bluuebunny/crossref_metadata_2025 huggingface dataset:
Modification of GABAergic Activity and Thyrotropin Secretion in Male Rats
Authors: Mattila Jyrki , Männistö Pekka T.
Published: July 2010

Abstract: The effect of GABA on basal and stimulated TSH secretion was studied in male rats. The effects of drugs on basal TSH levels were not consistent. Muscimol (0.5 mg/kg subcutaneously, but not 2 mg/kg) increased whereas baclofen (10 mg/kg intraperitoneally), amino‐oxyacetic acid (AOAA, 20 mg/kg intraperitoneally) and bicuculline (2 mg/kg intraperitoneally, but not 1 or 4 mg/kg) decreased basal TSH concentrations. Muscimol, AOAA and baclofen dose‐dependently reversed the TSH cold‐response, as did a large dose of di‐n‐propylacetate (DPA, 400 mg/kg intraperitoneally) and 500 mg/kg (but not 50, 100 or 1500 mg/kg intraperitoneally) of GABA itself. Bicuculline was not effective alone. Neither did it modify the effects of muscimol, AOAA and GABA on the cold‐stimulated TSH response. None of the drugs studied (AOAA, GABA, bicuculline) modified TRH‐induced (100 ng intraperitoneally) TSH‐response. GABA injected into the third ventricle (5–50 μg/rat) or into the medial basal hypothalamus (MBH, 5 μg/rat) had no effect on the basal TSH levels. However, the TSH cold‐response was inhibited when GABA (5 μg/rat) was infused into the MBH but not when it was infused into the third ventricle (5–50 μg/rat). The results suggest that GABAergic pathways may have an inhibitory effect on the stimulated TSH secretion in male rats. The locus of this inhibition is not situated in the anterior pituitary, but possibly in the MBH.
Digitalis Induced Haemodynamic Changes in Patients with Vascular Disease during a Preoperative Exercise Test
Authors: Bille‐Brahe N. E. , Engell H. C. , Sørensen M. Bredgaard
Published: July 2010

Abstract: Haemodynamic studies at rest and during exercise before and after digitalization were carried out in 11 patients with vascular disease. Haemodynamic parameters at rest were within normal limits except for one patient, who had a cardiac index (CI) below 2.5 l/min/m2. During exercise 7 of the patients showed impaired left ventricular function. In the resting patients digitalization produced a significant decrease in pulmonary capillary wedge pressure (PCWP) and an increase of approximately 15% in left ventricular stroke work index (LVSWI) and total oxygen consumption. Myocardial oxygen consumption seemed unchanged as no significant changes were found in the product of mean arterial blood pressure and heart rate. After digitalization 6 of the 7 patients with impaired left ventricular function showed improved haemodynamic response to exercise while the 4 patients with normal left ventricular function had an unchanged haemodynamic response.
Tricaine (MS‐222) Induced Modification on the Metabolism of Foreign Compounds in the Liver and Duodenal Mucosa of the Splake (Salvelinus fontinalis X Salvelinus namaycush)
Authors: Laitinen Matti , Nieminen Mauri , Pasanen Pentti , Hietanen Eino
Published: July 2010

Abstract:The splake, a popular game fish, is a crossbreed which must be reared in nurseries. The fish are marked under anaesthesia for later study. We analyzed the effect of a common anaesthetic, tricaine (MS‐222), on the metabolism of foreign compounds in the liver and duodenum of the splake. In the liver and to some extent in the duodenum, aryl hydrocarbon hydroxylase and epoxide hydrase activities were reduced during treatments. The ethoxycoumarin O‐deethylase activities were not affected in either the liver or duodenum. Tricaine significantly decreased the hepatic UDP‐glucuronosyltransferase activity. The decrease was greater when the aglycone used was p‐nitrophenol than with methylumbelliferone. A similar effect was also found after trypsin treatment of the microsomes. No significant decrease in the UDP‐glucuronosyltransferase activity was detected in the duodenal mucosa. This was the case when both p‐nitrophenol and methylumbelliferone were used as aglycones.
Sulfonamide Acetylation in Isolated Rat Liver Cells
Authors: Olsen Harald , Mørland Jørg
Published: July 2010

Abstract:Primary suspensions of isolated liver cells, prepared from rat livers perfused with Ca++free buffer and 0.05% collagenase, were used for studies of sulfadimidine and sulfanilamide uptake and metabolism at various temperatures (29°–41°) and pH (6.4–7.8). The intracellular: extracellular ratio for sulfanilamide was found to be insensitive to both temperature and pH variations, while the corresponding ratio for sulfadimidine was pH dependent but insensitive to temperature variation. Decreasing pH increased the cell content of sulfadimidine. Sulfanilamide was metabolized by acetylation only, while sulfadimidine gave rise to several metabolites. The rate of sulfanilamide acetylation in primary cell suspensions was of the same order of magnitude as the acetylation rate of sulfanilamide published previously for the intact organ. Sulfanilamide was acetylated at the highest rate in the pH‐region from 7.0 to 7.5, while sulfadimidine was metabolized most rapidly between pH 6.7 and 7.3. At pH 7.5 sulfadimidine was metabolized at a rate only 35% of the rate at pH 7.3. The acetylation rate of both drugs increased with increasing temperature, approximately 5% per degree celcius, and exhibited a Q10of 1.5.
Studies on Hydragogue Drugs: Effect of Surfactants on cAMP Levels in the Rat Jejunal Mucosa in Short Time Experimentsin Vivo
Authors: Sund Reidar Bredo , Hillestad Brit
Published: July 2010

Abstract:Theophylline and the surface active agents specified below were instilled into the jejunum of anaesthetized rats, and the cAMP levels in the mucosal tissue determined after 7 1/2 and 15 min. incubationin vivo.Most experiments were done in rats prepared with two tied intestinal loops; one of these served as the control loop and the other as the stimulated loop. The surfactants (mmol/l) included dodecylsulphate (17), dioctylsulphosuccinate (5.6), cetrimonium bromide (4.1), deoxycholic acid (2.4 and 3.6) and Lubrol WX (0.5% w/v). Theophylline (10 mmol/l) caused a substantial increase in cAMP (110%±17, n=7 and 60%±8.9, n=10, respectively) and dodecylsulphate a minor and transitory increase (28.1%±3.8, n=10 and 11.7%±4.9, n=8). The other agents were without stimulatory effect on cAMP, allthough like dodecylsulphate they may significantly affect normal intestinal cation and glucose transport under these conditions. The results, therefore, do not suggest that stimulation of cAMP and intestinal secretion induced thereby is any significant phenomenon in the overall hydragogue effect of these agents, at least not in short term jejunal experiments.
Plasma Accumulation and Metabolism of Orally Administered Single Dose L‐5‐Hydroxytryptophan in Man
Authors: Magnussen I. , Jensen T. S. , Rand J. H. , Van Woert M. H.
Published: July 2010

Abstract:Single oral doses of L‐5‐hydroxytryptophan (5‐HTP) were administered in combination with L‐aromatic amino acid decarboxylase inhibitors. The time courses of plasma concentrations of 5‐HTP, 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) and the concentrations of 5‐HT in blood platelets were measured. Carbidopa enhanced the rise in plasma concentrations of 5‐HTP 5–15 fold and counteracted the increase in plasma 5‐HIAA levels induced by 5‐HTP alone. A single dose of the decarboxylase inhibitor was equipotent to 14 days' pretreatment. Plasma or platelet concentrations of 5‐HT failed to reflect the metabolism of 5‐HTP. The ratio of 5‐HTP to carbidopa influenced the systemic bioavailability of single dose administered 5‐HTP indicating dose dependent absorption kinetics. Co‐administration of L‐dopa with 5‐HTP and decarboxylase inhibitors had no effect on gastrointestinal absorption of 5‐HTP in six parkinsonian patients.
Neurotransmitter Metabolizing Enzymes and Plasma Butyrylcholinesterase in Mice Exposed to Trichloroethylene
Authors: Kanje M. , Kjellstrand P. , Fex K. , Walldorf A.
Published: July 2010

Abstract: Acetylcholinesterase, glutamine synthetase, acid phosphatase and glutamate dehydrogenase activity in brain and cholinesterase activity in blood were investigated in mice exposed to 170 p.p.m. trichloroethylene (TCE) during 30 days. The neuronal enzymes remained unaffected which suggests that no general damage occurred to either the glia or the nerve cell populations. In accordance with this no effect was seen on acid phosphatase. In contrast, plasma butyrylcholinesterase increased twofold in exposed male mice while it was unaffected in females. Liver weight in males and females increased with a factor of 1.5 and 1.9, respectively.
Influence of Intoxication by Anticholinesterase Agents on Core Temperature in Rats: Relationships between Hypothermia and Acetylcholinesterase Inhibition in Different Brain Areas
Authors: Coudray‐Lucas C. , Prioux‐Guyonneau M. , Tassel A. , Coq H. M. , Cohen Y. , Wepierre J.
Published: July 2010

Abstract:The early and late effects of three anticholinesterase agents (physostigmine, paraoxon and soman) on core temperature and brain acetylcholinesterase (AcChE) inhibition are compared. The study was performed in adult male rats using sublethal doses of all drugs. AcChE activity was determined in hypothalamus, striatum, hippocampus, medulla oblongata‐pons and rest of the brain. The co‐existence of intoxication symptoms, hypothermia and AcChE inhibition was clearly shown by the early effects. However, no relationship was found between the degree of hypothermia and that of inhibition whatever brain area. In contrast, late AcChE inhibition was not accompanied by symptoms and lowering of core temperature. Several hypotheses have been suggested to explain this phenomenon:de novosynthesis of enzyme, decreased sensitivity of neurotransmitter or return to normal of brain acetylcholine level through a negative feed back at the presynaptic level. The present data suggest that this latter assumption is the most likely.
Mechanisms of β‐Adrenergic Desensitization in Rat Myometrium
Authors: Johansson Solveig R. M. , Andersson Rolf G. G.
Published: July 2010

Abstract:This study was performed in order to elucidate the mechanism behind the decreased responsiveness to β‐adrenergic stimulation occuring in uterine muscle after prolonged treatment with isoprenaline. Pretreatment of rats with isoprenaline, 20 nmol/kg, three times daily during four days, significantly decreased the myometrial relaxing effect of the β‐agonist. There was also a significant decrease of the β‐receptor binding capacity of the myometrial membranes measured by the (minus;)‐(3H) DHA binding technique. In the animals pretreated with isoprenaline no significant increase of the adenylate cyclase activity could be observed after isoprenaline stimulationin vitro. The uterine cAMP level was diminished in the desensitized rats. The phosphodiesterase activity was increased. Thus both decreased production and increased degradation contribute to the lower level of uterine cAMP content. The activity of cAMP dependent protein kinase was also depressed. In this work, where low concentrations of isoprenaline have been administeredin vivo, several biochemical parameters have been shown to contribute to the β‐adrenergic desensitization in myometrial tissue.
Actions of Lofepramine, a New Tricyclic Antidepressant, and Desipramine on Electrophysiological and Mechanical Parameters of Guinea Pig Atrial and Papillary Muscles
Authors: Arlock Per
Published: July 2010

Abstract:The effects of lofepramine on the isolated guinea pig atrial trabeculae were compared with those of desipramine. The preparations were taken from the same animal and mounted in the same tissue bath. All parameters were recorded in parallel. Lofepramine 10 μM was shown to exhibit minor changes in the transmembrane action potential duration only. The action potentials of the atrial trabeculae were prolonged, whereas they were shortened in the papillary muscles. Desipramine was about ten times more potent than lofepramine, but produced similar qualitative changes. Desipramine 10 μM and lofepramine 100 μM showed local anaesthetic properties: a decreased overshoot without a decreased resting potential, a decreased and rate‐dependent Vmax, and a decrease in propagation velocity. After the addition of either drug in a lower concentration, a transient increase in force development and a concomitant increase in repolarization phase height (atrial trabeculum) or plateau length (papillary muscle) were recorded. The steady state effect on the force development was a decrease accompanied by a shortening of the action potential duration (papillary muscle). It is suggested that the actions of lofepramine 100 μM and desipramine 10 μM on phase 0 of the action potential are produced by blockage of the fast sodium channel. The transient increase in developed force and the increase in repolarization phase height (atrial trabeculum) or plateau length (papillary muscle) could be caused by inhibition of the membrane re‐uptake system for released noradrenaline. The steady state shortening and flattening of the plateau (papillary muscle) and the decrease in force development could be the cause of a block in the slow channel system.
The Effect of Food on the Oral Absorption of Penicillin V Preparations in Children
Authors: Finkel Yigael , Bolme Per , Eriksson Margareta
Published: July 2010

Abstract: The oral absorption of pc V in different preparations, given at various times before and after a meal, was investigated in children with upper respiratory infections. The best absorption with respect to peak concentration was observed when potassium pc V (Calciopen®) was given after at least two hours of fasting with no food intake within the following hour. Shorter periods of fasting (1,1/2,0 hrs) before drug intake resulted in significantly lower plasma concentrations. When drug intake was followed by a meal, the absorption was also decreased to some extent. When pc V was given in an oil suspension (Fenoxypen®), or in a small volume (Roscopenin®) together with a meal, the peak concentration was significantly lower than when pc V was given in an aqueous solution with a larger volume (Calciopen®).
Investigation of the Role of Kidney Kallikrein on Bumetanide Induced Diuresis in Rats
Authors: Olsen Uffe Bang
Published: July 2010

Abstract:Administered to anaesthetized, laparatomized rats bumetanide (10 mg/kg intravenously) evoked a rapid and large diuretic response. This was associated with three to five fold enhancements of urine kallikrein (kininogenase) excretion. In addition bumetanide slightly decreased (approximately 10 mmHg) the blood pressure and temporarily increased renal blood flow (<10%). The capacity of bumetanide to increase urine kallikrein excretion was inhibited either by pretreatment with chlorazanil (3 mg/kg intravenously) or by the infusion of aprotinin (5000 KIE/kg/min.). Kallikrein inhibition did not significantly modify bumetanide induced diuresis, natriuresis, kaliuresis, lowering of blood pressure or renal vasodilating effect.
Effects of Indometacin, Naproxen and Paracetamol on Regional Blood Flow in Rabbits: A Microsphere Study
Authors: Hierton Claës
Published: July 2010

Abstract:Ulcerogenic side‐effects and prostaglandin‐synthesis‐inhibiting capacity are well documented in indomethacin treatment. According to recent works, indomethacin reduces gastrointestinal blood‐flow. Naproxen and paracetamol, claimed to be prostaglandin‐synthesis‐inhibitors, have few ulcerogenic side effects. In an attempt further to study the indomethacin effects and to reveal whether naproxen and paracetamol have similar effects, the labelled microsphere technique was used. The regional blood flow determinations were made before, and 12–15 min. after, the injection of the drugs. Indomethacin 3 mg/kg, reduced gastrointestinal blood flow and increased arterial blood flow to the liver. Naproxen, 10 mg/kg, and paracetamol, 25 mg/kg, had no effects except for a very small decrease in liver blood flow with paracetamol. The results strongly suggest that, at least under light general anaesthesia, prostaglandins influence resting blood flow in the gastrointestinal tract, the liver and parts of the brain. The results more raise doubts whether naproxen and paracetamol inhibit prostaglandin synthesis in these tissues. These data offer a plausible explanation as to why naproxen and paracetamol are usually well tolerated in the gastrointestinal tract. None of the drugs tested influenced resting blood flow in muscles, tendons, bones, joints or synovial membranes.
Effect of Ethanol and Ethanol Withdrawal on3H‐Muscimol Binding and Behaviour in the Rat: A Pilot Study
Authors: Linnoila M. , Stowell L. , Marangos P. J. , Thurman R. G.
Published: July 2010

Abstract:Effect of acute and chronic exposure to and withdrawal from ethanol on3H‐muscimol binding in the forebrains and cerebelli and on withdrawal behaviour was investigated in 30 rats. Chronic exposure to and withdrawal from ethanol produced a significant reduction in the number of muscimol binding sites in the cerebelli. A negative correlation was observed between the number of muscimol binding sites in the forebrain and cerebellum in the chronic ethanol and withdrawal groups. Relatively high correlations were found between the number of muscimol binding sites and audiogenic seizure scores during withdrawal from ethanol. Since impaired GABAergic function is associated with increased susceptibility to seizures, there may be a causal relationship between the observed changes in muscimol binding and ethanol‐induced audiogenic withdrawal seizures.
Pharmacokinetics of Terbutaline and Theophylline in Guinea Pigs when Administered Simultaneously
Authors: Madsen Søren Munk , Ribel Ulla
Published: July 2010

Abstract:Simultaneous administration of terbutaline and theophylline to guinea pigs did not cause significant alterations of the pharmacokinetic properties of any of the drugs. Terbutaline sulphate 24 μg kg−1and aminophylline 52 mg kg−1(7.42.10−8and 2.37.10−4mol kg−1respectively) were given by a bolus intravenous injection, producing plasma concentrations in the range 0–15 ng terbutaline sulphate per ml (0–46 nanomol 1−1) and 10–85μg theophylline per ml (50–429 μmol 1−1). Pharmacokinetic analyses of time courses of plasma concentrations of intact drugs and investigations of tissue distribution 1 hour after the administration were performed. The results showed a weak, statistically insignificant trend of the peripheral compartment of the 2‐compartment model to sequester a larger fraction of the drugs when these were administered simultaneously.
Inhibition of Erythema Induced by Pro‐inflammatory Esters of 12‐Deoxyphorbol
Authors: Williamson Elizabeth M. , Evans Fred J.
Published: July 2010

Abstract:The pro‐inflammatory tigliane esters 12‐deoxyphorbolphenylacetate (12‐DOPPA) and 12‐deoxy‐phorbolphenylacetate‐20‐acetate (12‐DOPPAA) at a dose of 0.1μg induced erythema in the mouse ear. Observations of ear redness were made both two and four hours after application. Indomethacin was only partly successful as an antagonist since 10% inhibition of 12‐DOPPA and no inhibition of 12‐DOPPAA induced erythema was produced four hours after application. The free radical scavengers, phenol, thioanisole and sodium benzoate all produced less than 30% inhibition of 12‐DOPPA induced erythema and less than 15% inhibition of 12‐DOPPAA, whereas aminopyrine produced 70% and 25% inhibition of 12‐DOPPA and 12‐DOPPAA respectively. The fact that free radical scavengers (with the exception of aminopyrine) and indomethacin, failed to markedly change the mouse ear reaction to 12‐deoxyphorbol esters, indicated that this erythema is not entirely mediated via cyclooxygenase products. Mepyramine and cyproheptadine also failed to inhibit the erythema, whereas hydrocortisone produced a 55% inhibition of the 12‐DOPPA and a 20% inhibition of the 12‐DOPPAA reaction. The membrane stabilising agents trifluoperazine, promethazine, imipramine and desmethylimipra‐mine were the most successful compounds used in inhibiting both 12‐DOPPA and 12‐DOPPAA induced erythema. In addition propranolol, which inhibits stimulus activation of phospholipase A2, produced 70% and 55% inhibition of the reaction of mice ears to 12‐DOPPA and 12‐DOPPAA.
Inhibition of Sarcolemma ATPases by some Membrane‐stabilizing Drugs
Authors: Røed Asbjørn , Brodal Bjørn
Published: July 2010

Abstract:Rat sarcolemma preparations were incubated with some membranes stabilizers to study their effects on the (Na+,K+)‐ and Ca2+‐ATPase activity. The drugs inhibited the enzymes with the same order of potency as in the earlier observed muscle contractures: chlorpromazine> dibucaine> propranolol> tetracaine> procaine (range 0.1–3.6 mM) (Røed & Brodal 1979). The contracture inducing effect of the stabilizers is suggested to be caused by a membrane depolarization due to the (Na+,K+)‐ATPase inhibition. Ouabain inhibited the (Na+,K+)‐ATPase activity in purified plasma membrane, but did not inhibit the sarcolemma located ATPases or induce any contracture.
Arterial Response to Ergotamine Tartrate in Abusing and Non‐abusing Migraine Patients
Authors: Tfelt‐Hansen Peer , Olesen Jes
Published: July 2010

Abstract: Ten former ergotamine abusers were given ergotamine tartrate 0.5 mg/70 kg intravenously. The arterial response was followed by measuring systolic blood pressures with strain gauge on arm, fingers, ankles and toes. Distal systolic blood pressures were significantly reduced relative to the arm level for 22 hours. The arterial response in these 10 patients was compared to the response in 17 migraine patients tested with the same technique. No differences were found. We conclude that hypersensitivity or tolerance to ergotamine tartrate is not observed in previous ergotamine abusers. Previous abuse is a relative contraindication to the use of ergotamine. But if ergotamine is the only effective drug, normal dosage can be used according to the present results.
Manganese Toxicity: Lipid Peroxidation in Rat Brain
Authors: Shukla Girja S. , Chandra Satya V.
Published: July 2010

Abstract:Albino rats were given intraperitoneally manganese chloride (Mn2+, 4 mg/kg) daily for a period of 30 days. Manganese significantly inhibited the lipid peroxidation potential of treated rat brain without altering the contents of iron and ascorbic acid, the two prooxidant factors.In vitrolipid peroxidation studies in the fresh and heated brain homogenates showed almost a non‐enzymatic mechanism of inhibition by this metal ion. 30 μM Mn2+concentrations completely inhibited the formation of malonaldehyde (MDA) at 3 hours of incubation. Iron was found to reverse, to some extent, the effect of manganese onin vitrolipid peroxide formation in the mitochondrial fraction of brain and at concentrations of 5 μM Fe2+the amount of MDA formed is comparable to that observed with 1 μM Fe2+in the mitochondrial fraction without manganese. These observations suggest that the central nervous system toxicity of manganese may not be associated with acceleratedin vivolipid peroxidation. However, the mechanism of iron induced reversal onin vitroinhibition of lipid peroxidation by manganese is not understood, at present.
Effect of Hypophysectomy and Adrenalectomy on 5‐Hydroxytryptamine Uptake by Rat Hypothalamic Synaptosomes and Blood Platelets
Authors: Tukiainen Erkki
Published: July 2010

Abstract:The effect of adrenalectomy and hypophysectomy on 5‐HT uptake by rat platelets and hypothalamic synaptosomes taken from the same animal was studied. The experiments were performed 1–2 weeks after the operations or the shamoperations. After adrenalectomy a significant decrease of 25% in 5‐HT uptake by platelets was noted. In synaptosomes there was a similar trend, but the decrease was not significant. After hypophysectomy a significant 25% decrease in 5‐HT uptake was observed both in platelets and in synaptosomes. These results suggest that corticosteroid hormones might mediate adaptive changes of 5‐HT uptake both in synaptosomes and in blood platelets. Blood platelets have been used as a peripheral model of serotoninergic nerve terminal in studies concerning physiology of monoamines systems, but the present results suggest that also in some pathological conditions changes in platelet biochemistry could reflect those in the CNS neurones.
Characterization of 5‐Hydroxytryptamine Uptake in Sliced Rat Lung
Authors: Wikberg Jarl E. S. , Hede A. Ragnar
Published: July 2010

Abstract:Slices of rat lung were incubated with tritiated 5‐hydroxytryptamine and the tissue uptake of tritium was studied after separating the free and bound radioactivity by filtration on glass fiber filters. At 37° a rapid uptake occured during the first 10 min. After that time the uptake was less marked but it was still present after 60 min. The uptake was moderately potentiated by the MAO inhibitor iproniazid (3 μM) after 30–60 min. incubation. The 5‐hydroxytryptamine uptake was inhibited by some uptake inhibitors, their order of potency beeing: clomipramine > imipramine ≥ nortriptyline ≥ cocaine ≥ desipramine > maprotiline. At 0° the uptake of 5‐hydroxytryptamine was negligible. Non‐linear regression analysis of uptake data indicated that 5‐hydroxytryptamine was taken up by two different mechanisms. One of the uptake processes was saturated by high concentrations of 5‐hydroxytryptamine and showed an apparent Kmof 8×10−7M. The other uptake was linearly related to the 5‐hydroxytryptamine concentration and could not be saturated even by concentration up to 5×10−5M of the amine.
Anabolic Stimulation of Blood Cell Count Recovery after Chlorambucil‐Induced Myelosuppression in Rats
Authors: Miintzing J.
Published: July 2010

Abstract:The recovery of leukocyte concentration in blood after chlorambucil(C)‐induced leukopenia was more rapid in intact than in castrated male rats. The enhancement of recovery caused by testicular hormones could be mimicked in orchiectomized animals by administration of 19‐nortestosterone hexyloxyphenylpropionate (NT) (Anadur®) given prior to but not after C. NT given prior to C also resulted in higher erythrocyte concentrations and packed blood cell volumes than in animals given only C. NT could not diminish the leukopenia induced by repeated administrations of C. A stimulation by NT of leukocyte count recovery also in patients might be of clinical importance especially in patients subjected to intermittent treatment with cytostatic agents.
On the Role of Cyclic Nucleotides in the Regulation of Cardiac Contractility and Glycolysis During Hypoxia *
Authors: Metsa‐Ketela T. , Laustiola K. , Lilius E‐M. , Vapaatalo H.
Published: July 2010

Abstract:A possible involvement of cyclic nucleotides (cAMP and cGMP) in the regulation of cardiac contractility and glycolysis during hypoxia was examined in spontaneously beating rat atria. A reduction of the high oxygen saturation (HiOxSa) of the incubation medium from 95–100% to half produced a rapid decline of the amplitude. The deterioration of 50% was seen after 30 sec. of hypoxia. The decline was partly antagonized by noradrenaline (NA, 1×10−6M) or hypercalcaemia (5.7×10−3M instead of 1.9×10−3M). The cAMP level remained unchanged during the first 12 min. of hypoxia, but the cGMP content increased gradually and reached a significantly increased level in 4–8 min. Paradoxically, the production of lactate decreased, after 30 sec. of hypoxia, but accelerated then 2–4 min. after the onset of hypoxia. The depletion of creatine phosphate and ATP stores was initiated after 2 min. of hypoxia. The atrial content of the active forms of phosphofructokinase and lactate dehydrogenase gradually rose during hypoxia. Sodium nitroprusside (SNP, 1×10−4M) and NA produced increases in cGMP and cAMP levels, respectively, both in HiOxSa and hypoxia. SNP induced a slight and NA a marked increase in the amplitude in HiOxSa. Verapamil (1×10−6M) decreased the contractility, but did not affect the levels of cAMP or cGMP. Both SNP and verapamil decreased the lactate production, but they could not resist the NA‐induced increase in the atrial lactate level. Hypercalcaemia increased the amplitude but slightly reduced the lactate production in HiOxSa.45Ca‐uptake was reduced to about 35 per cent of control as measured between 5 and 10 min. of hypoxia. It is concluded that the lack of oxygen could have direct and parallel effects on the sarcolemma and on the mitochondria. The former could result in the deterioration of contractility and the latter in the termination of aerobic energy production. Cyclic nucleotides are not involved in either of these phenomena. However, at the low rate of anaerobic glycolysis, e.g. in HiOxSa or at the very early stage of hypoxia, cGMP could inhibit and cAMP accelerate the lactate production.
Studies on the Mechanism of the GABAergic Inhibition of TSH Secretion in Male Rats
Authors: Mattila J.
Published: July 2010

Abstract:The mechanism of the GABAergic inhibition of the TSH cold‐response was studied in male rats. Picrotoxin, a putative GABA receptor antagonist (4 mg/kg but not 0.5 or 2 mg/kg intraperitoneally) significantly decreased the cold‐stimulated TSH secretion but did not modify the TRH‐induced (100 ng intraperitoneally) TSH‐response. The inhibitory effects of two GABAergic drugs muscimol (1 mg/kg subcutaneously) and aminooxyacetic acid (10 mg/kg intraperitoneally) were not antagonized by picrotoxin (1–4 mg/kg intraperitoneally), by phenoxybenzamine (2.5 or 5 mg/kg intraperitoneally), by two 5‐HT antagonists cyproheptadine (5 mg/kg intraperitoneally) and R 41468 (2.5 mg/kg intraperitoneally) or by pimozide (0.5,1.5 or 2.5 mg/kg subcutaneously). The results suggest that neither picrotoxin‐sensitive GABA receptors nor noradrenaline, 5‐HT or dopamine pathways seem to be involved in the inhibitory action of GABAergic drugs on the TSH cold‐response in male rats.
Myocardial Pharmacokinetics and Pharmacodynamics of Nifedipine in the Isolated Rabbit Heart
Authors: Nielsen‐Kudsk F. , Askholt J.
Published: July 2010

Abstract:The myocardial accumulation and disposition pharmacokinetics of the antianginal and antihypertensive calcium‐antagonistic drug nifedipine were investigated in isolated, perfused and spontaneously beating rabbit hearts. The myocardium behaved pharmacokinetically as a two‐compartment system with regard to the drug. The mean half‐lives of the α‐phase of distribution and of the β‐phase of disposition were about 1.2 and 6.5 min., respectively. Perfusion with a modified Krebs‐Henseleit solution containing nifedipine in a concentration of 50 ng ml−1caused an accumulation of about 1277 ng g‐1 in the myocardium at steady state. Stepwise increased concentrations of nifedipine from 3 to 60 ng ml−1in the liquid used in perfusions for 25 min. periods produced a pronounced progressive decrease in myocardial contractility to about 8%. The heart beating frequency simultaneously decreased gradually to about 76%. The mean coronary flow rate increased initially to 135% and then gradually decreased to 94%. These effects were accompanied by a decrease to about 0.27 in the ratio of the product of contraction amplitude and frequency to the oxygen consumption, a finding that was evaluated as an expression of reduced myocardial efficiency. No significant dromotropic effects were observed.
Effect of Manganese on Synthesis of Brain Catecholamines in Growing Rats
Authors: Chandra Satya V. , Shukla Girja S.
Published: July 2010

Abstract:The effect of short‐term exposure of manganese on the synthesis of brain catecholamines in growing rats has been investigated by using two methods, 1) measuring the amount of conversion of 3,5‐3H‐tyrosine to3H‐labelled dopamine and norepinephrine, and 2) measuring the rate of decline of endogenous dopamine and norepinephrine following inhibition of their synthesis with α‐methyl‐p‐tyrosine. The magnitude of conversion of 3,5‐3H‐tyrosine to3H‐dopamine and3H‐norepinephrine in the brain at 60 min after the administration of labelled amino acid to the manganese treated rats (1 mg MnCl2.4H2O/ml of water for 30 days) was significantly greater than observed in control rats. Manganese also increased turnover of dopamine and norepinephrine to a greater extent in the brains of treated animals.
A Comparison between the Natriuretic Response to Potassium in Lithium‐ and Amiloride‐treated Rats
Authors: Olesen Ole Vendelin , Thomsen Klaus
Published: July 2010

Abstract:The effect of an increase of the potassium content of the food on the natriuretic and diuretic effects of lithium and amiloride was examined in Wistar rats pretreated with the respective drugs for a period of three weeks. Lithium (60 mmol/kg) or amiloride (200 mg/kg) was added to the food and the animals had access to water and a 0.46 M NaCl solution. An increase of the potassium content of the food resulted in a potassium dose‐dependent increase of the natriuretic effect in both lithium‐treated and amiloride‐treated rats. The effect was temporary in lithium‐treated rats but persistent in amiloride‐treated rats. Lithium treatment resulted in a 10‐fold increase of the water intake compared to control rats and amiloride‐treated rats. An increase of the potassium intake reduced the water intake in the lithium‐treated animals and modestly increased the water intake in amiloride‐treated rats. The results show that the exaggerated natriuretic effect produced by administration of potassium to rats treated with lithium is not a specific phenomenon. It is suggested that a lowered ability of the kidneys to secrete potassium may be responsible for the exaggerated natriuretic response to potassium in amiloride‐ and lithium‐treated rats.
Lung Uptake and Antianaphylactic Effects of KWD 2131 (A β‐Adrenergic Agonist) in Perfused Guinea‐Pig Lungs
Authors: Ryrfeldt Åke , Nilsson Elisabeth
Published: July 2010

Abstract:The lung uptake and modulating effects of KWD 2131 [1(3,5‐dihydroxyphenyl)‐2‐(1,1‐dimethyl‐2‐hydroxyethyl) amino ethanol], a β‐adrenergic agonist, on pulmonary perfusion flow and histamine release from anaphylactic guinea‐pig lungs were studied using an isolated perfused lung model. The lung extraction ratio, as calculated from the concentration of drug in the inflowing and outflowing medium in single pass studies was <0.05 at steady state which was achieved within 3 min. after start of drug infusion. Statistically significant protection to antigen elicited reduction in perfusion flow and inhibition of histamine release were obtained at the inflowing concentration 1.5 × 10−6mol/l but not at 1.5 × 10−7mol/l. The observed inhibition of the anaphylactic decrease in the perfusion flow can partly be explained by the decreased histamine release.
Liver Damage in Rats by Allylisopropylacetamide (AIA), an Inducer of δ‐Aminolevulinic Acid Synthetase (ALAS)
Authors: Klinger W.
Published: July 2010

Abstract:Twentyfour hours after the intraperitoneal injection of a single dose of allylisopropylacetamide (AIA) in amounts of 100 mg/kg or more to 30‐day old male Wistar rats, the livers of most of the animals showed an irregular yellow colouration and a fragile consistency. No macroscopic changes were detected following AIA doses of 25 or 50 mg/kg. Bromsulphthalein retention was not significantly increased after the administration of 25 mg/kg AIA, but distinctly enhanced after 400 mg/kg. Succinate‐dehydrogenase‐activity in liver homogenate was not altered after 25 mg/kg, but significantly decreased after 400 mg/kg. Ethylmorphine‐N‐demethylation activity was enhanced after small doses without increase of cytochrome P‐450 (cyt. P‐450) concentration and decreased after higher doses, accompanied by a remarkable cyt. P‐450 loss. GPT activity in serum and liver was not altered after both 25 and 400 mg/kg AIA. GOT activity was slightly but significantly enhanced both in serum and liver after the high dose of 400 mg/kg. Thus in addition to the well‐known cyt. P‐450 destruction other signs of hepatotoxicity could be demonstrated.
Metabolism of Femoxetine
Authors: Larsson H. , Lund J.
Published: July 2010

Abstract:The metabolism of femoxetine, a serotonin uptake inhibitor, has been investigated in rats, dogs, monkeys, and human subjects using two14C‐femoxetine compounds with labelling in different positions. The metabolic pathways were oxidation (and glucuronidation) and demethylation, both reactions most probably taking place in the liver. Nearly all femoxetine was metabolised, and the same metabolites were found in urine from all four species. Only a small percentage of the radioactivity excreted in the urine was not identified. Rat and dog excreted more N‐oxide than monkey and man, while most of the radioactivity (60–100%) in these two species was excreted as two hydroxy metabolites. The metabolic pattern in monkey and man was very similar. About 50% was excreted in these two species as one metabolite, formed by demethylation of a methoxy group. A demethylation of a N‐CH3group formed an active metabolite, norfemoxetine. The excretion of this metabolite in urine from man varied from 0 to 18% of the dose between individuals. Most of the radioactivity was excreted with the faeces in rat and dog, while monkey and man excreted most of the radioactivity in urine. This difference in excretion route might be explained by the difference in the metabolic pattern. No dose dependency was observed in any of the three animal species investigated.
Chemistry of Metrifonate and Dichlorvos
Authors: Hofer Wolfgang
Published: July 2010

Abstract This is a survey of the chemistry of metrifonate and dichlorvos, including methods of synthesizing hydroxy‐phosphonic acid esters and enolphosphates. The reactive centres of metrifonate and dichlorvos and some kinetic measurements are included. Reaction mechanisms and the insecticidal mode of action are discussed.
Alkylating Properties of Dichlorvos (DDVP)
Authors: Segerbäck Dan , Ehrenberg Lars
Published: July 2010

Dichlorvos (DDVP) is a methylating agent. In DNA from mice given 1.9 ± 10‐6 mol/kg of DDVP, a degree of alkylation of guanine‐N‐7 amounting to 8 ± 10‐13 mol methyl per g DNA, was found. From this, a rate of clearence of 29 hr‐1 was estimated. This value is in reasonable agreement with the value (55 hr‐1), calculated from published data on the concentration over time of DDVP in the brain after injection of the compound in mice. Applying a risk estimation on humans exposed to DDVP, the genetic risk connected with the methylating activity of DDVP is low or very low. Comparing the mutagenic effectiveness of DDVP with that of methyl methanesulfonate, indicates that DDVP is more effective than expected from reaction kinetic data. The possible contribution of the dichloroacetaldehyde formed in vivo from DDVP has to be evaluated before a complete risk estimate can be made for DDVP.
Factors Modifying the Toxicity of Organophosphorus Compounds Including Dichlorvos
Authors: Sterri Sigrun H.
Published: July 2010

The effect of repetitive doses of organophosphorus agents in experimental animals has been studied. The cumulative LD50 dose depended upon the time interval between injections of toxic agent. From these data it was possible to obtain the rate of detoxification of these agents. In the case of soman and sarin TOCP pretreatment, an inhibitor of plasma aliesterase, modified both the acute LD50 and the rate of detoxification. The results therefore suggest that recovery of plasma aliesterase contributes to a large extent in detoxification of chronically administered soman and sarin. In contrast, tolerance to chronically administered dichlorvos can not be correlated to recovery of plasma aliesterase, but correlates well with a rapid spontaneous reactivation of acetylcholinesterase.
Studies of the Mode of Action of Metrifonate and DDVP in Schistosomes ‐ Cholinesterase Activity and the Hepatic Shift
Authors: Bloom Amanda
Published: July 2010

Abstract Preliminary studies have been carried out in order to determine the role of cholinesterase inhibition in the metrifonate‐induced hepatic shift of S. mansoni adults. Results suggest that cholinesterase inhibition may not be the only factor involved in hepatic shift and that reduction of cholinesterase activity to less than 20% of control values does not result in paralysis of the recovered worms.
Therapeutic Properties of Metrifonate
Authors: Snellen W. M.
Published: July 2010

Abstract The chronology of the clinical trials with metrifonate is described: the first phase where independently of Bayer use was made of the veterinary product, the second phase representing the work done in collaboration with WHO to confirm the correct indication (schistosomiasis due to S. haematobium) and dosage schedule, and the third phase as from 1970 on about the use of the product in large groups of patients. The particular aspects of schistosomiasis are discussed, as well as the place of chemotherapy in antischistosomal projects. In this conjunction the snail control measures are mentioned. Mass treatment is described and the question is raised whether repeated administrations at half‐yearly or yearly intervals are of value in decreasing the total egg output, thus lowering the possibilities of reinfection.
Metrifonate in Schistosomiasis ‐ Therapy and Prophylaxis
Authors: Jewsbury J. M.
Published: July 2010

Abstract The introduction and development of the organophosphorous drug metrifonate, first as an insecticide and then for the treatment of urinary schistosomiasis, has followed an unusual course. In its most widely accepted treatment regimen it is safe, effective and apparently without significant side effects. These facts, together with its low cost and ease of dosing, lead to a field trial of its efficacy in the treatment and prevention of infection in children in an area of high S. haematobium and S. mansoni endemicity in Rhodesia (Zimbabwe). Three doses of 7.5 mg/kg b. wt. given at fortnightly intervals reduced significantly the infection rates and the egg counts in S. haematobium patients. Subsequent treatment at the same dose level but at intervals of four weeks maintained a low level of infection and of egg output. On the other hand infection rates and egg output rose in unprotected children. There was however no comparable effect on S. mansoni. Apart from the expected and previously reported drop in cholinesterase values there were no untoward side effects: the exact significance of the drop in cholinesterase values remains unclear. The implications of these results for the wide‐scale use of metrifonate as a therapeutic and as a prophylactic for Schistosoma haematobium infection is discussed.
Studies of Metrifonate in Onchocerciasis
Authors: Awadzi K. , Orme M. L'E. , Breckenridge A. M. , Haddock D. , Gilles H. M.
Published: July 2010

Abstract Metrifonate has been studied in the treatment of infections with Onchocerca volvulus in West Africa. In doses of 10 mg/kg daily for six days, metrifonate was effective against the microfilariae but produced unpleasant reactions due both to the death of the microfilariae and to the muscarinic effects of the drug. In a comparison of 10 mg/kg metrifonate, for 3 doses at 10 day intervals, with diethylcarbamazine (D.E.C.) in a total dose of 6.6 g, metrifonate was significantly less effective than D.E.C. in killing microfilariae but produced significantly fewer adverse effects. In a final study comparing metrifonate 10 mg/kg/day given for 3 or for 6 days there was little difference in their therapeutic effect. However, metrifonate 10 mg/kg given for 6 days produced more severe adverse reactions due largely to the muscarinic and nicotinic effects of acetylcholine and these effects were not prevented by the administration of belladonna alkaloids. Metrifonate 10 mg/kg given for 3 doses at 10 day intervals is effective in the treatment of onchocerciasis but is unlikely to replace diethylcarbamazine. Metrifonate has no action on the adult worms.
Differences between α‐Adrenergic and β‐Adrenergic Inotropic Effects in Rat Heart Papillary Muscles
Authors: Skomedal Tor , Osnes Jan‐Bjørn , Øye Ivar
Published: July 2010

Abstract:α‐And β‐adrenergic inotropic effects have been shown to be qualitatively different. In order to further characterize these differences we compared the mechanical responses to α‐ and β‐adrenoceptor stimulation, respectively, in electrically driven left ventricular papillary muscles from rat heart. The muscles were stimulated by either isoprenaline (β‐adrenoceptor stimulation), phenylephrine in the presence of propranolol (α‐adrenoceptor stimulation) or phenylephrine alone (combined α‐ and β‐adrenoceptor stimulation). Isometric tension (T), rate of rise and decline of tension (first derivative = T′) and rate of transition from tension rise to tension decline (negative part of second derivative = T″) were recorded. These recordings disclosed qualitative differences between the α‐ and β‐inotropic response both in dose‐response and time course experiments. Maximal β‐adrenoceptor stimulation caused a small increase in Tmax(18%), intermediate increases in T′max(45%) and T′min(68%) and a considerable increase in T″min(145%) (“β‐type” effect). Maximal α‐adrenoceptor stimulation increased all qualities by about the same degree (23–24%) (“α‐type” effect). While β‐adrenoceptor stimulation gave a dose‐dependent and pronounced increase in the ratio T″min/T′max(relaxation‐onset index), α‐adrenoceptor stimulation decreased it to subcontrol values and phenylephrine alone gave a small dose‐dependent increase at higher doses. The time course of the α‐adrenoceptor stimulation was characterized by a transient decrease in all qualities followed by an increase which reached maximum at 4–5 min. β‐Adrenoceptor stimulation gave a monophasic response which reached maximum after 1–2 min. Phenylephrine alone gave mainly an “α‐type” effect although T″minincreased significantly more in the absence than in the presence of propranolol and T″min/T′maxshowed a small increase which developed slowly. Thus β‐adrenoceptor stimulation activated relaxation compared to contraction by a higher degree than did α‐adrenoceptor stimulation. This probably reflects different mechanisms of action. While the α‐effect may rely primarily on an increased calcium influx, the β‐effect probably is the final result of several subcellular effects of cyclic AMP.
Functional Importance of Nucleus Accumbens Noradrenaline in the Rat
Authors: Svensson Lennart , Ahlenius Sven
Published: July 2010

Abstract: l‐Noradrenaline·HCl (l‐NA), d‐noradrenaline·HCl (d‐NA) and dopamine·HCL (DA) were locally applied in the nucleus accumbens of awake rats. When the animals were observed in a dark open field arena it was found that low doses of l‐NA or DA produced suppression of ambulatory activity followed by an increase in the activity at higher doses. l‐NA was more potent than DA in producing these effects and about 4 times higher doses of DA were required to produce the same effect. d‐NA was not without effects but was less efficient than DA.
Induction of Liver Microsomal Cytochrome P‐450 and Associated Monooxygenases by Octachlorostyrene in the Rat
Authors: Holme Jørn A. , Dybing Erik
Published: July 2010

Abstract: The inducing effects of octachlorostyrene (OCS) and hexachlorobenzene (HCB), chlorinated hydrocarbon contaminants found in fish, on the microsomal cytochrome P‐450 system were studied in rats. Administration of single doses of OCS and HCB at 50mg/kg intraperitoneally and higher led to increases in microsomal protein and cytochrome P‐450 content, cytochrome P‐450 reductase, ethylmorphine N‐demethylase, 4‐nitroanisole O‐demethylase, acetanilide 4‐hydroxylase, but not in benzo(a)pyrene hydroxylase activities. Similar patterns of induction were seen after 14 days repeated intraperitoneal or oral dosing. Sodiumdodecylsulfate polyacrylamide gel electrophoresis of microsomes from OCS and HCB treated rats showed increases in proteins similar to those found after phenobarbital (PB) induction. Under the present experimental conditions OCS and HCB were found to be PB‐type inducers.