bluuebunny/crossref_metadata_2025 huggingface dataset:
O,O,S‐Trimethyl Phosphorothioate Increases Ca2+ Independent Nitric Oxide Synthase Activity in the Lung but Decreases Ca2+/Calmodulin Dependent Type in the Cerebellum in Fischer 344 Rats
Authors: Yamazaki Yutaka , Ohtaka Kosei , Suzuki Masahiro , Hamade Naoto , Wada Yasuhiko , Koizumi Akio
Published: March 2009

Abstract: In the present study, we investigated the possible role of nitric oxide synthase in lung injury using female Fischer 344 rats as a model animal and O,O,S‐trimethyl phosphorothioate as an example of lung toxicants. One form of nitric oxide synthase, Ca2+/calmodulin dependent type, decreased monotonously in a dose‐dependent manner in the cerebellum. In contrast, O,O,S‐trimethyl phosphorothioate increased activities of Ca2+ independent nitric oxide synthase in the lung in a dose‐associated manner from 5 mg/kg to 15 mg/kg, but decreased at 30 mg/kg. Lung toxicity of O,O,S‐trimethyl phosphorothioate, however, as judged both by functional impairments (PaCO2 and [HCO3‐]) and histopathological changes, increased sharply at 30 mg/kg. We thus tested the hypothesis that a potent nitric oxide synthase inhibitor, NG‐nitro‐L‐arginine‐methyl ester, may modify lung injury induced by O,O,S‐trimethyl phosphorothioate. Treatment with NG‐nitro‐L‐arginine‐methyl ester at 20 mg/kg/day aggravated lung injury induced by O,O,S‐trimethyl phosphorothioate: Pulmonary oedema and bleeding occurred, leading to an increase in mortalities at 15 mg/kg of O,O,S‐trimethyl phosphorothioate, at which level it did not induce such changes as when dosed alone. These findings indicate that nitric oxide synthase in the lung might play a protective role in lung injury.
Fat Diet, Osmotic Fragility of Erythrocytes and Inotropic Response of Rat Heart Papillary Muscle to Noradrenaline Stimulation: Early Appearance of the Diet Effect by Lovastatin
Authors: Skomedal Tor , Høstmark Arne T. , Osnes Jan‐Bjørn
Published: March 2009

Abstract:Intake of lovastatin, an inhibitor of endogenous cholesterol synthesis, leads to a compensatory increase in the uptake of cholesterol from plasma (low density lipoprotein endocytosis). The drug might exert effects also by facilitating uptake of fatty acids carried in low density lipoprotein. It has been reported that dietary fat may alter physical properties of erythrocytes as well as adrenergic effects in heart muscle. We have therefore studied osmotic fragility of erythrocytes and inotropic and lusitropic responses of isolated heart papillary muscles taken from rats fed for 3 weeks either a purified high fat diet (olive oil/coconut oil 16 g/6 g/100 g diet), prepared plus and minus lovastatin, or similar diets in which 4 g/100 g diet of the olive oil was replaced by cod liver oil. Three weeks feeding of a high fat diet containing cod liver oil did not affect osmotic fragility of erythrocytes or indices of inotropy or lusitropy in papillary muscles in response to noradrenaline stimulation neither in the absence nor in the presence of lovastatin. In contrast, purified high fat diet lacking cod liver oil increased osmotic fragility in a fraction of the erythrocytes. When lovastatin was added to this diet the osmotic fragility was increased for the whole population of erythrocytes. In this situation the “relaxation‐onset index” ‐ an index of early relaxation in the papillary muscles ‐ was shifted to higher concentrations of noradrenaline. Thus, intake of lovastatin may lead to an early appearance of effects of dietary fat on osmotic fragility of erythrocytes and on heart muscle responses to catecholamines. These effects of lovastatin are, however, apparently dependent upon the kind of dietary fat as they are prevented by the presence of cod liver oil.
Lidocaine Interactions with Exogenous and Endogenous Adenosine in the Isolated Rat Heart
Authors: Schjøtt Jan , Brurok Heidi , Jynge Per
Published: March 2009

Abstract: We examined whether pretreatment with lidocaine could influence the cardiac kinetics of adenosine and thereby strengthen the physiologic responses of the nucleoside, either exogenously administered or endogenously produced. Isolated rat hearts perfused with lidocaine, 0.05 μM to 500 μM, were subjected to 6 min. of adenosine infusion followed by 30 min. of perfusion. The hearts were then subjected to 6 min. of total global ischaemia and then perfused for 30 min. Effects on cardiac kinetics and physiologic responses of adenosine were based on a comparison of uptake or release of adenosine in effluate (kinetics), and the effects of adenosine on aortic pressure and left ventricular developed pressure (physiologic responses), to a lidocaine‐free control group. A low concentration of lidocaine, 0.05 μM, increased the uptake of exogenously administered adenosine. A high concentration of lidocaine, 50 and 500 μM was associated with a reduced release of endogenously produced adenosine. However, these effects on cardiac kinetics of adenosine were not associated with any increase of the physiologic responses to the nucleoside. The results failed to support the hypothesis that lidocaine increases the physiologic responses of adenosine in the isolated rat heart by a kinetic interaction.
Pharmacological Comparison of Antipsychotic Drugs and σ‐Antagonists in Rodents
Authors: Lang A. , Soosaar A , Kõks S. , Volke K , Bourin M. , Bradwejn J. , Vasar E.
Published: March 2009

Abstract:We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and σ antagonists (remoxipride, cinuperone, α‐(4‐fluorophenyl)‐4‐(‐fluoro‐2‐pyrimidinyl)‐1‐piperazine butanol (BMY 14802) and rimcazole) in the radioligand binding and behavioural experiments in rodents. A good correlation was established between the affinity of compounds at dopamine2‐receptors in the striatum and their ability to block apomorphine‐, amphetamine‐ and quipazine‐induced behavioural effects in rodents. By contrast, no correlation was found between the behavioural effects of these drugs and their affinity at dopamine1‐, 5‐HT2‐ and a receptors. The rank order of potency among the studied antipsychotic drugs in the behavioural tests and at dopamine2‐receptors was following: haloperidol≫chlorpromazine≥clozapine. The effectiveness of chlorpromazine and clozapine was nearly similar against apomorphine‐induced aggressiveness and yawning, whereas at 5‐HT2‐receptors clozapine was more active than chlorpromazine. The weak activity of σ antagonists at dopamine2receptors could be a possible reason why these compounds were less effective in the behavioural studies compared to antipsychotic drugs. However, the antagonism of remoxipride against apomorphine‐induced stereotypy and aggressiveness is not related to its activity at σ receptors, because the other σ antagonists did not block these effects of apomorphine. It is probable that remoxipride exerts its action through blocking of dopamine2receptors. In conclusion, the present study revealed only weak activity of σ antagonists in the behavioural models widely used to study the antipsychotic drugs. Therefore, the antipsychotic activity of σ antagonists is doubtful.
Nickel Absorption from Perfused Rat Jejunal and Ileal Segments
Authors: Tallkvist Jonas , Tjälve Hans
Published: March 2009

Abstract: The intestinal absorption of Ni2+ was studied in isolated perfused jejunal and ileal segments of rats, by a method which allows continuous sampling of the absorbates. The results showed that the Ni2+‐absorption proceeds at a much higher rate in the jejunum than in the ileum. Several observations indicate that Ni2+ is absorbed actively in the jejunum. There are indications in the literature that Ni2+ at least partly may share the transport mechanism for iron across the intestinal mucosa and our results may reflect the participation of Ni2+ in this absorptive process. The transfer of Ni2+ across the ileal epithelium may occur by passive diffusion. Addition of Zn2+, Co2+, Cd2+ or Hg2+ to the jejunal perfusates affected the Ni2+‐absorption to varying extents. Thus, Zn2+ had minor effects on the Ni2+‐absorption. Co2+ decreased the Ni2+‐concentration in the absorbates, possibly by interfering with Ni2+ in the iron transfer process. Addition of Cd2+ or Hg2+ to the perfusates resulted in decreased jejunal water absorption. Hg2+ also depressed the glucose absorption. These results show that Cd2+ and Hg2+ at low concentrations are toxic to the jejunal mucosal cells. Thus, these metals can inhibit the amount of Ni2+ transferred across the intestinal mucosa by decreasing the volume of the absorbate.
Enhanced Intestinal Nickel, Absorption in Iron‐Deficient Rats
Authors: Tallkvist Jonas , Wing Anncatherine Moberg , Tjälve Hans
Published: March 2009

Abstract: The absorption of nickel was studied in isolated perfused jejunal and ileal segments of iron‐deficient and iron‐sufficient rats. The uptake of nickel in tissues of iron‐deficient and iron‐sufficient rats given a low oral nickel‐dose was also examined. The results showed enhanced nickel absorption in vitro and in vivo in iron‐deficient rats. In the in vitro perfusions, increased absorption was observed both in jejunum and ileum. The enhancement was very prominent in jejunum and the nickel concentration in the jejunal absorbate of iron‐deficient rats even exceeded the nickel concentration in the perfusate. This indicates that nickel is absorbed actively in the jejunum of iron‐deficient animals. Twenty‐four hr after an oral dose of nickel the uptake of the metal in various tissues was 1.5‐2.5 times higher in iron‐deficient rats compared to iron‐sufficient rats. Our data indicate that nickel is absorbed at least in part by the active transfer system for iron in intestinal mucosal cells.
The Pyrimido‐Pyrimidine Derivatives, Dipyridamole and RA‐642, Reduce Opacitlcation of Crystalline Lens in Diabetic Rats
Authors: De La Cruz J. P. , Moreno A. , Mérida F. , Carcia‐Campos J. , De La Cuesta F. Sánchez
Published: March 2009

Abstract: We assessed the effect of dipyridamole, RA‐642 and mopidamol. on lenticular opacities in a model of experimental diabetic cataracts in rats. All three pyrimido‐pyrimidine derivatives caused a statistically significant reduction of opacification in crystalline lens as compared with untreated diabetic animals. The production of superoxide anions (phenazine methosulphate [PMS]‐induced nitroblue tetrazolium [NBT] reduction) showed a decrease of 81.6%1, 78.9% and 1.8% in lens tissue homogenates from rats treated with dipyridamole, RA‐642 and mopidamol, respectively. Dipyridamole and RA‐642 produced a statistically significant inhibition (50% and 64.8%, respectively) of lipid peroxidation (ferrous sulphate and ascorbic acid [FeAs]‐induced malondialdehyde [MDA] production) as compared with the group of untreated diabetic rats. Mopidamol did not exert any inhibitory effect on lipid peroxidation. There was a statistically significant correlation between opacification of lens and PMS‐induced NBT reduction and FeAs‐induced MDA production. We conclude that the protective effect of dipyridamole and RA‐642 from free radical damage to crystalline lens in the model of experimental diabetes used in this study, is the result of the antioxidant action of these compounds. The effect exerted by mopidamol, however, suggest a possible complementary effect of the pyrimido‐pyrimidine derivatives through interaction with other mechanisms (e.g., the sorbitol pathway) implicated in the development of cataracts.
Excitatory Actions of Dehydroabietic Acid on Mammalian Synaptosomes
Authors: Nicholson Russell A.
Published: March 2009

Abstract: The presynaptic effects of dehydroabietic acid were investigated using mouse brain synaptosomes as the in vitro model. At concentrations ranging from 10 to 100 μM, dehydroabietic acid depolarises the synaptosomal membrane and causes pronounced release of the neurotransmitters γ‐aminobutyric acid, acetylcholine and L‐glutamate. The effects on membrane potential and transmitter release occur predominantly at concentrations below which any lytic actions of this compound can be detected. Dehydroabietic acid‐induced depolarisation and release of neurotransmitters are not influenced by tetrodotoxin and are associated with only marginal inhibition of membrane‐associated ATPase activity. When synaptosomes are challenged with dehydroabietic acid in calcium‐free saline, a partial reduction in the stimulated release of transmitters is observed. These results provide clear evidence that dehydroabietic acid is neuroactive and capable of causing substantial increases in the release of both excitatory and inhibitory neurotransmitter substances. The mechanism which underlies the neuroexcitatory effects of dehydroabietic acid remains to be resolved however it is proposed that release of transmitters from central nerve endings may be a contributory factor in the toxicity of resin acids.
Effect of Tetraethylthiuramdisulphide and Diethyldithiocarbamate on Nickel Toxicokinetics in Mice
Authors: Nielsen Gitte Dalsgaard , Andersen Ole
Published: March 2009

Abstract: A new experimental pharmacokinetic model using the γ‐emitting isotope 57Ni for studying nickel toxicokinetics was employed in a recent investigation (Nielsen et al. 1993) in order to quantitatively study, for the first time, the effect of tetraethylthiuram disulphide (disulfiram, Antabuse®, TTD) and sodium diethyldithiocarbamate (DDC) on whole‐body retention and organ distribution of nickel in mice. TTD or its decomposition product DDC given orally by stomach tube shortly after oral administration of a low dose of nickel chloride labelled with 57Ni resulted in an approximately ten times higher whole‐body retention of nickel compared to the retention in a control group exposed to nickel only. These chelators increased the whole‐body retention of nickel also when given by intraperitoneal injection shortly after oral or intraperitoneal administration of nickel. Oral administration of a single dose of TTD or DDC rapidly after an oral dose of nickel chloride also resulted in extensive changes in the organ distribution of nickel, thus the nickel content in the brain was at least 700 times higher than in a control group given the same dose of nickel only. If DDC was given intraperitoneally after nickel given orally, the relative organ distribution of nickel to most organs was the same as if the chelator was given orally, though the contents of the liver and lungs were lower. That TTD and DDC resulted in a transport of nickel to the brain, is underlined by the fact that after 20 hr, approximately 15% and after 45‐50 hr, 30% of the total body burden of Ni was found in the brain. Stating the nickel content as concentrations, we found after 19 hr to 23 hr the highest nickel concentration in the brain, kidneys, lungs and liver, in order of decreasing concentration. From 68 hr to 122 hr the order was brain, lungs, kidneys and liver. TTD and DDC are widely used clinically. These results indicate, that long‐term simultaneous administration of nickel and TTD or DDC to humans should be avoided, as enhanced body‐burden and extensive brain deposition of nickel may occur, possibly leading to toxicity.
Effect of Atropine, HLö 7 and HI 6 on Respiratory and Circulatory Function in Guinea‐pigs Poisoned by O‐ethyl S‐[2‐(diisopropylamino) ethyl] Methylphosponothioate (VX)
Authors: Worek Franz , Kirchner Thomas , Szinicz Ladislaus
Published: March 2009

Abstract:In a guinea‐pig model with on‐line respiratory and circulatory monitoring the therapeutic efficacy of atropine, HLö 7 and HI 6 in VX poisoning was compared. In female urethane‐anaesthetized Pirbright‐white guinea‐pigs the a. carotis, v. jugularis and trachea were cannulated. After base line measurements the animals received VX (22.5, 45 or 90 μg/kg=5, 10 or 20XLD50) intravenously and 2 min. later the antidotes: HLö 7 or HI 6 (30 μmol/kg, each) or atropine 10 mg/kg or a combination of atropine and one of the oximes (all intravenously). Respiratory and circulatory parameters were recorded for 60 min. or until death of the animal. Erythrocyte, brain and diaphragm acetylcholinesterase (AChE) activity was determined after the experiment. VX poisoning caused a rapid respiratory arrest within 4‐5 min. Atropine treatment was effective in improving the respiratory function after VX, 22.5 pg/kg, but had only a small effect after the higher VX doses. The treatment of VX (10 or 20XLD50) poisoned animals with oxime plus atropine improved respiration to various extents, restored circulation and prolonged the survival time, HLö 7 being more effective than HI 6 after VX 90 μg/kg. Oximes alone were completely ineffective. Erythrocyte and diaphragm AChE was reactivated by HLö 7 and, less effectively, by HI 6, while brain AChE remained almost completely inhibited in all groups. The results of this investigation demonstrate a reasonable efficacy of atropine after lower VX doses and of HLö 7 and HI 6 (plus atropine) after high‐dose VX poisoning, HLö 7 being slightly more effective than HI 6.
Protective Effect of Atrial Natriuretic Peptide on Electrical‐Field‐Stimulated Rat Ventricular Strips During Hypoxia
Authors: Ljusegren Marie Ekstam , Andersson Rolf G. G.
Published: March 2009

Abstract:We have previously shown that atrial natriuretic peptide reduces lactate accumulation in non‐beating rat ventricular myocardium exposed to hypoxic conditions, and that hypoxia induces release of atrial natriuretic peptide from isolated rat atrial tissue. In these studies we suggested that atrial natriuretic peptide may be physiologically important for protection of the myocardium during periods of oxygen deficit. In the present study, we used isolated strips of rat right ventricle, contracted by electrical‐field‐stimulation, as a model of a beating myocardium. After contraction stabilization, hypoxic conditions were introduced through aeration with 20% O2, held for 20 or 30 min., and then interrupted by reoxygenation with 95% O2The contractile force was recorded and the percentage regain of the contractions after reoxygenation was considered as an indication of the amount of cell damage induced during the period of hypoxia. The results show that after 30 min. of hypoxia and subsequent reoxygenation, ventricular strips treated with atrial natriuretic peptide (0.1 μM) recovered 67.9 ± 2.8% of the prehypoxic force of contraction; control strips from the same ventricle regained 44.9 ± 4.4% (P=0.015) of their initial contractile activity. After 20 min. of hypoxia followed by reoxygenation, a ventricular strip incubated together with an atrium regained 78.6 ± 2.4% of the prehypoxic force of contraction as compared to a 60.2 ± 2.7% regain (P=0.002) for the control strip. We conclude that atrial natriuretic peptide protects the working ventricular myocardium during hypoxia, which further supports our previously reported suggestion that the effect on myocardial metabolism is physiologically relevant during situations of oxygen deficit in heart muscle.
Inhibition by (−)‐Deprenyl of Agonist‐Evoked Contractions in Rabbit Aorta
Authors: Nedergaard Ove A. , Meller Jacob
Published: March 2009

Abstract:The effect of (−)‐deprenyl, a relatively selective MAO‐B inhibitor, was examined for its ability to inhibit the contractions of rabbit isolated aorta evoked by various agonists and potassium. (−)‐Deprenyl (10−5−3 × 10−4M) antagonized the contractions evoked by noradrenaline (10−8−3 × 10−4M); pA2: 5.10. The antagonism was reversible. It was attenuated by cocaine (3x M); pA2: 4.38, unchanged by corticosterone (4 × 10−5M); pA24.79 and enhanced by cocaine (3 × 10−5M) plus corticosterone (4 × 10−5M); pA2: 5.48. (+)‐Deprenyl (10−6−10−4M) did not alter the contractions evoked by noradrenaline (3 × 10−9−10−4M). Clorgyline (10−5and 10−4M) antagonized the noradrenaline‐evoked contractions. Pargyline (10−4and 3 × 10−4M) had no effect. (−)‐Deprenyl (10−5−3 × 10−4M) antagonized the contractions evoked by phenylephrine (10−8−10−4M); pA2: 5.10. Removal of the endothelium did not alter the antagonism; pA2: 5.35. (−)‐Deprenyl (10−5−3 × 10−4M) antagonized the contractions evoked by either 5‐hydroxytryptamine (3 × 10−8−3 × 10−4M); pA2: 4.61 or by histamine (10−6−3 × 10−2M); pA2: 4.84. (−)‐Deprenyl (3 × 10−4M) caused a non‐competitive antagonism of the contractions evoked by potassium (1.5‐5.5 × 10−2M). It is concluded that (−)‐deprenyl is a weak inhibitor of postjunctional α‐adrenoceptors, 5‐hydroxytryptamine (5‐HT2) receptors, and histamine (H1) receptors.
The Influence of Dichloromethylene Bisphosphonate on the Healing of a Long Bone Fracture, Composition of Bone Mineral and Histology of Bone in the Rat
Authors: Hyvönen Pekka M. , Karhi Tero , Kosma Veli‐Matti , Liimola‐Luoma Leena , Hanhijärvi Hannu
Published: March 2009

Abstract: The effects of dichloromethylene bisphosphonate (clodronate) on the composition of bone mineral, morphology and histology of a long bone with an artificial femoral fracture were studied in a 22 week experiment. Two hundred twenty‐four female rats were allocated to dose groups of 0, 3, 10, and 30 mg/kg clodronate daily subcutaneously. Bone calcium, phosphorus and magnesium concentrations remained stable and fluoride concentration rose with time. There were no statistical differences between different groups. Clodronate did not alter the histology of the callus nor delayed the healing of the fracture. It caused mild to moderate prominence of the metaphyseal area in the fractured bone in a dose‐ and time‐dependent manner. Serum osteocalcin levels were lowered in the treated animals dose‐dependently. Other serological as well as haematological values were within normal range. Clodronate seems in this experimental arrangement to be a safe agent to administer in different pathological conditions of bone even when they are complicated by fractures of long bones.
Liposolubility and Protein Binding of Oxycodonein Vitro
Authors: Pöyhiä R. , Seppälä T.
Published: March 2009

The liposolubility and protein‐binding of oxycodone were studiedin vitroand compared with other opioids. Liposolubility was assessed by three different methods: 1) the shake‐flask method with n‐octanol at pH 4‐9, 2) measuring the retention time in reversed‐phase high‐performance liquid chromatography (RP‐HPLC) with a LiChrosorb® RP‐18 and 3) studying the solubility in human epidural and subcutaneous fat. Human fat was obtained from patients undergoing surgery for herniated intervertebral disc. After incubation, pieces of fatty tissue immersed in a buffer solution containing oxycodone, morphine, pethidine or fentanyl for 10‐40 min.; tissue pieces were homogenated, opioids extracted and opioid concentrations measured by gas‐ and high‐performance liquid chromatography. The binding of oxycodone, morphine and fentanyl in plasma proteins was studied by ultrafiltration (Amicon®‐kit). The mean apparent partition coefficients Pappof oxycodone, morphine, pethidine and fentanyl in n‐octanol at pH 7 were 0.7, 0.5, 10.5 and 399, respectively. The retention times in RP‐HPLC for oxycodone, morphine, pethidine, fentanyl and buprenorphine were 0.6 min., 0.2 min., 2.4 min., 2.3 min. and 10.5 min., respectively. Only buprenorphine and fentanyl appeared to be highly lipophilic in the human fat tissue experiments; no difference was found between epidural or subcutaneous fat in this respect. Thein vitroprotein binding of oxycodone was 38%, of morphine 31% and of fentanyl 87% in average. It is concluded that, in terms of physicochemical properties, liposolubility and protein‐binding, oxycodone resembles morphine more than it does fentanyl.
The Involvement of Muscarinic Receptor Subtypes in the Mediation of Hypothermia, Tremor, and Salivation in Male Mice
Authors: Sánchez Connie , Lembøl Hanne Løve
Published: March 2009

The potency of centrally administered non‐selective (atropine and N‐methyl scopolamine) and putatively selective muscarinic antagonists (pirenzepine, AF‐DX 116 and 4‐DAMP) in inhibition of oxotremorine‐induced hypothermia, tremor and salivation in male mice has been compared with their potencyin vitroin three functional systems, where muscarinic effects are mediated preferentially by M1(i.e. superior cervical ganglion), M2(i.e. atrium), and M3(i.e. ileum) receptors. Atropine, N‐methyl scopolamine and 4‐DAMP potently abolished the effects of oxotremorine. Pirenzepine abolished tremor and salivation, whereas hypothermia was antagonized partially only. AF‐DX 116 had but weak antagonistic effects. Atropine and N‐methyl scopolamine were potent antagonists in all threein vitrotest systems. High potency was also seen with 4‐DAMP, in particular in the ileum preparation. Pirenzepine showed its highest potency in the ganglion preparation. AF‐DX 116 was a weak and non‐selective antagonist in all threein vitropreparations. Our studies indicate that the muscarinic induction of tremor and salivation may be preferentially mediated by M3receptors whereas both M2and M3receptors may be involved in the mediation of hypothermia. However, the overall conclusion is that compounds with higher receptor subtype selectivity are needed.
Effect of Dopexamine Hydrochloride on Contractions of Rabbit Isolated Aorta Evoked by Various Agonists
Authors: Nedergaard Ove A.
Published: March 2009

The inhibitory affinity of dopexamine hydrochloride to postsynaptic adrenoceptors, cholinoceptors, 5‐hydroxytryptamine and histamine receptors was studied in rabbit isolated aorta. Dopexamine (10−7–10−5M) antagonized competitively the contractions of rabbit aorta evoked by noradrenaline (pA2: 6.60). Neither cocaine plus corticosterone nor cocaine, corticosterone plus propranolol altered the inhibition (pA2: 6.77 and 6.63, respectively). The antagonism of dopexamine against noradrenaline‐evoked contractions was the same after 1 and 4 hr of pretreatment with dopexamine. In the presence of cocaine plus corticosterone, dopexamine antagonized the contractions evoked by phenylephrine (pA2: 6.94). Removal of endothelium did not influence this antagonism (pA2: 7.06). Dopexamine (10−7–10−5M) did not antagonize the contractions of aorta evoked by histamine (3×10−7–6 × 10−5M) and by 5‐hydroxytryptamine (3 × 10−7–3 × 10−4M). Dopexamine (10−8and 10−7M) did not alter the contractions of endothelium‐free aorta evoked by carbachol. Dopexamine (10−7–10−5M) slightly enhanced the contractions of aorta evoked by potassium (10−2–5.5 × 10−2M). These results suggest that dopexamine is an α1‐adrenoceptor antagonist. Furthermore, dopexamine has no affinity to cholinoceptors, histamine and 5‐hydroxytryptamine (5‐HT2) receptors and is apparently not a calcium antagonist.
Absorption Kinetics of Two Highly Concentrated Preparations of Growth Hormone: 12 IU/ml Compared to 56 IU/ml
Authors: Laursen Torben , Susgaard Søren , Jensen Flemming Steen , Jørgensen Jens Otto L. , Christiansen Jens S.
Published: March 2009

The purpose of this study was to compare the relative bioavailability of two highly concentrated (12 IU/ml versus 56 IU/ml) formulations of biosynthetic human growth hormone administered subcutaneously. After pretreatment with growth hormone for at least four weeks, nine growth hormone deficient patients with a mean age of 26.2 years (range 17‐ 43) were studied two times in a randomized design, the two studies being separated by at least one week. At the start of each study period (7 p.m.), growth hormone was injected subcutaneously in a dosage of 3 IU/m2. The 12 IU/ml preparation of growth hormone was administered on one occasion, and the 56 IU/ml preparation on the other. Serum profiles of growth hormone were monitored by frequent measurements for 24 hr. Bioavailability and absorption dynamics were evaluated by the absorption fraction, F56 IU/12 IU, calculated from the mean integrated levels (AUC) of growth hormone, and the observed time, Tmax, to reach maximum concentration, Cmax. Levels of serum IGF‐I, IGFBP‐3, insulin and blood glucose were measured to study the short term metabolic effects of growth hormone. The absorption fraction, F (S.D.) was 1.034 (0.163). The 90% confidence interval was 0.934‐1.144, which is included in the interval 0.8‐1.25, implying that the two preparations are bioequivalent. Neither AUC (P = 0.90), Cmax (p = 0.47) or Tmax (P = 0.86) for the two formulations of growth hormone were significantly different. Similar levels of serum IGF‐I, IGFBP‐3, insulin and blood glucose were obtained. In conclusion, the absorption kinetics and short term metabolic effects of two highly concentrated formulations of growth hormone containing 12 IU/ml and 56 IU/ml were similar.
Chronic L‐α‐Glyceryl‐phosphoryl‐choline Increases Inositol Phosphate Formation in Brain Slices and Neuronal Cultures
Authors: Aleppo G. , Nicoletti F. , Sortino M. A. , Casabona G. , Scapagnini U. , Canonico P. L.
Published: March 2009

Repeated, but not single injections of L‐α‐glyceryl‐phosphorylcholine (αGPC) significantly increased basal [3H]inositol monophosphate (InsP) formation in hippocampal, cortical, and striatal slices of male rats. The effect was dose‐dependent and was accompanied by an increased incorporation of [3H]inositol into the phospholipid fraction. Incubation of brain slices with different neurotransmitter antagonists, such as atropine, prazosin, or L‐2‐amino‐4‐phosphonobutanoate (L‐AP4) did not modify the increase in [3H]InsP formation produced by αGPC, suggesting that the effect is not mediated by an increased availability of a specific neurotransmitter. Similar results were obtained in cerebellar and cortico‐striatal neurones in primary culture exposed to daily addition of αGPC since the second day of maturation in vitro. We suggest that αGPC treatment may result in an increased rate of phospholipid synthesis, including the phosphoinositides available for signal transduction at central nervous system level.
One‐year Treatment of Streptozotocin‐Induced Diabetic Rats with Vanadyl Sulphate
Authors: Dai S. , Thompson K. H. , McNeill J. H.
Published: March 2009

Streptozotocin‐diabetic and non‐diabetic rats were given various concentrations of vanadyl sulphate in drinking water for one year. It was found that vanadyl sulphate caused significant decreases in body weight gain and plasma insulin level in non‐diabetic rats, but did not significantly alter fluid and food intakes or plasma levels of glucose, triglycerides, or cholesterol. In diabetic animals, vanadyl treatment significantly alleviated or prevented the occurrence of hyperglycaemia, hypoinsulinaemia, hyperphagia, polydipsia, hyperlipidaemia, or cataract formation, but the slower body weight gain was not improved. There were gradual decreases in the intake of the compound required to correct hyperglycaemia in the values of ED50 with age of the rats. The beneficial effects of vanadyl treatment persisted 16 weeks following the withdrawal of the compound. It is concluded that vanadyl sulphate is an effective agent for chronic therapy of streptozotocin‐induced diabetes in rats, and its prolonged use does not lead to the development of tolerance.
Atrial Natriuretic Peptide and Cyclic Guanosine‐3′5′‐monophosphate in Hypertensive Pregnancy and During Nifedipine Treatment
Authors: Manninen Auli , Vuorinen Pauli , Laippala Pekka , Tuimala Risto , Vapaatalo Heikki
Published: March 2009

Atrial natriuretic peptide exhibits natriuretic. diuretic and vasodilatory properties. We compared plasma concentrations of atrial natriuretic peptide, cyclic guanosine‐3′,5′‐monophosphate (cGMP), electrolytes and urinary excretion of cGMP and electrolytes in hypertensive pregnant women to those in normotensive pregnant and normotensive non‐pregnant women. Plasma atrial natriuretic peptide concentrations in hypertensive pregnant and normotensive nonpregnant women were equal, whereas in normotensive pregnant women it was lower (P<0.05), than in non‐pregnant. Urinary cGMP excretion was higher in both normotensive and hypertensive pregnant than in non‐pregnant women (P<0.01). whereas plasma cGMP levels were similar. A five‐day nifedipine treatment (10 mg t.i.d.) had no effects on any of the variables. In hypertensive pregnancy, a reduction of systolic blood pressure by nifedipine correlated with the initial plasma atrial natriuretic peptide (P<0.05) and a decrease in diastolic blood pressure with the initial plasma cGMP concentration (P<0.05). The results of this small material suggest that plasma atrial natriuretic peptide concentration predicts the response to nifedipine in hypertensive pregnancy. However, the atrial natriuretic peptide‐cGMP system does not seem to mediate the antihypertensive effect of nifedipine, while plasma atrial natriuretic peptide remained unaltered. Increased urinary cGMP excretion in both pregnant groups but lowered plasma atrial natriuretic peptide in normotensive pregnancy suggest other factors than circulating atrial natriuretic peptide to promote renal cGMP excretion during pregnancy.
Effect of Methyl Mercury Exposure on the Uptake of Radiolabeled Inorganic Mercury in the Brain of Rabbits
Authors: Dock Lennart , Mottet Karle , Vahter Marie
Published: March 2009

Exposure to mercuric compounds at high dose levels has previously been shown to alter the integrity and function of the blood‐brain barrier in laboratory animals. In the present study, we have investigated the distribution of intravenously administered inorganic203Hg in rabbits additionally exposed to MeHg. A single dose of203HgCl2was administered together with or 5 min. or 24 hr after administration of a single dose (10 or 37.5 μmol/kg b.wt.) of MeHg. In another experiment,203HgCl2was administered to rabbits subchronically exposed to MeHg (1 μmol/kg b.wt. daily for three weeks) 24 hr after cessation of treatment. The integrity of the blood‐brain barrier was assayed by measuring the uptake of203Hg in the brain, as the blood‐brain barrier usually serves to exclude inorganic Hg from the brain. The concentration of203Hg within the brain was similar in all MeHg‐treated rabbits, corresponding to 0.02% of the administered dose, and not different from that of control animals. Under these conditions, no obvious damage to the blood‐brain barrier by MeHg could be observed.
The Metabolism of Mebeverine in Man: Identification of Urinary Metabolites by Gas Chromatography/Mass Spectrometry
Authors: Kristinsson Jakob , Snorradóttir Ingibjörg , Jóhannsson Magnüs
Published: March 2009

The urinary metabolites of orally administered mebeverine hydrochloride (270 mg) were studied in five healthy volunteers with the aid of gas chromatography/mass spectrometry. Mebeverine, which is an ester of veratric acid and 4‐{ethyl‐[2‐(4‐methoxyphenyl)‐1‐methylethyl]amino}butan‐1‐ol, was completely hydrolysed to the corresponding acid and alcohol moieties. The acid moiety was subsequently O‐demethylated to vanillic acid and isovanillic acid, which in turn were further O‐demethylated to protocatechuic acid. The alcohol moiety was O‐demethylated to the corresponding phenol 4‐{ethyl‐[2‐(4‐hydroxyphenyl)‐1‐methylethyl]amino}butan‐1‐ol. In 24 hr, 44% of the dose was accounted for as follows: Veratric acid 32%, vanillic acid 2.7%, isovanillic acid 6.5%, 4‐{ethyl‐[2‐(4‐methoxyphenyl)‐1‐methylethyl]amino}butan‐1‐ol 0.9% and 4‐{ethyl‐[2‐(4‐hydroxyphenyl)‐1‐methylethyl]amino}butan‐1‐ol 2.1%. Only trace amounts of protocatechuic acid were found in the urine. The results indicated that the metabolites were mostly excreted as conjugates. The total excretion of the acid moiety, unchanged or in the form of metabolites was 97.6%. The corresponding value for the alcohol moiety was 5.5%.
Neuropeptide Y in Sympathetic Co‐Transmission: Recent Advances in the Search for Neuropeptide Y Antagonists
Authors: Edvinsson Lars , Erlinge David , Sun Xiang Ying , Hedner Thomas
Published: March 2009

Since the discovery of neuropeptide Y which is co‐stored and co‐operate with noradrenaline (NA) in sympathetic nerve fibers, several scientific groups have searched for structures with neuropeptide Y antagonistic properties. Research has mainly focused on various peptide fragments which originate from or are related to the neuropeptide Y sequence. Some non‐peptide antagonists have been proposed but they are mostly of low potency and non‐selective. Our recent observations that α‐trinositol (D‐myo‐inositol 1.2.6‐trisphosphate) is an inhibitor of neuropeptide Y effects will hopefully lead to the development of useful non‐peptide neuropeptide Y inhibitors. As a novel approach the highly selective approach of down‐regulating neuropeptide Y receptors with antisense oligodeoxynucleotides is also discussed. Neuropeptide Y antagonistic agents would help us to understand the physiological role of neuropeptide Y and may serve as useful medication in circulation disorders.
Effect of Deltamethrin on Regional Brain Polyamines and Behaviour in Young Rats
Authors: Husain Raghib , Malaviya Madhu , Seth P. K. , Husain Raushan
Published: March 2009

The present study examines the mechanism of neurotoxic action of a synthetic pyrethroid formulation deltamethrin in young rats. Newly weaned Wistar Albino male rats received deltamethrin of technical grade at a dose of 7.0 mg/kg body weight/day in corn oil, orally from postnatal day 22 to postnatal day 37. Deltamethrin significantly decreased the wet weight of the hippocampus without much affecting the weight of cerebellum, pons medulla, hypothalamus, frontal cortex and corpus striatum in comparison to respective controls. A significant increase in the activities of mitochondrial monoamine oxidase and microsomal acetylcholinesterase without any effect on microsomal Na+, K+‐ATPase activity was observed in the brain of experimental animals. Our results further indicate that deltamethrin markedly impaired learning function and significantly increased the spontaneous locomotor activity while aggressive beahviour remained unaffected. An overall enhancement of polyamine levels in hypothalamus and corpus striatum accompanied with an overall decline in pon medulla and cerebellum was also noted. Maximum decrease of spermine and spermidine was registered in hippocampus, while these polyamines showed an increase in frontal cortex. In striatal membranes the binding of3H‐spiperone decreased and3H‐quinuclidinyl benzilate was elevated significantly. Deltamethrin‐induced deviations in regional brain polyamine levels may be a possible cause for altered pathophysiology of the neurone.
Renal Adaptations to Continuous Administration of Furosemide and Bendroflumethiazide in Rats
Authors: Lunau Hanne E. , Bak Martin , Petersen Jørgen S. , Shalmi Michael , Marcussen Niels , Christensen Sten
Published: March 2009

During continuous treatment with diuretics, the kidney adapts to the initial Na loss by activating antinatriuretic mechanisms which serve to prevent further Na and volume losses. To study the renal sites of adaptations to constant diuretic treatment, bendroflumethiazide (4 mg daily), furosemide (8 mg daily) or vehicle (0.24 ml daily) was infused intraperitoneally to female Wistar rats by implanted osmotic minipumps. Half of the animals (groups vol.) were randomized to receive a balanced saline solution to drink in addition to water in order to replace Na, K and volume losses. On the 6th day of treatment, clearances of inulin, Na, and Li were determined during four consecutive 6 hr periods. Orcadian changes in renal excretions occurred in all groups with highest excretions of Na, Li and water in the dark period (6 p.m. to 6 a.m.). Renal changes induced by continuous infusion of diuretics were most pronounced in the dark period and would probably not have been disclosed if the clearance experiments had been restricted to the daytime. The average 24‐hour clearance for inulin (glomerular filtration rate) was not different among groups, except for a 20% decrease in the furosemide group. The 24‐hour fractional Na excretion, being ‐0.5% in the vehicle group, increased to ‐0.8% in group (bendroflumethiazide + vol) and to ‐2.8% in group (furosemide + vol) but was not different from the vehicle group in the diuretic groups without volume replacement. Fractional Li excretion was ‐28% in groups (vehicle + vol), ‐19% in groups (bendroflumethiazide + vol), ‐30% in the furosemide group and ‐37% in group (furosemide + vol). Finally, CNa/CLiwas ‐1.7% in group (vehicle + vol), ‐3.7% in group (bendroflumethiazide + vol) and ‐7.0% in group (furosemide + vol). The results indicate that even though continuous furosemide administration caused a fall in glomerular filtration rate, there was no change in the flow rate of tubular fluid to the distal nephron (CLi) following treatment with loop diuretic. This contrasts the effects of continuous thiazide treatment, being a reduction of CLiin absence of changes in glomerular filtration rate. The reason for this difference may be that the adaptive increase in proximal tubular Na reabsorption is outbalanced by an inhibitory effect of furosemide itself on the proximal tubule. Both diuretics caused an adaptive increase in fractional distal Na reabsorption, probably at nephron sites beyond their respective sites of action. Furosemide but not bendroflumethiazide induced a persistent increase in urine flow.
In vivoStudy of Angiotensin II Tachyphylaxis in Freely Moving Normo‐ and Hypertensive Rats
Authors: Sim M. K. , Radhakrishnan R.
Published: March 2009

In vivotachyphylaxis to the angiotensin II‐induced increase in mean arterial blood pressure was studied in conscious freely moving rats by telemetry blood pressure monitoring. The animals studied were the normotensive Sprague Dawley rats (SD), the spontaneously hypertensive rats (SHR), and two models of experimentally‐induced hypertensive rats, namely, the left renal artery stenosed SD hypertensive rat (LRAS) and the deoxycorticosterone acetate/salt SD hypertensive rat (DOCA). Two consecutive dose‐response curves to angiotensin II in each rat were obtained. The increase in mean arterial pressure (MAP) at each bolus dose of the first dose‐response curve was found not to be significantly different from the corresponding value of the second dose‐response curve in the four models of rat studied (i.e. no significant difference in the intra‐rat response to AII). In addition, the slope of the dose‐response curve is similar for each model of rat indicating that there was no inter‐model variation to the response of AII. The results show that the response to AII in the SD and the three models of hypertensive rats was remarkably similar and that they did not develop tachyphylaxis to the pressor response of AII at concentrations ranging from circulating level of 0.0005 nmoles/kg (10−11M) to 10 nmoles/kg (2 × 10−7M). This was despite the fact that the SD had normal blood pressure and the genesis of hypertension in each model of the hypertensive rats was different. These findings support our earlier suggestion that the development of tachyphylaxis to the concentration range of AII inin vitropreparations is prevented from occurring in the intact animal by circulating spasmogens.
Lack of Maternal and Developmental Toxicity in Mice Given High Doses of Aluminium Hydroxide and Ascorbic Acid During Gestation
Authors: Colomina M. Teresa , Gómez Mercedes , Domingo Jose L. , Corbella Jacinto
Published: March 2009

The present study was conducted to assess if the concurrent ingestion of high doses of aluminium hydroxide and ascorbic acid might result in maternal and developmental toxicity in mice. Three groups of pregnant Swiss mice were given by gavage daily doses of aluminium hydroxide (300 mg/kg), ascorbic acid (85 mg/kg), or aluminium hydroxide (300 mg/kg) concurrent with ascorbic acid 85 (mg/kg) on gestational days 6‐15. A fourth group of animals received distilled water and served as control group. Dams were killed on gestation day 18 and foetuses were examined for external, internal, and skeletal abnormalities. The reproductive data did not show embryotoxic or foetotoxic effects in any group. No gross, internal, or skeletal malformations or variations related to the different treatments were found. There were no significant differences between control and treated groups on the aluminium levels in maternal liver and bone as well as in whole body foetuses, whereas aluminium concentrations were significantly higher in placenta and kidney of dams receiving aluminium hydroxide and aluminium hydroxide plus ascorbic acid than in those from the control group. Although in this study aluminium hydroxide was given at doses higher than those usually consumed by pregnant women, no signs of maternal or developmental toxicity were observed when the compound was given alone or concurrently with high doses of ascorbic acid.
UV‐Dependent Quinolone‐Induced Human Erythrocyte Membrane Lipid Peroxidation: Studies on the Phototoxicity of Y‐26611, a New Quinolone Derivative
Authors: Wada K. , Saniahadi A. R. , Umemura K. , Takiguchi Y. , Nakashima M.
Published: March 2009

Quinolone antibacterial drugs are widely used as oral therapeutic agents. However, in some patients they cause ultraviolet (UV)‐dependent dermatitis. Using lipid peroxidation as an index of phototoxicity, we studied the effects of a new quinolone derivative, Y‐26611 together with ofloxacin, sparofloxicin and lomefloxacin on washed human erythrocyte suspensions. Irradiation of erythrocytes with UV‐A or UV‐B for 60 min. in the presence of Y‐26611 (30‐600 μg/ml) strong dose dependent lipid peroxidation, up to 17.01 nmoles/ml was induced. Under identical conditions, lipid peroxidation induced by up to 600 μg/ml ofloxacin, sparofloxacin or lomefloxacin were 0.94, 3.36 and 2.98 nmoles/ml respectively. The lipid peroxidation was entirely dependent on both UV as well as the drug. The lipid peroxidation responses to drug + UV could completely be inhibited by sodium azide (hydroxyl radical, HO‐ and singlet oxygen, 1O2 scavenger) or by phenyl N‐tert‐butylnitrone (PBN, HO and superoxide anion radical, O2− scavenger). It is likely that reactive oxygen species generated by interaction between UV‐sensitized drug molecules and oxygen molecules mediate erythrocyte membrane lipid peroxidation. The method used in this study is rapid and convenient for screening drugs for UV‐dependent cytoloxicity.
Drug Interaction Effects on Antitumour Drugs (XV): Disulfiram as Protective Agent Against Cyclophosphamide‐Induced Urotoxicity Without Compromising Antitumour Activity in Mice
Authors: Ishikawa Masaaki , Aoki Tomoko , Yomogida Shin , Takayanagi Yoshio , Sasaki Ken‐ichi
Published: March 2009

The prevention of cyclophosphamide‐induced urotoxicity by disulfirum was studies in mice. A single dose of cyclophosphamide (100‐400 mg/kg, intraperitoneally) produced a significant dose‐dependent increase in urinary bladder weight within 48 hr of treatment. Disulfiram prevented cyclophosphamide‐induced bladder damage in a dose‐dependent manner in mice when orally administered simultaneously with antitumour agents, but failed to diminish the acute toxicity. leukocytotoxicity and immunotoxicity of cyclophosphamide. The protective effect of disulfiram on the bladder was critically dependent on administration timing. Oral administration of disulfiram between 60 min. before and 60 min. after the injection of cyclophosphamide was found to be effective. The optimum time was simultaneous administration of both drugs. Diethyldithiocarbamate and carbon disulfide, metabolites of disulfiram, prevented cyclophosphamide‐induced bladder damage when administered simultaneously with cyclophosphamide 1 to, 3 or 5 hr afterwards. Disulfiram slightly potentiated the antitumour activity of cyclophosphamide against Sarcoma 180 or EL‐4 leukaemiain vivowhen administered simultaneously with cyclophosphamide. In contrast, diethyldithiocarbamate or carbon disulfide did not interfere with cyclophosphamide antitumour activity when administered 3 hr after cyclophosphamide. From these preliminary studies, disulfiram appears to be a likely candidate for protection against cyclophosphamide‐induced urotoxicity without compromising the therapeutic utility of the alkylating agent.