bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of Methylergometrine (Methylergonovine) in the Rabbit and Man
Authors: Mäntylä R. , Kleimola T. , Kanto J.
Published: July 2010

Abstract: Methylergometrine concentrations in human and rabbit plasma were determined by a new radioimmunoassay after a single intravenous injection (0.2 mg in man and 0.05, 0.1 and 0.2 mg/kg in rabbits). Both in man and in the rabbit methylergometrine disappeared quickly from the plasma with a mean T1/2β of 1.8 and 1.2–1.7 min. respectively. Similarly, the T1/2/α‐values were 32.1 and 27.3–93.2 min. The mean maximal response in the rabbit uterus in situ after 0.05, 0.1 and 0.2 mg/kg intravenously dose was found at 40 sec, 26 sec, and 26 sec. after the drug administration, respectively, and the dose response curve was quite steep. A significant correlation was found between the dose and response.
Enzyme Activities of Myocardial Energy Metabolism during Prolonged Digoxin Treatment in Rats
Authors: Pelkonen K. H. O.
Published: July 2010

AbstractThe effect of prolonged digoxin treatment (1 mg/kg day for 8 days) on the activity levels of some enzymes of energy metabolism (phosphofructokinase, lactate dehydrogenase, citrate synthase, succinate dehydrogenase) in rat myocardium was studied. In the control animals receiving the solvent mixture (glycerol: ethanol:water in 1:1:1) a transient decrease in the lactate dehydrogenase and citrate synthase activity levels was observed. In the hearts of digoxin treated rats the level of activity of phosphofructokinase was permanently lowered by the fourth day and the level of activity of citrate synthase permanently increased after the first day of treatment. A transient increase in the activity level of succinate dehydrogenase in the myocardium of digoxin treated animals was seen between days 1 and 6. In this study a permanent decrease in phosphofructokinase and an increase in citrate synthase activity levels in rat heart muscle was noted during prolonged digoxin treatment.
Effects of Verapamil and Nitroglycerin on Contractile Responses to Potassium and Noradrenaline in Isolated Human Peripheral Veins
Authors: Mikkelsen E. , Andersson K.‐E. , Bengtsson B.
Published: July 2010

AbstractIsolated ring preparations of human vein were contracted by potassium (127 mM) and noradrenaline (1.8 × 10‐5M). The potassium‐induced contracture developed more rapidly and had a higher maximum amplitude than that produced by noradrenaline. Addition of phentolamine (10‐5M) reduced the amplitude of the potassium contracture by 22% and abolished the noradrenaline response. Verapamil and nitroglycerin relaxed preparations contracted by potassium and noradrenaline, and, when added prior to stimulation, reduced the contractile responses to these agents. Both verapamil and nitroglycerin inhibited the contractile effect of noradrenaline more strongly than that of potassium. After immersion of the preparations for 30 min. in a calcium‐free medium, the responses to potassium and noradrenaline were reduced to 21.3 ± 2.5% and 7.1 ±0.8%, respectively, of the control. Addition of verapamil caused a further reduction of the response to potassium, but not of that to noradrenaline. Nitroglycerin caused a further reduction of the contractions induced by both agents. When the calcium concentration in the extracellular medium was increased from 0 to 4 mM, the contractile responses to potassium and noradrenaline returned to the control level. Both verapamil and nitroglycerin inhibited the contractile responses to calcium; the inhibiting effects of verapamil were significantly more marked than those of nitroglycerin. Tachyphylaxis to nitroglycerin was demonstrated on contractions induced by potassium, but not on noradrenaline‐produced responses.
Inhibition of Noradrenaline‐Stimulated Lipolysis and Cyclic AMP Accumulation in Isolated Rat Adipocytes by Purified Phospholipase C and Theta‐Toxin from Clostridium Perfringens
Authors: Fredholm Bertil B. , Möllby Roland , Anderson Per , Malmquist Torsten , Smyth Cyril J.
Published: July 2010

Abstract Purified phospholipase C (phosphatidylcholine cholinephosphohydrolase, EC 3.1.4.3) and thetatoxin from Clostridium perfringens both inhibited noradrenaline‐stimulated lipolysis and cyclic AMP accumulation in isolated rat adipocytes in a dose‐dependent manner. The action of phospholipase C was gradual in onset, while the effect of theta‐toxin was almost immediate. Phospholipase C., but not theta‐toxin, hydrolyzed membrane phospholipids and inhibited adenylate cyclase (EC 4.6.1.1) in a crude membrane fraction from fat cells. The inhibitory effects of phospholipase C were associated with morphological alterations detectable by electron microscopy, whereas effects of theta‐toxin were observed at a time when no clearcut morphological alterations could be observed. It is concluded that the two purified principles from C. perfringens, which are both present in commercial preparations of phospholipase C., antagonize noradrenaline‐stimulated cyclic AMP accumulation and lipolysis. Although their exact mechanisms of action have not been elucidated, phospholipase C and theta‐toxin have different modes of attack.
A Procedure for the Isolation of Noradrenaline (together with Adrenaline), Dopamine, 5‐Hydroxytryptamine and Histamine from the Same Tissue Sample Using a Single Column of Strongly Acidic Cation Exchange Resin
Authors: Atack Colin , Magnusson Tor
Published: July 2010

AbstractUsing a single column of a strongly acidic cation exchange resin (Dowex 50W, X‐4, 200–400 mesh, resin bed 4.0 mm diameter × 75 mm long in sodium form), noradrenaline (NA) (together with adrenaline (A)), dopamine (DA), 5‐hydroxytryptamine (5‐HT), and histamine (Hm), are recovered in separate eluates after a single extraction of the same tissue sample into perchloric acid. Recoveries of the amines from homogenates and filtrates were approximately the same: for NA (together with A), about 90% in a 7‐ml eluate; for DA, about 95% in 3.5 ml; for 5‐HT, about 75% in 7 ml; and for Hm, about 85% in 4.5 ml. The establishment and routine use of the procedure are presented in detail. Several metabolites of the amines, including 5‐hydroxyindole‐3‐acetic acid (5‐HIAA), the precursor amino acids, and 3‐methoxytyramine (3‐MT), can be recovered from the same Dowex 50 column by incorporating the procedures developed by Carlsson, Kehr & Lindqvist in this laboratory. All the amines and many of their metabolites can be purified successively into their eluates in a normal working day. We now have increased opportunities to study aspects of the metabolism of the biogenic amines. Thus, for the catecholamines can be monitored tyrosine → DOPA → DA → NA → A and also DA → 3‐MT; and for 5‐HT, the metabolic pathway tryptophan 5‐hydroxytryptophan → 5‐HT → 5‐HIAA. The column purification contributes considerable specificity to the overall procedure. Most compounds which are acidic; e.g. 5‐HIAA, neutral or amphoteric, e.g. all the precursor amino acids, are eluted before the amines. Considerable resolution of basic compounds into separate fractions is also achieved: notably Hm is eluted before spermidine, and DA is separated from NA plus A. Thus, many compounds are prevented from interfering in fluorimetric assays which have been especially adapted for measuring these amines in the Dowex 50 eluates. Salt equivalent to at least 10 g of tissue placed on the column does not affect the recoveries of the amines. For quantitative determinations of endogenous amines, approximately 10 ng of each amine on the Dowex 50 column are sufficient, and smaller amounts can be detected. The procedure was developed particularly for measuring amines in nervous tissue, but it has been applied successfully to several peripheral tissues and body fluids.
The Kinetics of Imipramine‐N‐Oxide in Man
Authors: Nagy Adam , Hansen Tage
Published: July 2010

AbstractFive healthy volunteers received single doses of imipramine‐N‐oxide (1 mg/kg) by the oral, intramuscular, and intravenous routes. Peak plasma level of imipramine‐N‐oxide was reached one hour after oral administration. The plasma curves of imipramine‐N‐oxide following oral and intravenous administration suggested a monophasic decay with a half‐life ranging between 1.5–2.5 hrs. Pronounced individual differences were observed in the plasma and blood cell concentrations of imipramine‐N‐oxide and the formed metabolites, imipramine and desipramine. The systemic availability of the oral dose of imipramine‐N‐oxide averaged 100 per cent, whereas the systemic availability of the intramuscular injection of imipramine‐N‐oxide averaged 54 per cent. The formation of metabolites was more extensive after intramuscular injection compared with the other routes of administration. The concentration of imipramine‐N‐oxide was lower and the imipramine concentrations higher in blood cells compared to the plasma after all three routes of administration. Thirteen depressed patients received continuous treatment with weekly increasing oral doses of imipramine‐N‐oxide for three weeks and intramuscular injections during the fourth week. They received imipramine during the fifth week. The concentration of imipramine‐N‐oxide and the formed imipramine and desipramine were determined every week both in the plasma and blood cells. The concentration of imipramine and desipramine was lower during treatment with imipramine‐N‐oxide than during treatment with the same dose of imipramine in samples taken 12 hrs after the last dose. In spite of the low concentrations a good clinical effect was noted in the patients investigated. There is a possibility of extensive intracellular formation of imipramine as indicated by the high content of imipramine in the blood cells during the first hours after the administration of imipramine‐N‐oxide.
Effect of Methotrexate on Folate Binding to a Folate Binding Protein in Cow's Milk
Authors: Holm Jan , Hansen Steen Ingemann , Lyngbye Jørgen
Published: July 2010

Abstract Folate in cow's milk was strongly bound to a minor whey protein. Methotrexate inhibited the folate binding in a log dosis dependent manner, but was a rather weak inhibitor. The binding mechanism of folate changed from a cooperative to a non‐cooperative type in the presence of methotrexate. This model system could be used in investigations on human body fluids and tissues.
Studies on the Duration of Local Anaesthesia: A Possible Mechanism for the Prolonging Effect of Dextran on the Duration of Infiltration Anaesthesia
Authors: Åberg G. , Friberger P. , Sydnes G.
Published: July 2010

AbstractThe mechanism of the prolonged effect of dextran on the duration of local anaesthesia has been studied. Using radio‐active mepivacaine it was found that dextran prolonged the duration of infiltration anaesthesia in guinea‐pigs by delaying the absorption of the local anaesthetic agent. Experimentsin vitroindicate that molecular complexes between the local anaesthetic and dextran may be formed and it is assumed that the delayed absorption might be due to the formation of such molecular complexes. This hypothesis was strengthened by experiments in which dental infiltration anaesthesias were performed in healthy volunteers.
Cadmium Feeding: Apparent Depression of Atrioventricular‐His‐Purkinje Conduction System
Authors: Kopp Stephen J. , Hawley P. L.
Published: July 2010

AbstractMale rats were exposed to 0,10 and 130 p.p.m. cadmium administered in 0.5% saline drinking water for 71 days. Biweekly records of ECGs, Hct, body weight and blood levels of cadmium were made. Rats exposed to 130 p.p.m. cadmium showed slower growth rates and declining Hct indicative of acute cadmium poisoning. At the end of the experimental period, carotid artery blood pressures and whole heart cadmium levels were determined. Although no significant blood pressure changes were observed in the experimental groups, the cadmium content of the hearts of the higher dose group was significantly higher than in the hearts of the lower dose group. The PR interval of the ECG was lengthened progressively and to the same extent in both experimental groups with continued cadmium feeding. These experiments offer evidence that the accumulation of even moderate amounts of cadmium will be manifested in marked changes in cardiac conduction without overt signs of cadmium poisoning.
Cardio‐Respiratory Toxicity of Propoxyphene and Norpropoxyphene in Conscious Rabbits*
Authors: Lund‐Jacobsen Henrik
Published: July 2010

AbstractThe toxic effects of α‐d‐propoxyphene (P) and its primary metabolite α‐d‐norpropoxyphene (NP) were compared by intravenous infusions (100 min.) of equimolar doses of P and NP (80 μmol/kg equivalent to 30 mg/kg P HCl) in conscious rabbits. During P infusion severe respiratory depression and convulsions were seen in all the animals, and six of the nine animals died. During NP infusion, however, only minimal respiratory depression was seen and all the animals survived. Considerable prolongation of the QRS complex and cardiac arrhythmias like intermittent A‐V block and ventricular extrasystoles were seen in the ECG during both P and NP infusion, while the arterial blood pressure was unchanged. In P injection experiments (6 mg/kg P HC1), ECG changes preceded reduction in respiratory rate and during NP infusion only minor changes were seen in arterial blood gases, demonstrating that the ECG changes produced by P and NP are independent of respiratory depression. The ECG changes were found to be similar to those reported in quinidine intoxication. The QRS prolongation was markedly correlated with plasma concentrations during and after P and NP infusions. The results of the present investigation favour the hypothesis that the contribution of NP to the toxicity of oral P overdosage in man is ascribed to its cardiotoxic action whereas P is responsible for the CNS toxicity (respiratory depression and convulsions) as well as cardiotoxicity.
Neuroleptic Blockade of the Effect of Various Neurotransmitter Substances
Authors: Fjalland Bjarne , Boeck Vita
Published: July 2010

AbstractThe antagonistic effect of neuroleptics to acetylcholine, histamine, 5‐HT, and noradrenaline was examined in variousin vivoandin vitromodels. Piflutixol, a new potent thioxanthene neuroleptic, markedly antagonizes the effect of dopamine, noradrenaline, 5‐HT and to some extent histamine, whereas the affinity for muscarinic receptors was rather weak. Clozapine and chlorprothixene on the other hand, have high affinity for muscarinic receptors and also antagonize the effect of histamine and 5‐HT, whereas clozapine was a weak antagonist of noradrenaline and dopamine when compared to the effect of piflutixol. Chlorprothixene, however, also exhibits a rather good antagonism of noradrenaline and dopamine. Haloperidol proved to be weak in all models when compared with the other neuroleptics examined. Flupenthixol specifically antagonizes dopamine and noradrenaline, whereas fluphenazine was a more potent antagonist of dopamine than of the other transmitters. The data show, that neuroleptic compounds possess very different profiles with regard to interaction with various neurotransmitter substances. It is suggested, that the rather potent anti 5‐HT and antihistamine effects observed for certain substances may contribute to the central effect of these drugs.
A Pharmacokinetic Evaluation of Free and DNA‐Complexed Adriamycin: A Preliminary Study in Children with Malignant Disease
Authors: Kummen M. , Lie K. K. , Lie S. O.
Published: July 2010

AbstractThe pharmacokinetics of adriamycin given as free and in DNA‐complexed form was compared in six children with malignant disease. The two types of adriamycin were given to the same child at 3–4‐week intervals, thereby excluding genetic variations when comparing the results. Plasma and urine were collected during and after the drug infusion, and the drug concentrations were measured by means of a sensitive fluorimetric procedure. The study shows that one obtains: 1. a much higher plasma concentration of adriamycin when it is given in the complexed form. 2. a lower urine excretion of adriamycin and fluorescent metabolites when adriamycin is administered as the DNA‐complex.
Treatment of Methyl Mercury Poisoning in Mice with 2,3‐Dimercaptosuccinic Acid and other Complexing Thiols
Authors: Aaseth Jan , Friedheim Ernst A. H.
Published: July 2010

Abstract Treatment with 2,3‐dimercaptosuccinic acid was more effective than N‐acetyl‐DL‐penicillamine and monomercaptosuccinic acid in mobilizing mercury from mice after the injection of methyl mercuric chloride. Dimercaptosuccinic acid treatment started 4 days after the mercury injection and given for 8 days at a dose of 1 mmol SH/kg per day removed more than 2/3 of the mercury in the brain, while acetylpenicillamine and mercaptosuccinate correspondingly removed less than 1/2 of the brain deposits. Neither treatment with 2,3‐dimercaptopropano‐1‐sulphonate nor with a new thiolated resin, mercaptostarch, mobilized significant amounts of mercury from the brain. Since the toxicity of dimercaptosuccinate seems to be almost as low as that of D‐penicillamine this dithiol may provide a potentially useful agent in clinical poisoning due to methyl mercury.
Effects of Pure Chlorobiphenyls (2,4′,5‐Trichlorobiphenyl and 2,2′,4,4′,5,5′‐Hexachlorobiphenyl) on the Reproductive Capacity in Female Mice
Authors: örberg Jan
Published: July 2010

AbstractThe effects of two pure chlorobiphenyls (2,4′,5‐trichlorobiphenyl and 2,2′,4,4′,5,5′‐hexachlorobiphenyl) on the reproductive capacity in female mice have been studied. The results obtained show that females given 0.5 mg 2,4′,5‐trichlorobiphenyl (TCB)/day or 0.5 mg 2,2′,4,4′,5,5′‐hexachlorobiphenyl (HCB)/day for six consecutive days, starting on the first day of pregnancy, have significantly lower frequencies of implanted ova than the control females, whereas the frequency of implanted ova does not differ either between females given 0.05 mg/day of TCB or HCB and the control females, or between females given TCB 0.05 mg/day or 0.5 mg/day and those given the corresponding dose of HCB. Females given 0.5 mg/day of TCB or HCB, respectively, also have significantly higher contents in the livers of cytochrome P‐450, on Day four of pregnancy, than the control females. The results also show that, under the experimental conditions used, neither the frequency of pregnancies nor the number of implanted ova per pregnant female differ significantly between the different groups.
Unaltered Metabolism of Phenytoin in Thyroid Disorders
Authors: Hansen Jens Melholm , Skovsted Lis , Kampmann Jens P. , Lumholtz Bo I. , Siersbæk‐Nielsen Kaj
Published: July 2010

AbstractThe metabolism of phenytoin was studied in 9 hyperthyroid and 7 hypothyroid patients before and after treatment with either antithyroid drugs or 1‐thyroxine. No difference in the half‐life, volume of distribution and metabolic clearance rate was found between untreated hyper‐ and hypothyroid subjects. Furthermore, normalisation of thyroid function test did not change the kinetic parameters of phenytoin. The results indicate that the well‐known correlation between thyroid function and antipyrine kinetics cannot be extrapolated uncritically to other drugs. It is concluded that no general rules are valid in the kinetics among different drugs in thyroid pathological conditions. Each drug must be evaluated by itself in different pathological conditions.
Inhibitory Effects of Imidazolines on Histamine Liberation from Human Leukocytes and on Tracheal Smooth Muscle Tone
Authors: Andersson Rolf G. G. , Lindgren Björn R. , Colldahl Helge
Published: July 2010

AbstractAntigen‐induced IgE‐mediated release of histamine from human leukocytes, anin vitromodel of allergic reactions, was blocked by imidazole and imidazole‐compounds such as oxymetazoline and clonidine. The H‐2‐antihistamines antagonized this effect of imidazolines. Alpha‐ and H‐1‐receptor blocking agents did not antagonize the effect. The contractile effects of the imidazolines were tested on tracheal preparations from the cow and guinea‐pig. Imidazole was found to be a rather potent contracting agent, while oxymetazoline only caused weak contractions. Clonidine relaxed the tracheal muscles, when used in the concentration range which were inhibitory in the leukocyte experiments. The contractions caused by imidazolines were non‐competitively inhibited by clemastine, while the relaxing effects were blocked by a combination of propranolol, phentolamine and cimethidine. The results suggest that imidazolines which inhibit histamine release and relax bronchial smooth muscles may be of therapeutic importance in the treatment of human allergic disorders.
Reduced Myocardial Blood Flow in Acute and Chronic Digitalization
Authors: Steiness Eva , Bille‐Brahe Niels Erik , Hansen Jørgen Fisher , Lomholt Niels , Ring‐Larsen Helmer
Published: July 2010

AbstractThe myocardial blood flow was measured by the133Xenon disappearance curve from the left ventricular wall following an injection of133Xenon in the left coronary artery in 8 dogs without digoxin pretreatment and in 8 chronically digitalized dogs. The myocardial blood flow was significantly less (30%) in the digitalized dogs than in the dogs without pretreatment. In the digitalized dogs as well as in those without pretreatment an intravenous injection of digoxin resulted in a further significant decrease of the myocardial blood flow of about 20% and a significant increase of the coronary vascular resistance. The reduced myocardial blood flow both during acute and chronic digitalization is believed to be of clinical importance.
The Effects of Aromatic Amino Acid Decarboxylase Inhibitors on Plasma Concentrations of 5‐Hydroxytryptophan in Man
Authors: Magnussen I. , Engbæk F.
Published: July 2010

Abstract5‐Hydroxytryptophan has been found to be beneficial when administered alone or in combination with extracerebral aromatic amino acid decarboxylase inhibitors for therapeutic purposes in various disorders in which myoclonus is prominent. In five subjects the effect of decarboxylase inhibitors on the accumulation and elimination of 5‐hydroxytryptophan in plasma was studied. The plasma concentrations of 5‐hydroxytryptophan were increased about ten fold by pretreatment with the decarboxylase inhibitors, carbidopa and benserazide. Half‐lives of 2.2‐3.0 hrs. were obtained following oral administration of a single dose of 5‐hydroxytryptophan with or without pretreatment. In one subject the half‐life of 5 hydroxytryptophan in plasma increased to 5.5 hrs. during long‐term treatment with carbidopa.
Disposition and Oxidative Metabolism of Antipyrine in the Rat
Authors: Aarbakke Jarle
Published: July 2010

AbstractThe main routes of excretion of antipyrine‐N‐methyl‐14C and the role of oxidation in the metabolism of antipyrine were studied in the rat. After an intraperitoneal dose of 15 mg/kg14C‐antipyrine (1.0‐1.5 uCi14C), 74.2% of the radioactivity was found in the urine, 2.5% appeared in the faeces and 2.6% was recovered from expired CO2after 48 hrs. Most of the radioactivity (98%) was excreted during the first 24‐hrs. The cumulative excretion of radioactivity in the bile amounted to 18% of the dose in 24 hrs. Only 1‐2% of the radio activity in the urine represented unchanged antipyrine. Antipyrine was extensively metabolized by oxidation followed by conjugation. In urine 3‐CH2OH‐antipyrine and 4‐OH‐antipyrine (unconjugated and conjugated) accounted for 35 and 18% of the radioactivity, respectively. 3‐carboxy antipyrine represented 17% of the radioactivity. The corresponding figures for bile were 51,19 and 9%. In addition, the non‐radioactive N‐demethylated metabolite, nor‐antipyrine, was found. The quantitation of N‐demethylation based on radioactivity recovered from expired CO2suggested that at least 2.6% of antipyrine was metabolized by this pathway. The results show that antipyrine was extensively oxidized in the rat. Thus, in this species, antipyrine meets a fundamental requirement of a model compound for the study of factors influencing drug oxidationin vivo.
A Study on the Fate of Curcumin in the Rat
Authors: Wahlström Bo , Blennow G.
Published: July 2010

Abstract The uptake, distribution and excretion of curcumin in Sprague‐Dawley rats has been studied. When administered orally in a dose of 1 g/kg, curcumin was excreted in the faeces to about 75%, while negligible amounts of curcumin appeared in the urine. Measurements of blood plasma levels and biliary excretion showed that curcumin was poorly absorbed from the gut. No apparent toxic effects were seen after doses of up to 5 g/kg. When intravenously injected or when added to the perfusate of the isolated liver, curcumin was actively transported into bile, against concentration gradients of several hundred times. The major part of the drug was however metabolized. In suspensions of isolated hepatocytes or liver microsomes 90% of the added curcumin was metabolized within 30 min. In view of the poor absorption, rapid metabolism and excretion of curcumin, it is unlikely that substantial concentrations of curcumin occur in the body after ingestion.
A Fine Structural Study of Liver (Littoral) Cells of Methylmercury Fed Japanese Quail (Coturnix coturnix japonica)
Authors: Gullvåg B. M. , Aagdal J.P. , Eskeland B.
Published: July 2010

Abstract Tissues of Japanese quails were subjected to electron microscopical study. The birds had received 0–8 ppm methylmercury added to their diets for 6 weeks. The ultrastructural changes in the littoral cells of the liver were swollen mitochondria, with dilatation of the endoplasmic reticulum, loss of ribosomes from the rough endoplasmic reticulum and an increase in the number of vesicles in the cytoplasm. The nuclear membrane in some littoral cells became dilated, and the nuclear chromatin was condensed. The physiological effect of the destruction of the littoral cells is discussed.
Choline Acetyltransferase Activity in Postganglionic Parasympathetic Nerves after “Pharmacological Decentralization”
Authors: Ekström Jörgen , Lindmark Bertil
Published: July 2010

AbstractThe ganglion blocking drug chlorisondamine given frequently and in gradually increasing doses over a period of time to adult rats causes the activity of choline acetyltransferase to fall in the postganglionic parasympathetic nerves of parotid glands. Such a “pharmacologically” decentralized gland was also found to have lost weight and to have developed a supersensitivity to chemical stimuli. All these phenomena are thought to be consequences of loss or reduction of secretory impulses from the central nervous system due to impaired ganglionic transmission.
Effects of Extracellular Calcium on Potassium and Noradrenaline Induced Contractions in the Aorta of Spontaneously Hypertensive Rats – Increased Sensitivity to Nifedipine
Authors: Pedersen O. Lederballe , Mikkelsen E. , Andersson K.‐E.
Published: July 2010

AbstractIsolated preparations of the thoracic aorta from spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR) were contracted by noradrenaline (NA) 1.8 × 10‐5M, and potassium (K+) 127 mM, after 30 min. pretreatment in a Ca++‐free medium. In both SHR and NWR aortae, the contractions were markedly reduced; no significant differences were found between the two types of vessels in Ca++‐free medium. On addition of Ca++, the contractions were restored to a significantly greater extent in the NWR than in the SHR aortae. In the presence of nifedipine 7.2 × 10‐9M, the response to Ca++was significantly more reduced in the SHR than in the NWR preparations. Relaxation of NA and K+contracted preparations was induced by wash‐out of the contractile agents, by addition of nifedipine 2.9 × 10‐8M, and by introduction of a Ca++‐free medium. After wash‐out of NA, relaxation was slower in SHR than in NWR vessels. Relaxation induced by nifedipine and Ca++‐free medium was more complete in SHR than in NWR preparations. After wash‐out of K+, relaxation was more rapid in NWR than in SHR aortae. Nifedipine and Ca++‐free medium induced relaxation was more complete in SHR than in NWR preparations. The results suggest that in the SHR aortae contraction induced by NA and K+is more dependent on extracellular Ca++than is the response in the NWR preparations; the SHR vessels are also more sensitive to the relaxing effects of nifedipine.
Is Moderate Ethanol Consumption Teratogenic in the Rat?
Authors: Øisund Jan Fredrik , Fjorden Ann‐Elin , Mørland Jørg
Published: July 2010

AbstractFemale Wistar rats were given ethanol in their drinking fluid to cover 20–25% of the total calories consumed for 3–4 weeks prior to, during and also after pregnancy in some experiments. Soya oil was substituted for ethanol isocalorically in the control groups.

Apart from a statistically significant reduction in litter size based on the number of apparent normal foetuses at intrauterine examination, no significant changes in reproductive performance could be recorded after ethanol treatment. In the offspring, examined up to 24 days of age, the body and some viscera weights were statistically significantly higher at some stages from 2 to 14 days. The general trend, however, showed that there were no significant differences in body, brain, liver, kidney, and heart muscle weights between control and ethanol offspring measured in rats between 0 and 24 days of age. Two gross malformations were recorded among 321 pups of ethanol treated mothers, whereas no malformations were found in 444 control pups. It was concluded that moderate ethanol consumption by rat mothers for 3–4 weeks before and during pregnancy as well as during the suckling period, had no serious effects on their reproductive performance and the development of their offspring measured by the parameters used in the present investigation.
Dextran Induced Hypoalbuminaemia as a Model for the Study of Influences of Protein Binding on the Pharmacokinetics of Drugs
Authors: Ladefoged Ole
Published: July 2010

Abstract A model for examination of the effect of hypoalbuminaemia on drug pharmacokinetics in laboratory animal is described. The model has been used to investigate the effect of protein binding on the kinetics of sulphadimethoxine in rabbits. A greater volume of distribution of sulphadimethoxine is shown in the dextran induced hypoalbuminaemic rabbits in comparison with control animals. It is concluded that the suggested model is convenient for investigation of the influences of protein binding on drug pharmacokinetics.
Percutaneous Toxicity of Hexachlorobutadiene
Authors: Duprat P. , Gradiski D.
Published: July 2010

AbstractRabbits have been epicutaneously exposed to pure hexachlorobutadiene (0.25; 0.50; 0.75 and 1.00 ml/kg) during 8 hrs. This solvent was completely absorbed; some animals died within 24 hrs and others a few days later. The LD50 is 0.72 ml/kg (Bliss' method). Hexachlorobutadiene inducedin situcutaneous necrosis and its absorption induced systemic damage (fatty liver degeneration and epithelial necrotizing nephritis). These lesions are reversible. The present results confirm the toxicological profile of this solvent, previously established by the intraperitoneal and oral routes: hexachlorobutadiene is the most nephrotoxic aliphatic chlorinated hydrocarbon.
The Copper Induced Modification of Duodenal Biotransformation Reactions in Rats During Fat Deficiency
Authors: Laitinen Matti , Hietanen Eino
Published: July 2010

AbstractThe effect of ingested copper on the composition of duodenal postmitochondrial supernatnat fraction (PMS), the aryl hydrocarbon hydroxylase (AHH) and UDPglucuronosyltransferase (GT) activities was analyzed in rats given normal or fat free diets. There were only minor changes in the composition of PMS or in the activities of the measured enzymes when rats received a normal diet. During fat deficiency the phospholipid‐protein ratio and the GT activity were markedly increased following 10 mM copper concentration in the drinking water. It is concluded that during fat deficiency copper modifies the structure of the microsomes, as analyzed in the PMS, and that this is reflected in the membrane bound GT activity.
The Uptake of 6‐Methoxy‐1,2,3,4‐Tetrahydro‐β‐carboline and its Effect on 5‐Hydroxytryptamine Uptake and Release in Blood Platelets
Authors: Airaksinen M. M. , Huang J‐T. , Ho B. T. , Taylor D. , Walker K.
Published: July 2010

AbstractThe uptake of 6‐methoxy‐1,2,3,4‐tetrahydro‐β‐carboline (6‐MeOTHBC, 5‐methoxytryptoline) by rabbit blood platelets was studied by using3H‐labelled compound. A high rate active uptake (Km 6.6 μM), which was inhibited by 5‐hydroxytryptamine (5‐HT) and cinnanserine, and a slow rate uptake, not inhibited by 5‐HT were observed. The intracellular distribution of3H‐6‐McOTHBC in platelets clearly differed from that of14C‐5‐HT. 6‐MeOTHBC also competitively inhibited the high‐rate active (but not the slow passive) uptake of14C‐5‐HT, being more active than 5‐HT itself. The spontaneous release of the newly taken‐up14C‐5‐HT from platelets was increased only with high concentrations of 6‐MeOTHBC.
Effects of Detergent Formula Chelating Agents on the Metabolism and Toxicity of Cadmium in Mice
Authors: Engström Birgitta , Nordberg Gunnar F.
Published: July 2010

Abstract Chelating agents like NTA (nitrilotriacetic acid) STPP (sodiumtripolyphosphate, Na5P3O10) and EDTA (ethylenediaminetetraacetic acid) are used as components of detergents. An increased toxicity of some metal compounds when combined with NTA has led to decreased use of this chelating agent in relation to STPP. In the present studies short‐term and long‐term effects of these chelating agents on cadmium toxicity in mice were investigated. I: In the short‐term study, mice subcutaneously exposed to CdCl2 (3.2 mg Cd/kg b.wt.) in combination with STPP (32 mg/kg b.wt.) demonstrated a markedly higher mortality compared to animals given CdCl2 alone. This increase in mortality was similar to the one encountered when CdCl2 (3.2 mg Cd/kg b.wt.) and NTA (32 mg/kg b.wt.) were combined. Animals exposed subcutaneously to CdCl2 + STPP or CdCl2 + NTA showed histological evidence of liver necrosis 24 hrs after exposure not seen in animals given the same dose of CdCl2 alone and also had markedly lower cadmium concentrations in the livers compared to only Cd‐exposed animals. II: In the long‐term study, mice were exposed orally to CdSO4 (50 p.p.m. Cd) alone or in combination with STPP (500 p.p.m.), NTA (500 p.p.m.) or EDTA (50 p.p.m.) by continuous administration via the drinking water for 18 months. A decreased total excretion of urine proteins was seen in all Cd‐ treated animals irrespectively of the combination with various chelating agents. The conclusion of the present work was that NTA and STPP given by subcutaneous injection to mice markedly increased the toxicity of cadmium but that neither NTA, STPP nor EDTA given orally altered the toxicity of cadmium during a period of long‐term exposure of 18 months.
Contractile Effects of Prostaglandin F2αon Isolated Human Peripheral Arteries and Veins
Authors: Mikkelsen E. , Andersson K.‐E.
Published: July 2010

AbstractThe effects of prostaglandin F2α(PGF2α, 2.8 × 10‐7‐2.8 × 10‐5M) on isolated segments of human peripheral arteries and veins were investigated. In both types of vessel, PGF2αhad a concentration‐dependent contracting effect. The contraction developed more slowly and had a longer relaxation time after washing than responses induced by noradrenaline or potassium. In the veins, the maximum response to the prostaglandin was 128 ± 3.6% of that to potassium (P<0.01); in the arteries, the maximum amplitudes of PGF2αand potassium induced contractions were of similar magnitude. The arterial preparations were less responsive to PGF2αthan to noradrenaline. On a molar basis, noradrenaline was approximately 10 times more potent than PGF2α. Veins, maximally contracted by noradrenaline or potassium, increased their tension further on addition of PGF2α. Similarly, preparations maximally contracted by PGF2αalso showed a further increase in tension after addition of noradrenaline or potassium. The PGF2αinduced contractions were not affected by α‐adrenoceptor blockade (phentolamine, prazosin). The calcium antagonists verapamil and nifedipine relaxed preparations contracted by PGF2αand reduced the responses in a concentration‐dependent way when added 15 min. before the prostaglandin. Immersion for 30 min. in a calcium‐free medium, reduced the PGF2αinduced response in both arteries and veins. In the veins, but not in the arteries, the responses to potassium and noradrenaline were more reduced than that to PGF2α(P < 0.01). Contractions induced by all agents were further depressed by verapamil and nifedipine after exposing the preparations to the calcium‐free medium. It is suggested that PGF2αinduces contraction both by enhancing the transmembrane flow of calcium, and by facilitating release of calcium from intracellular stores.
Cholinergic Innervation of the Human Urethra and Urinary Bladder: A histochemical study and review of methodology.
Authors: Alm Per
Published: July 2010

AbstractThe present work gives a survey of the various methods for the histochemical demonstration of cholinergic nervous structures. The theoretical background and the specificity and sensitivity of the various methods are compared. It is concluded that the histochemical localization of the cholinergic transmitter metabolizing enzyme acetylcholine esterase still probably is the best method, giving a fairly good reflection of the distribution of cholinergic nerves. In comparison with the Falck and Hillarp technique for the demonstration of adrenergic nerves this method is much less specific and sensitive. The present work describes a rich supply of cholinergic nerves in the human urethra and urinary bladder in comparison with the scanty adrenergic innervation. Various functional aspects of the cholinergic innervation are discussed.
Cholinergic Mechanisms in the Rat Detrusor Muscle
Authors: Elmér Mats
Published: July 2010

AbstractThe motor response of the urinary bladder to nerve stimulation is resistant to atropine, and it has been proposed that the nerves are non‐cholinergic, but are possibly purinergic. In this review evidence is presented suggesting a cholinergic transmission in the rat detrusor muscle, part of the receptors being inaccessible to atropine.

The rat bladder receives postganglionic cholinergic fibres not only from the pelvic but also from the hypogastric nerves, some fibres passing outside the pelvic ganglia and some relaying distal to them. There is a functional overlap between the right and the left pelvic nerve, but the contractile response to stimulation of the hypogastric nerves is added to the pelvic nerve response with no functional overlap or antagonism.
Pilot Study on the Growth Inhibition by Estramustine Phosphate (Estracyt®) of Rat Mammary Tumours Sensitive and Insensitive to Oestrogen
Authors: Müntzing Jonas , Jensen Gunborg , Högberg Bertil
Published: July 2010

Abstract Rat mammary tumours induced by 7,12‐dimethylbenz(a)anthracene had a higher concentration of 3H and 14C than muscle after injection of estramustine phosphate labelled with 3H in the oestrogen moiety and 14C in the alkylating moiety. Thin‐layer chromatography showed that dephosphorylated estramustine phosphate was present in the tumours but no free oestradiol‐17β. The uptake of the drug in the tumours was parallelled by a dose dependant retardation of tumour growth and a prevention of tumour number increase. Estramustine phosphate also retarded growth of mammary tumours resistant to treatment with oestradiol‐17β. It is concluded that estramustine phosphate has a greater effect on tumour growth than oestrogen.
Effect of Food, Food Constituents and Fluid Volume on the Bioavailability of Sotalol
Authors: Kahela P. , Anttila M. , Tikkanen R. , Sundquist H.
Published: July 2010

AbstractThe effect of food, some food constituents, and large volumes of fluid taken with the drug on the relative bioavailability of sotalol has been examined in five healthy volunteers. Each subject received an oral 160 mg dose in six different experimental schedules. Venous blood samples were drawn 1, 2, 3, 4, 6 and 8 hrs after the dosing, and sotalol concentrations in serum were determined fluorometrically. The results indicate that large volumes of fluid delay but do not affect the extent of sotalol absorption. Food, especially milk, decreases the bioavailability of the drug and an interaction with calcium seems to be the major reason for the reduced absorption.
Kinetic Studies of Dose‐Dependent Metabolism of Alprenolol:In VitroandIn VivoStudies in Different Species
Authors: Skånberg Inger , Borg Karl Olof , Fellenius Erik , Hoffmann Kurt‐Jürgen , von Bahr Christer , Moldéus Peter
Published: July 2010

AbstractKinetic studies of the metabolism of alprenolol were performed with isolated microsomes from the rat, guinea‐pig, dog and man at an initial substrate concentration of 0.17‐150 μM. In all species the rate of aromatic hydroxylation reached a plateu above 50 μM of alprenolol in contrast to the rate of desisopropylation, where consistent saturation level was not obtained. The Km‐values for the aromatic hydroxylation in the guinea‐pig and man,2,7 μM and 1.3 μM respectively, showed no concentration dependency in contrast to the rat (Km1= 0.20 μM, Km2= 26 μM) and the dog (Km1= 0.78 μM, Km2= 66 μM). The apparent Km‐value of 0.20 μM for aromatic hydroxylation in the rat seemed to be of the same order of magnitude as reported spectral dissociation constant (Ks = 0.34 μM).In vivoexperiments in the rat by oral administration of 7‐700 μmol/kg demonstrated a dose‐dependent presystemic elimination of alprenolol. The urinary excretion of hydroxy‐alprenolol was significantly lower after the highest dose. It is proposed, that the saturation of the aromatic hydroxylation, catalyzed by a high affinity site or subspecies of cytochrome P‐450 with a low capacity. contributes to the dose‐dependent kineticsin vivo.
Renal, Biliary and Intestinal Clearance of a Quaternary Ammonium Compound, Emepronium in the Dog
Authors: Hallén B. , Sundwall A. , Elwin C. E. , Vessman J.
Published: July 2010

AbstractDifferent routes of elimination of emepronium have been quantitated in conscious and anaesthetized dogs. Smoothed plasma concentration time curves and urinary excretion data obtained following intravenous bolus injection of 5 mg/kg indicate at least four different phases with the following half‐lives: 5 min., I hour, 10 hours and 9 days. The initial dilution space, 0.2‐0.6 l/kg, is rather similar to the extracellular volume (0.20‐0.35 l/kg). From infusion experiments plasma clearance of emepronium have been found to be 33±2 ml. min‐1.kg‐1(meani ± S.E.M., n = 14). The drug is secreted by the renal tubules at a maximum rate of 20 μg/min. at a plasma concentration of about 200 μg/l. Compared with other quaternary ammonium compounds, this is an easily saturated mechanism with a low capacity. The renal clearance constitutes about 30 % of the plasma clearance at a plasma concentration of 200 μg/l. The biliary excretion rate increases proportionally to a plasma concentration up to 100 μg/l and then reaches a maximal rate which is dependent on the bile flow. The biliary clearance decreases from 7 to 2 ml.min.‐1.kg‐1when the bile flow changes from 7 to 4 g/ hour and the plasma concentration is 200 μg/l. Experiments with bile diversion and saline perfusion of isolated intestinal segments reveal an intestinal route of elimination of both emepronium and metabolites. The bile diversion experiments indicate that about 5‐15% of an intravenous dose is excreted through the gastrointestinal epithelium. Perfusion of isolated intestinal loops indicates an apparent clearance of 4‐5 ml. min‐1.m‐1over a wide range of steady state plasma concentrations (20‐1200 μ/l). An apparent total intestinal clearance could be calculated to about 7 ml. min.‐1.kg‐1. The remaining part of the plasma clearance (about 8 ml. min.‐1. kg‐1in an anaesthetized dog) is accounted for by metabolism. The degree of protein binding has been shown to be low, about 20 per cent, and the red blood cell penetrationin vitrois only 1‐10% of the total amount present in whole blood.
Calcium, Nifedipine and Arrhythmias in Isolated Rat Atria
Authors: Refsum Helge , Landmark Knud , Bjerve Kristian S.
Published: July 2010

AbstractArrhythmias were induced in isolated rat atrial muscle preparations by increasing the calcium concentration of the Ringer solution, while the potassium concentration was kept low. A rise in the resting tension occurred simultaneously. The release of aspartate aminotransferase (ASAT) from the fibrillating atria was not higher than the release from non‐fibrillating atria pretreated with a calcium‐antagonistic drug, nifedipine 100 μg/l. It is suggested that calcium‐induced rat atrial arrhythmias in the present experiments are caused by a direct effect on calcium influx through the excitable membrane and not as a result of myocardial lesion caused by calcium overload.
Haemodynamic Effects of the Quaternary Ammonium Compound QX 572 in Anaesthetized Cats. II. Studies on the Mechanism for the Cardiac Chronotropic Effects
Authors: Åberg G. , Kopp U.
Published: July 2010

Abstract The antiarrhythmic compound, QX 572, has been shown to increase heart rate both in patients and experimental animals. In anaesthetized cats the positive cardiac chronotropic effects were mainly due to increased sympathetic activity. The present experiments were designed to localize the active sites within the sympathetic nerve system. It was found that QX 572 caused an increased heart rate in response to electrical stimulation of the cardiac sympathetic nerves, but this was not due to effects on the CNS, the sympathetic ganglia or the cardiac adrenergic beta‐receptors. It is concluded that QX 572 by some action increased the amount of noradrenaline released from the cardiac sympathetic nerve endings. The mechanism for this effect has not been clarified.
Physicochemical Modification of Lidocaine Uptake in Rat Lung Tissue
Authors: Post By C. , Andersson R. C. C. , Ryrfeldt Å. , Nilsson E.
Published: July 2010

AbstractThe uptake of lidocaine, methyllidocaine, bupivacaine, etidocaine was studied in rat lung slices at different pH‐values. The accumulation of the quaternary analogue, methyllidocaine, was not changed in the pH interval 7.0‐8.0. The uptake of the three other substances was about 3‐4 times lower at pH 7.0 than at pH 8.0. The rank order of distribution at a fixed catiodbase ratio was bupivacaine>etidocaine>lidocaine. Interactions between lidocaine and other substances were studied in lung slices and in isolated perfused lungs. Bupivacaine and nortriptyline counteracted the accumulation of14C‐lidocaine in lung slices in a dose‐dependent manner. Nortriptyline was more effective than bupivacaine. In isolated perfused lung, bolus injections of nortriptyline and lidocaine rapidly displaced14C‐lidocaine from the tissue. In this study we suggest that the base form of local anaesthetics accumulate in the lung tissue, while the cationic form binds to accessible binding sites in the cell membranes.
Beta‐adrenoceptors in the Pregnant and Non‐pregnant Myometrium of the Goat and Cow
Authors: Larsen Jens‐Jørgen
Published: July 2010

AbstractThe muscle relaxing effect of beta‐adrenoceptor agonists was examined without and with the presence of beta‐adrenoceptor antagonists in strips from the pregnant and non‐pregnant myometrium of the goat and from the pregnant myometrium of the cow. Isoprenaline, salbutamol and ritodrine caused a dose‐dependent reduction of the spontaneous contractions of the pregnant myometrium and a dose‐releated and parallel shift to the right of the isoprenaline dose‐response curve was obtained with butoxamine but not with practolol. Isoprenaline but neither salbutamol nor ritodrine caused a dose‐related reduction of the spontaneous contractions in the non‐pregnant myometrium and a dose‐related and parallel shift to the right of the dose‐response curve of isoprenaline was brought about with propranolol but not with either butoxamine or practolol. The muscle relaxing effect of ritodrine on the pregnant myometriurn of the goat and cow shownin vitrowas also demonstratedin vivoin the same species within eight hours of delivery. It is concluded that the beta‐adrenoceptors in the pregnant myometriurn of the goat and cow belong to the beta2‐group whereas those in the non‐pregnant myometriurn cannot be classified as either beta1‐ or beta2‐adrenoceptors.