroxypropyl)‐B. About 20 per cent of the administered dose was recoverable in the urine. The kinds and amounts of metabolites were the same as previously found in human urine. Neither enimobal nor the metabolites were detectable in the bile or in the small‐intestinal contents within the first four hours after the injection.
The Effect of Mercaptodextran on Distribution and Toxicity of Mercury in Mice
Authors: Aaseth Jan
Published: July 2010

Abstract:Mercaptodextran (SH‐dextran) proved to be less toxic than BAL in rodents and better tolerated in intravenous infusion therapy. Immediate therapy with SH‐dextran was superior to any other treatment for the removal of sublethal doses of mercury (1.8 μmol Hg/kg) from the body. The life‐saving effect of SH‐dextran given immediately after a lethal HgCl2‐dose (74 μmol Hg/kg) was demonstrated. When chelation therapy was given two hours after the poisoning, however, SH‐dextran was without any significant effect, while BAL was still life‐saving. Mercury mobilized from the kidneys was redistributed to other organs when immediate chelation treatment with low molecular thiols was given, whereas SH‐dextran brought about an excretion of mobilized mercury. SH‐dextran, in contrast to certain other antidotes, did not induce an increased deposition of mercury in the brain.
Kidney Changes in Mice due to Oriental Hornet (Vespa orientalis) Venom: Histological and Electron Microscopical Study
Authors: Sandbank U. , Ishay J. , Gitter S.
Published: July 2010

Abstract: Administration to mice of Vespa orientalis venom was found to cause acute tubular necrosis of the kidney. The proximal tubular epithelial cells showed an abundance of autophagic vacuoles, suggesting disintegration of mitochondria. A few necrotic cells were found. The mechanism of the action of the venom on the kidney tubule cells is as yet unknown but there is evidence for direct effect of the venom on the mitochondria.
Excretion of Some Drugs in Bovine Tears
Authors: Pedenen Knud Bsrge
Published: July 2010

Abstract:The excretion of drugs in the tears of cattle was studied, while almost constant plasma concentrations were maintained by continuous intravenous infusion. The examination included both acid and basic drugs. A fairly constant ratio between the concentrations in the tears and the ultrafiltrate of plasma was found for each drug examined. The ratio was not influenced by the rate of secretion or the plasma concentration. For drugs of an acid nature the ratio was less than or equal to 1 (sulphanilamide 0.99, sulphadimidine 0.80, sulphadiazine 0.35, sulphadoxine 0.48, benzylpenicillin 0.004), whereas the ratio for drugs of a basic nature was greater than 1 (penethamate 7.1, trimethoprim 2.2). The above described investigations provide reasons for believing that the passage of the examined drugs from the plasma to the tears may take place by diffusion of the non‐protein‐bound, unionized fraction.
The Functional Role of Cholinergic Receptors in the Outlet Region of the Urinary Bladder: Anin VitvoStudy in the Cat
Authors: Nergårdh Arne , Boréus Lars O.
Published: July 2010

Abstract:A method for experimental studyin vitroof the outlet region (bladder base, bladder neck and proximal urethra) from the cat is described which allows simultaneous recording of resistance to flow through the region and of isometric tension in the longitudinal muscles. The results suggest that acetylcholine (ACh) may influence the smooth muscles in the outlet region by several mechanisms. Contractions in the longitudinal muscles are mediated by atropine sensitive cholinergic receptors. The resistance to flow could be either increased or decreased following ACh stimulation and in neither case could the response be blocked with atropine. If the response was an increase, however, it was blocked by phentolamine and if it was a decrease, it was blocked by propranolol. It is concluded that ACh stimulates the circular musculature in the outflow region through α‐ and β‐adrenergic receptors. It is suggested that the effects of ACh on flow are brought about through short intramural adrenergic neurons. ACh stimulates their ganglion‐cells which results in a release of nor‐adrenaline at the nerve endings and in activation of adrenergic receptors in the circular muscle layer.
Determination of Guanethidine in Sympathetic Ganglia
Authors: Juul Per , Sand Ole
Published: July 2010

Abstract: Guanethidine sulphate was administered intraperitoneally in a dose of 10‐60 mg/kg for up to two months to adult male rats and the content of guanethidine in the superior cervical ganglia was determined fluorometrically after combination with ninhydrin in alkaline solution. Guanethidine was shown to concentrate in the superior cervical ganglia. Twenty four hours after the discontinuation of guanethidine sulphate 20 mg/kg for 14 days, the mean total gang‐lionic content of guanethidine base was 50 ng/ganglion (S.D. 8.8, n = 10) corresponding to 83 μg/g dry weight or 17 μg/g wet weight. Following a single injection of guanethidine sulphate and following discontinuation of prolonged administration of the drug the ganglionic guanethidine declined with a half‐life of 35 hours. Most of the ganglia were excised 24 hours after discontinuation of administration of the drug at which time the decline in ganglionic guanethidine was exponential. Desmethylimipramine largely prevented the accumulation of guanethidine in the ganglia indicating a mainly intraneuronal localization of guanethidine, a localization which was confirmed by microautoradiography. Reserpine only lowered the content to a small extent possibly indicating a mainly extragranular localization of guanethidine in the nerve cells. The selective morphological effects of guanethidine on sympathetic ganglia previously demonstrated were almost completely prevented by desmethylimipramine but only to a small extent by reserpine. SKF‐525‐A potentiated the ganglionic effects of guanethidine. It is assumed that the ganglionic effects are due to a cytotoxic effect of guanethidine concentrating selectively in the sympathetic ganglion nerve cells with the major part being located outside the noradrenaline storage granules as opposed to a mainly intragranular localization in the peripheral sympathetic terminals.
Reversal by Promazine of Acetylcholine‐Induced Changes in Rat Atrial Action Potentials
Authors: Landmark Knud , Haffner Jon F. W. , Lindberg Per‐Erik
Published: July 2010

Abstract:In isolated electrically stimulated left rat atria, the application of acetylcholine (ACh) 5 × 10−6M caused a pronounced shortening of the action potential without changing the resting membrane potential. The times required to reach fifty and ninety % repolarization were reduced to 52.5 and 47.9 % of the initial values (P < 0.001); the height of the action potential was reduced to 94.8 % (0.1 > P > 0.05) and the maximum rate of rise (dv/dt) of depolarization was increased to 105.2 % (0.1 > P > 0.05). The addition of promazine 5 × 10−6M and 10−5M to atria pretreated with ACh, increased the duration of the action potential and thus reversed the effects of ACh. The effects were most marked after promazine lWsM, which prolonged 50 and 90% repolarization times to 135.8 (P< 0.001) and 140.0 % (P < 0.001) of the initial values and reduced dvldt to 71.2 % (P < 0.001). The height of the action potential was reduced by promazine 10−5M to 94.9 % (P < 0.02) of the initial value, this being the only indication of a similarity of effect between these two cardio‐depressive agents. The alterations in ionic fluxes underlying the changes in electrical activity are briefly discussed.
The Initial Fate of a Trace Amount of Intravenously Administered Selenite
Authors: Sandholm Markus
Published: July 2010

Abstract:Selenite injected intravenously was rapidly taken up by the erythrocytes, after which it was ejected into the plasma in which the selenium became bound to protein (mainly to albumin). The selenium was then taken up by other cells mainly in the liver which maximally contained radioselenium 15 min. after the injection. Following this a gradual discharge into the plasma occurred.
Contractile Responses to Phenylephrine and Carbachol in Circular Rabbit Fundus Strips at Varying External K+and Ca++Concentrations
Authors: Haffner J. F. W.
Published: July 2010

Abstract:Both phenylephrine and carbachol produced dose‐dependent contraction in isolated circular strips from the fundus of rabbit stomachs. The threshold concentration required to produce contraction (phenylephrine 10‐6M, carbachol 2 × 10−7M) remained the same when the external K+concentration ([K+]o) was altered from zero to 94.4 mM, and the external Ca++concentration ([Ca++]o) from zero to 3.75 mM. The magnitude of the contractions produced by the two drugs was greatly altered, however, and these alterations were best seen in the responses to the highest concentrations used (phenylephrine 10−4M, carbachol 2 × 10−5M). The responses to carbachol 2 × 10−5M were significantly (P < 0.05) greater than the response to phenylephrine 10−4M at all [K+]oand [Ca++]oother than [Ca++]o= 0. In order to compare the influence of varying [K+loand [Ca++]oon the responses to the two drugs, the per cent alterations in the responses were studied. The contractions produced by both phenylephrine and carbachol increased when [K+]owas raised from zero to 23.8 mM (P < 0.005), but were reduced when [K+]owas raised further (to 47.2 and 94.4 mM) (P < 0.05). Increasing [Ca++Iogave increasing responses to both drugs. The reduction in the response to phenylephrine 10−4M when [K+]owas reduced from 5.9 mM to zero was less marked than the reduction in the response to carbachol 2 × 10−5M (0.1 > P > 0.05 for the difference), but the increase in the response to phenylephrine when [Ca++]owas increased from 0.31 to 3.75 mM was significantly greater (P < 0.05) than the increase in the response to carbachol. It is suggested that the increase in response with increasing [K+]ofrom zero to 23.8 mM may be due to a secondary increase in available Ca++, while the reduction in response at higher [K+]omay be due to the depolarization which these [K+]oproduce.
Interspecies Variations in Small Intestinal and Hepatic Drug Hydroxylation and Glucuronidation
Authors: Hietanen E. , Vainio H.
Published: July 2010

Abstract:In order to study the interspecies variations in small intestinal and hepatic drug metabolism, the benzpyrene hydroxylase and UDP glucuronyl‐transferase activities were determined in the cat, guinea pig, mouse, rabbit and rat. The cat exhibited very low benzpyrene hydroxylase and UDP glucuronyl‐tranferase activities both in its liver and small intestine. Of the other species the guinea pig had the highest benzpyrene hydroxylase activity, the rabbit an intermediate and the rat and mouse the lowest activity in the small intestine. The hydroxylation of 3,4‐benzpyrene by liver microsomes was most active in the mouse and guinea pig, the rat liver showed an intermediate activity and the rabbit liver was least active. The UDP glucuronyl‐transferase activity was highest in the small intestinal mucosa of the rabbit and rat, whereas the guinea pig and mouse exhibited an 80 per cent lower activity. The guinea pig liver microsomes showed the highest activity and the mouse, rabbit and rat livers had an intermediate activity. The rat small intestinal benzpyrene hydroxylase activity could be enhanced to the same level as in the guinea pig by feeding the rats with a guinea pig diet.
The Effect of Sodium Chloride on Kidney Function in Rats with Lithium Intoxication
Authors: Thomsen Klaus
Published: July 2010

Abstract:The effect of lithium was studied in 3 groups of rats given food containing 20, 40, or 60 mmol LiCl/kg dry weight for 3‐4 weeks. The animals had free access to demineralized water. The mean serum lithium levels after 3 days were 0.4, 0.7, and 1.1 mM, respectively. The rats with low and medium lithium intakes could be maintained at this level for a very long time. In the rats with a high lithium intake the serum lithium concentration after 2‐3 weeks rose to high values as a result of a decrease in the renal lithium clearance; the rats developed severe lithium intoxication. Replacement of demineralized water with 80 mM NaCl solution in severely intoxicated rats reversed the toxic effects; the lithium clearance rose, and the serum lithium returned to the same level as observed before the intoxication. Administration from the start of the experiment of 20 mM NaCl as the only drinking fluid prevented the development of severe intoxication even in rats given food with 100 mmol LiCl/kg dry weight. No decrease in the lithium clearance occurred during an observation period of 8 weeks, and the serum lithium concentration remained constant with a mean value of 1.4 mM. The results indicate that the decrease in lithium clearance produced by prolonged administration of high lithium doses is not due to irreversible kidney damage; it can be reversed by the administration of sodium. The development of severe intoxication can also be prevented by administering sodium along with lithium. These observations support the hypothesis that sodium depletion plays an important role in the development of severe lithium intoxication.
Adrenergic and Serotoninergic Mechanisms in Gastric Secretion in Rats
Authors: Fjalland B.
Published: July 2010

Abstract:The influence of adrenergic and serotoninergic mechanisms on gastric secretion was investigated using fistula‐ and pylorus‐ligated rats. Secretion was increased by the tyrosine hydroxylase inhibitor α‐methyltyrosine. This effect could be reversed by L‐DOPA. 6‐hydroxydopamine also increased gastric output. The tryptophane hydroxylase inhibitorp‐chlorophenylalanine reduced gastric output and abolished the increase in gastric secretion induced by α‐methyltyrosine.

The antisecretory effect of serotonin was found to be antagonized by α‐methyltyrosine. Pre‐treatment with 6‐hydroxydopamine also diminished the anti‐secretory effect of serotonin.

The results indicate the possibility of the existence of an inhibiting peripheral adrenergic tonus in the regulation of gastric secretion in rats. Furthermore it is suggested, that the anti‐secretory effect of large doses of serotonin may be due to displacement of noradrenaline in catecholamine neurones. Finally the question is raised whether a balance between serotoninergic and adrenergic mechanisms in the regulation of gastric secretion may exist in rats.
Absorption of Salicylic Acid from the Perfused Human Rectum
Authors: Becbgaard Erik
Published: July 2010

Abstract:The absorption of salicylic acid from solutions, in which it is highly ionized, was investigated by means of a newin vivoperfusion technique in human subjects. The absorption rate shows proportionality to the concentration (15.6 mM‐250 mM), while the rate decreases with increasing pH (5.9‐8.9). This is in agreement with the theory of passive diffusion of the unionized form of the drug. From a 47 mM sodium salicylate solution, buffered to pH 7.9 with phosphate, 7.5 cm of rectum absorbs about 100 mg per hour. When a glycine buffer is used instead of the phosphate buffer, the absorption rate increases about 2.5 times.
Alterations in Neurochemical and Behavioural Parameters in the Mouse Induced by Low Doses of Methyl Mercury
Authors: Salvaterra Paul , Lown Bradley , Morganti John , Massaro Edward J.
Published: July 2010

Abstract:The effects on mouse behaviour in the open field situation of controlled single doses of methyl mercury (MeHg) (1, 5, 10 mg Hg/kg) were investigated at varying times after intraperitoneal injection (1, 3, 72 hours). In an effort to correlate behavioural and biochemical data, the effects of dose and time after dose on the levels of selected glycolytic pathway intermediates, a‐glycerophosphate, adenine nucleotides and phosphocreatine were monitored. A very good correlation between brain biochemistry and behavioural effects of MeHg was observed. That is, the dose response relationship for the open field task correlated with alterations in levels of metabolic intermediates. At 1 and 3 hours after administration of MeHg, when the levels of the metabolic intermediates were significantly different from those of controls, altered behaviour was observed. At 72 hours post administration, when the biological parameters were approaching control values, a return to normal behaviour was observed.
Biliary Excretion and Intestinal Reabsorption of Mercury in the Rat after Injection of Methyl Mercuric Cloride
Authors: Norseth Tor
Published: July 2010

Abstract: The relative amount of methyl mercuric compounds in rat bile is not dose dependent for doses from 1 mg Hg/kg rat weight to less than 1 μg Hg/kg given as methyl mercuric chloride. Binding of mercury in the bile and reabsorption from the intestinal tract are similar for doses several orders of magnitude apart. The reabsorption of mercury is not part of an enterohepatic circulation, as mercury which is reabsorbed is not predominantly reexcreted. The distribution of sulfhydryl groups between the liver and the bile does not explain the distribution of mercury. The excretion of mercury does not increase when the volume of bile increases. The mercury concentration in the bile reflects the liver concentration and not the plasma concentration. There have been no indications of an active transport mechanism for methyl mercuric compounds from the liver cell to the bile demonstrated.
The Toxicity of Chlorpromazine and Mescaline on Mouse Cerebellum and Fibroblast Cells in Culture*
Authors: Roubein I. F. , Samuelly M. , Keup W.
Published: July 2010

Abstract: The toxicity of chlorpromazine (CPZ) and mescaline (MCL) to mouse cerebellum and fibroblast cells was studied in vitro. CPZ proved to be more toxic than MCL to both tissues. Fibroblast celles are more sensitive than the cerebellum to both CPZ and MCL.
Characteristics of the “Receptor” for Narcotic Analgesics in Synaptic Plasma Membrane Fraction from Rat Brain
Authors: Terenius Lars
Published: July 2010

Abstract:The characteristics of the interaction between dihydromorphine (DHM) and a synaptic plasma membrane (SPM) fraction from rat brain cerebral cortex have been studied. DHM at 10+9M concentration is bound in a reversible process which is partly specific. The specific binding is inhibited by the sulphydryl reagents, N‐ethylmaleimide andp‐chloromercuribenzoic acid. The binding is strongly inhibited by 10−8M levorphanol but significantly less inhibited by its optical antipode, dextrorphan, which is much less analgetic. At 10−8M concentration, nalorphine and naloxone were strongly inhibitory while heroin at 10−8M and codeine at 10−7M were nearly inactive. A mixture of 10−5M acetylcholine and 2.5 × 10−5M eserine caused a moderate inhibition while dopamine, noradrenaline, serotonin, histamine and propranolol were classified as inactive (i. e. caused less than 25 % inhibition at 10−5M). The observed binding characteristics of the SPM fraction are compatible with those which might be expected for the actual narcotic receptor. Analogous SPM preparations from subcortical parts of the cerebrum and from the brain stem also showed stereospecific binding of narcotics.
Binding of 2,4‐Dichloro‐ and 2,4, 5‐Trichlorophenoxyacetic Acid to Bovine Serum Albumin
Authors: Kolberg Jan , Helgeland Kristen , Jonsen Jon
Published: July 2010

Abstract:The binding of 2,4‐dichloro‐ and 2,4,5‐trichlorophenoxyacetic acid (2,4‐D and 2,4,5‐T) to bovine serum albumin has been studied by a gel filtration technique (Hummel & Dreyer 1952). Both compounds were extensively bound to albumin,2,4,5‐T to a higher extent than 2,4‐D. The binding of both herbicides was reduced when the protein contained palmitic acid.
Effect of Guanethidine on the Ultrastructure of the Small, Granule‐containing Cells in Cultures of Rat Sympathetic Ganglia1
Authors: Heath John , Eränkö Olavi , Eränkö Liisa
Published: July 2010

Abstract:Sympathetic chain ganglia of newborn rats were cultured in Rose chambers with and without guanethidine. After one week, the cultures were examined by light microscopy for formaldehyde‐induced catecholamine fluorescence and by electron microscopy after fixation in 5% glutaraldehyde and 1% osmium tetroxide. Guanethidine sulphate (2 mg/l) caused an increase in the number of the small, intensely fluorescent (SIF) cells in the ganglion explants. Electron microscopic examination of guanethidine‐containing cultures revealed an increased number of small, granule‐containing (SGC) cells, which corresponded in size and shape to the SIF cells. Round vesicles (about 100 nm in diameter) and elongated vesicles (about 80 nm in cross section and about 200 nm in length) containing an electron‐dense core were observed in the cytoplasm of the SGC cells both in control and guanethidine‐containing cultures. The granular vesicles were most frequent in the periphery of the cytoplasm. In ganglia cultured with guanethidine, most SGC cells observed contained a greatly reduced number of granular vesicles as compared to SGC cells of the control cultures.
THE SEA URCHIN EGG AS A TESTING OBJECT IN TOXICOLOGY
Authors: Hagström Berndt E. , Lönning Sunniva
Published: July 2010

Abstract: The sea urchin egg offers unique properties for experimental work on the cellular and embryologic level. The developmental stages are well suited for the study of teratogenic effects exerted by drugs. The development of the sea urchin egg is holoblastic and resembles the early development of the human ovum considerably. The gametes and embryos of the regular sea urchin species Paracentrotus lividus and Psammechinus microtuberculatus have been used in a study of the teratogenic effects of chloramphenicol, nicotine, chlorpromazine, imipramine and thalidomide. All the substances tested were found to influence the fertilization, cleavage and differentiation of the larvae. The effects of the substances on the cellular and embryonic level are described and the possible mechanism of action is discussed.

During the past decade the interest in substances inflicting malformations or general injuries in living organisms has gained an increasing interest. The extensive use of biocides and their repercussions on living organisms of immediate economic interest and on man created an extending research in this field. Of particular importance was, however, the discovery of the teratogenic properties of the sedative hypnotic drug thalidomide. In spite of the elaborate pharmacological methods applied in testing drugs before their adoption in clinical use thalidomide, if administered during pregnancy, was ascertained to cause congenital malformations in man. This was a surprise since thalidomide was regarded as a particularly safe drug and even the intake of large overdoses did not seem to cause any persisting ill effects. There is, however, some confusion about the teratogenic effect of thalidomide and its mode of action is still obscure.

In the present investigation a number of substances with known or suspected teratogenic effect in man were studied on the cellular and embryonic level. As material served the gametes and larvae from the regular sea urchin Paracentrotus lividus (LAMARCK), which is the classic material for the study of fertilization, cleavage and development. Few organisms have been subjected to a more conclusive experimental work, and the main advantage with this material is that every ripe female delivers several millions of fairly uniform transparent eggs, particularly suited for microscopic examination in the living state. Subsequent to insemination the eggs develop within the course of a few days into self‐maintaining larvae. Cleavage and organogenesis are also easy to observe and even minor changes taking place after the addition of an active drug can be registered in the microscope.

The fact that the cleavage and embryogenesis are so well investigated also makes it possible to study the specific effect on e.g. the ectoderm or the endoderm of a certain substance. The short period of time necessary for the embryo to reach the self‐maintaining pluteus stage also minimizes the influence of external experimental factors.
Determination of ATP‐Induced45Calcium Uptake in Rat Mast Cells
Authors: Dahlquist Rune
Published: July 2010

Radioactively labelled calcium (45Ca) was taken up into isolated rat mast cells incubated with adenosine 5′‐triphosphate (ATP). This uptake did not occur in the presence of lanthanum. After a short period of incubation of the mast cells with ATP and45Ca, the addition of lanthanum markedly decreased the amounts of45Ca associated with the cells. Exchange between cellular45Ca and added unlabelled calcium in the medium was counteracted by the presence of lanthanum. It was concluded that lanthanum inhibited calcium fluxes and in addition displaced bound45Ca from sites accessible to the trivalent cation. From indirect evidence it was concluded that the ATP‐induced uptake of45Ca in rat mast cells contained one component of net increase in the cellular calcium contents and one component of increased exchange of calcium.
Chlorpromazine and Purine Transport in Cultured Human Skin Epithelial Cells
Authors: Dybing Erik
Published: July 2010

Chlorpromazine (CPZ) 1.5 × 10‐4M inhibits the uptake of hypoxanthine into the acid‐soluble fraction of human skin epithelial cells (NCTC 2544) grown in culture to 42 % of the controls, whereas the uptake of adenine is only reduced to 85 % of the controls. The cellular uptake of guanine is virtually absent. CPZ does not change the activity of hypoxanthine, adenine or guanine phosphor‐ribosyltransferases in homogenates of the cells. Excess adenine inhibits the cellular uptake of hypoxanthine, whereas excess hypoxanthine does not alter the uptake of adenine.
Pharmacological Properties of 1‐(3′5′‐diisobutyryloxy‐phenyl)‐2‐(t‐butylamino)‐ethanolhydrochloride (KWD 2058), a New Sympathomimetic Bronchodilator
Authors: Olsson O. A. T. , Persson C. G. A. , Persson H. , Sörenby L.
Published: July 2010

KWD 2058 is the diisobutyric acid ester of terbutaline (bricanyl®), a β2‐re‐ceptor selective sympathomimetic bronchodilator. KWD 2058 relaxed isolated bronchial smooth muscle obtained from the guinea‐pig, cat and man, but in isolated cat bronchial preparations pre‐treated with the esterase inhibitor eserine, KWD 2058 was inactive in concentrations that relaxed the normal preparations (ED50: 0.2 μg/ml). This indicates that the effect of KWD 2058 is due to the formation of terbutaline and not to the unchanged diester. KWD 2058 had no effects on isolated guinea‐pig auricle preparations (up to 2 ug/ml) or on isolated guinea‐pig hearts (up to 10 μg). In isolated cat hearts, KWD 2058 increased the frequency but lacked positive inotropic effects. In anaesthetized cats, KWD 2058 and terbutaline were equipotent on a molar basis as to the inhibitory effects following respiratory overflow. On cardiovascular parameters KWD 2058 was somewhat less potent than terbutaline, whereas the effect on the soleus muscle of the two compounds did not differ significantly. KWD 2058, given subcutaneously and orally, protected unanaesthetized guinea‐pigs against histamine aerosol. Administered orally, KWD 2058 was 6 times more active than terbutaline. KWD 2058 given in bronchodilating doses did not affect the barbiturate sleeping time or the locomotor activity in mice. The LD50 for KWD 2058 in mice was 52 mg/kg intravenously, 450 mg/kg subcutaneously, 270 mg/kg intraperitoneally and 1750 mg/kg given orally. It is concluded that KWD 2058 is hydrolyzed to terbutaline, which is the active agent responsible for the β2‐receptor stimulating effect seen after administration of KWD 2058. The esterification of terbutaline has resulted in a significantly improved oral potency in guinea‐pigs and a tendency to less cardiovascular effects in relation to the bronchodilator effects.
14C‐Antipyrine as a Model Compound in the Study of Drug Oxidation and Enzyme Induction in Individual Surviving Rats
Authors: Bakke Olav M. , Bending Michael , Aarbakke Jarle , Davies Donald S.
Published: July 2010

A rapid method for the estimation of antipyrine‐N‐methyl‐14C in small samples of whole blood has been developed. A study of the metabolite pattern in the urine of rats given this compound confirmed the overall importance of oxidative mechanisms in the metabolism of antipyrine. None of the metabolites interfered with the estimation of14C‐antipyrine in plasma. Applied to the determination of antipyrine in liver perfusate the present method compared favourably with the widely used spectrophotometric method. The mean half‐life of antipyrine in male Wistar rats was 88 min. with inter‐individual values in the range of 63‐128 min. The intra‐individual variation, as judged by the half‐lives found on 2 occasions, was considerably smaller. A brief course of phenobarbital treatment resulted in a significant shortening of the half‐life of antipyrine in all of the individual rats. These findings suggest that the determination of the half‐life of14C‐antipyrine in individual rats using the animals as their own controls, is a useful experimental tool for the study of factors which influence drug oxidation.
The Biotransformation of Cyclophosphamide in Man: Analysis of the Variation in Normal Subjects
Authors: Mouridsen H. T. , Faber O. , Skovsted L.
Published: July 2010

The metabolism of cyclophosphamide was studied in 40 subjects aged 33‐84, mean 64 years. After the intravenous injection of14C‐cyclophosphamide the radioactivity of the plasma and urine samples was analysed as regards unchanged cyclophosphamide and its metabolites. The parameters of the metabolism, half‐life of cyclophosphamide in the serum, peak and integrated serum concentration of the metabolites, distribution volume of injected radioactivity and the rate of excretion of cyclophosphamide and metabolites in the urine all exhibited a very large interindividual variation of a factor of 3‐10. Spontaneous intra‐individual variation, however, studied in 9 subjects, did not exceed that due to inaccuracy of the analysis. The possible clinical implications of these results are discussed.
Effects of Ethyleneglycol Dinitrate and Related Compounds on Ethanol Preference and Ethanol Metabolism
Authors: Komura Setsuo
Published: July 2010

Ethanol preference in rats (ALKO strains) was studied by injecting ethyleneglycol dinitrate, glyceryl trinitrate, propyleneglycol dinitrate and ethyleneglycol mononitrate. Their effects on ethanol metabolism and on the activities of liver alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (AldDH) were also examined. All four compounds caused a marked decrease in ethanol preference. When administered 30 minutes before the injection of ethanol, all four drugs significantly delayed the disappearance of ethanol and acetaldehyde from the blood. With 150 mg/kg b.wt. of ethyleneglycol dinitrate, the blood acetaldehyde level reached 770 nmol/ml one hour after ethanol (2 g/kg b.wt.) injection. This contrasted with 30 nmol/ml for the control. Similar results were obtained with the other compounds. 3 hours after the administration of 150 mg/kg of nitrate, the liver ADH activities were inhibited by 21‐46% and the liver Ald DH activities by 32‐60%. These findings suggest that the decrease in ethanol preference and the inhibition of ethanol and acetaldehyde elimination are closely related to the decrease in liver ADH and AldDH activities in the presence of these four organic nitrates.
Hepatic Tryptophan Oxygenase Activity as a Marker of Changes in Protein Metabolism during Chronic Ethanol Treatment
Authors: Mørland Jørg
Published: July 2010

Rats were given ethanol daily to provide 22, 30 or 38 per cent of the total calories consumed. Sucrose substituted ethanol isocalorically in the respective control groups. The two diets providing the largest amount of ethanol caused a significant reduction of hepatic tryptophan oxygenase, TO, activity, which occurred after 7 days (38 per cent of the calories as ethanol), or after 21 days (30 per cent of the calories as ethanol). The reduction of enzyme activity persisted throughout the remainder of the experimental period. Hepatic triglycerides, plasma lipids, plasma enzymes (alkaline phosphatase, GOT and GPT) and hepatic histology was only slightly or transiently affected during the period of ethanol treatment. The reduction of TO‐activity was accompanied by reduced dexamethasone induction of TO and tyrosine aminotransferase, TAT, during liver perfusion. The incorporation of labelled amino acids into hepatic protein was reduced in perfused livers and alsoin vivowhen TO‐activity was decreased. It was concluded that the activity of tryptophan oxygenase was most probably an indicator of the synthesis of this enzyme and other proteins sensitive to the chronic administration of ethanol.
Pharmacokinetic Interaction between Neuroleptics and Tricyclic Antidepressants in the Rat
Authors: Gram Lars F. , Christiansen Johannes , Overø Kerstin Fredricson
Published: July 2010

The metabolism and disposition of14C‐nortriptyline and14C‐imipramine in the rat was studied after intraperitoneal administration of single doses of the drug. With14C‐nortriptyline, it was found that concomitant administration of perphenazine caused a rise in plasma level and tissue concentration of unchanged nortriptyline. With14C‐imipramine, it was found that administration of perphenazine caused an increase in tissue concentration of imipramine, desipramine, and iminodibenzyl. At the same time total excretion by the faeces and the urinary excretion of glucuronides and other polar metabolites was decreased. The urinary excretion of imipramine‐N‐oxide was increased in perphenazine pretreated rats. These results indicate that perphenazine in rats inhibits the hydroxylation and/or glucuronide formation of imipramine, whereas demethylation, N‐oxidation, and dealkylation seem to be unaffected. Dose response studies showed that perphenazine and chlorpromazine have equivalent potency with regard to the increased tissue concentration of14C‐imipramine.
Renal Tubular Transfer of Phenoxyacetic Acids in the Chicken
Authors: Erne Kurt , Sperber Ivar
Published: July 2010

The differential renal excretion of phenoxyacetic acid, 2‐chlorophenoxyacetic acid, 4‐chlorophenoxyacetic acid,2,4‐dichlorophenoxyacetic acid (2,4‐D) and 2,4,5‐trichlorophenoxyacetic acid (2,4,5‐T) was measured in chickens by the method ofSperber (1948&1954). Doses of approximately 50 and 100 μmol of either test compound were infused during 3 min. into a leg vein and the amounts excreted by the two kidneys determined during consecutive 15‐min. periods. At the lower dose level the mean apparent tubular excretion fractions (EF) of the compounds, expressed as per cent of the dose, where 16.5, 22.9, 12.8, 11.3 and 4.2, respectively. All the values except that for 2,4,5‐T are sufficiently high to be indicative of tubular excretion. On increasing the dose, the EF values decreased, thus suggesting the involvement of a saturable mechanism. The test compounds proved to depress the excretion of phenol red, the effect being most marked with 2,4,5‐T.
The Possible Role of Cytochrome P‐450 in the Liver “First Pass Elimination” of a P‐Receptor Blocking Drug
Authors: Grundin Robert , Moldéus Peter , Orrenius Sten , Borg Karl Olov , Skånberg Inger , von Bahr Christer
Published: July 2010

The highly lipid soluble β‐receptor blocking drug alprenolol interacts with high affinity with rat liver microsomal cytochrome P‐450, is rapidly metabolized in the liver and exhibits a marked liver “first pass elimination” (FPE) in the rat. It thus has a low oral bioavailability in this species. In order to investigate the possible role of the cytochrome P‐450 system in the FPE we studied the influence of the three P‐450 inhibitors SKF 525‐A, imipramine and metyrapone and of phenobarbital treatment on the disposition kinetics of alprenolol in a series of experimental models. Alprenolol rapidly gave rise to a type I spectral change on addition to intact liver cells, indicating a rapid hepatic uptake. The maximal magnitude of this spectrum increased about twofold after phenobarbital treatment of rats in both microsomes and isolated liver cells. Imipramine, SKF 525‐A and metyrapone partly displaced3H‐al‐prenolol from non‐metabolizing partly purified cytochrome P‐450 and liver cell preparations (20°). Imipramine and SKF 525‐A were about equally effective in this respect whereas metyrapone was much less potent. At 37° the metabolism of alprenolol was rapid and of about similar activity (per nmoles of cytochrome) in liver microsomes, isolated liver cells and in the perfused liver (at a high dose). The Km‐value was similar in microsomes and in isolated liver cells. A similar metabolic inhibitory pattern was found in microsomes and isolated liver cells. SKF 525‐A was the most efficient inhibitor followed by imipramine and then metyrapone. The same inhibitory pattern was found for the hepatic extraction of alprenolol. Moreover, the hepatic extraction of alprenolol was dose dependent. Imipramine in a high dose increased the area under the blood concentration curve by a factor of ten after oral administration of alprenolol in the conscious rat. The above findings suggest that cytochrome P‐450 is, at least partly, responsible for the degree of hepatic extraction and metabolism (FPE) of alprenolol. This view was also supported by the findings that the perfused liver showed an increased capacity for the extraction and metabolism of alprenolol after phenobarbital treatment. The cytochrome P‐450 system may influence the hepatic extraction of alprenolol in rat liver by providing an intracellular “high affinity binding pool” for the unchanged drug. The subsequent metabolic step seems to be important since it “unloads” P‐450 so that it can bind new drug molecules.
Biotransformation of Hg‐203 Labelled Methyl Mercuric Chloride in Rat Brain Measured by Specific Determination of Hg2+
Authors: Syversen Tore L. M.
Published: July 2010

Adult Wistar rats were injected with Hg‐203 labelled methylmercuric chloride or mercuric chloride. After a methylmercury injection 3‐6 % of the total brain mercury is present in the inorganic form. This represents more inorganic mercury in the brain than after an equal dose of mercuric chloride. The time course of the inorganic mercury content in the brain is dependent on the compound given. Subcellular fractionation shows that the myelin and mito‐chondrial fractions accumulate more inorganic mercury than the other fractions. There is an inverse relationship between the dose of methylmercury given and the amount of inorganic mercury in the brain.
Sympathomimetic Amines and Gastric Secretion in Rats
Authors: Fjalland B.
Published: July 2010

The influence of amphetamine, apomorphine and methylphenidate on basal gastric secretion was investigated using fistula‐ and pylorus‐ligated rats. The antisecretory effect of amphetamine was reversed by pretreating the animals with α‐methyl‐p‐tyrosine (α‐MT). Moreover the decreased output following methylphenidate in shay‐rats was reduced by α‐MT pretreatment. On the other hand α‐MT was not able to antagonize the antisecretory effect of methylphenidate in fistula rats. Apomorphine exhibited antisecretory properties in fistula rats and gastric stimulating effects in shay‐rats, the latter effect being reversed by α‐MT pretreatment. The results obtained indicate that the antisecretory effects of amphetamine and methylphenidate may be due to their amine releasing properties.
Lithium‐induced Loss of Body Sodium and the Development of Severe Intoxication in Rats
Authors: Thomsen Klaus , Jensen Jurgen , Olesen O. Vendelin
Published: July 2010

Four groups of rats were given food containing 0, 40, 70, or 100 mmol LiCl per kg dry weight, respectively. They had free access to water and 0.46 M‐NaCl. This regimen was maintained for one month, and the rats did not develop lithium intoxication in spite of the high lithium dosage. The rats given lithium‐containing food drank more sodium chloride solution than the control rats, and the intake increased with the lithium content of the food. Access to sodium chloride solution was then discontinued. In the two groups given the highest lithium dosages this led within four days to a marked loss of body sodium and a proportionate loss of body weight, a significant decrease of serum sodium, and the development of severe lithium intoxication. Half of the rats in these groups died within 16 days. When rats with severe lithium intoxication were given access to 0.15 M‐NaCl, they drank so much of the sodium chloride solution within one hour that their body weight prior to the intoxication was re‐established. The experiments indicate that administration of lithium leads to a lowered ability of the kidneys to conserve sodium and a consequent increased requirement for sodium. If this is not fulfilled, the animals lose sodium and develop severe lithium intoxication.
The Effect of Prolonged Lithium Ingestion on Morphine Actions in the Rat
Authors: Jensen Jørgen
Published: July 2010

Rats were given lithium with the food in a dose which maintained the serum lithium concentration at about 1.0 mM. Morphine, given subcutaneously in a dose of 8 mg/kg body weight, was administered both acutely and chronically. Lithium increased the analgesic effect of morphine but did not affect tolerance development. Following chronic morphine administration, lithium increased the hyperthermic action of morphine and the morphine‐induced motor hyperactivity. The interaction of lithium with morphine may take place through brain amines and brain cyclic AMP.
Inhibition by Diphenylhydantoin of Vasopressin Release from Isolated Rat Neurohypophyses*
Authors: Guzek Jan W. , Russell James T. , Thorn Niels A.
Published: July 2010

Abstract:Diphenylhydantoin (40 μg/ml) inhibited vasopressin release from isolated hemilobes of rat neurohypophyses, both during resting conditions and after electrical stimulation.