bluuebunny/crossref_metadata_2025 huggingface dataset:
Binding of β‐Carbolines and Tetrahydroisoquinolines by Opiate Receptors of the δ‐Type
Authors: Airaksinen M. , Saano Veijo , Steidel Eeva , Juvonen Helena , Huhtikangas Aarre , Gynther Jukka
Published: July 2010

Abstract:Effects of various β‐carbolines (BC's) and two tetrahydroisoquinolines (TIQ's) on the specific binding of a natural opiate δ‐receptor ligand, leucine enkephalin, have been studied in rat synaptosomal membranes, and compared with the effects on the binding of mu‐receptor ligands dihydromorphine and naloxone. Harmaline (7‐MeO‐1‐Me‐dihydro‐BC) was the most potent compound studied (Ki value 3.5 μM), while the two TIQ's (salsolinol and salsolidine) were less potent than BC's (Ki> 100 μM) in inhibiting the binding of δ‐receptors. In general, BC's showed more affinity for δ‐receptors than for μ‐receptors; salsolinol was more potent against the binding of μ‐receptors. Inhibition of binding was generally of the competitive type: Kd values increased and Bmax values were not altered. The Na dependence suggests that BC's and salsolinol are antagonists or partial agonists of opioids. Since the binding affinity of BC's and TIQ's was on the micromolar level only, the opiate receptors do not appear to be the major sites of action for BC's or TIQ's.
Metabolism of Trimethoprim in Neonatal and Young Pigs: Comparativein Vivoandin VitroStudies
Authors: Gyrd‐Hansen N. , Friis C. , Nielsen P. , Rasmussen Folke
Published: July 2010

Abstract:Metabolism of trimethoprim (TMP) was investigated inin vivoandin vitroexperiments on 1 day (group A), 8 days (group B), and 60 days (group C) old piglets. In thein vivostudies piglets received an intravenous injection of14C‐trimethoprim. Urine was then collected for 3 hours after which the animals were killed. During the collection period 13, 24, and 40% of the dose was excreted in the urine in group A, B, and C, respectively. Trimethoprim and the following metabolites: Metabolite 1 and 4, minor metabolites, and conjugates were determined in plasma, liver, kidney, urine, and bile. The results show that newborn piglets have little capacity for oxidation of TMP while the ability to conjugate with glucuronic acid and sulfate seems somewhat higher. During the following 8 weeks a marked increase in the oxidative as well as conjugative potential took place. The microsomal fractions of liver and kidney were used for thein vitrometabolism studies of TMP. No metabolic activity could be demonstrated in the kidney preparations. Oxidative demethylation was just detectable in livers from the newborn piglets but increased considerably with age. Glucuronidation of metabolite 4 took place in the liver preparations from all three groups but at the highest rate in group C. The development in metabolic capacity was found to be qualitatively similarin vivoandin vitro.
Influence of Long‐term Zimeldine Treatment on LSD‐induced Behavioural Effects
Authors: Smith Lena A. C. , Meyerson Bengt J.
Published: July 2010

Abstract: The effect of lysergic acid diethylamide (LSD) on copulatory and exploratory behaviour in hormone‐treated, ovariectomized rats was investigated 4 weeks after chronic treatment with either saline or zimeldine (ZIM). A decrease in sensitivity to the lordosis‐inhibiting effect of LSD was observed in the group treated with ZIM. The two groups also differed in their reaction to LSD in the exploratory test. The ZIM‐treated animals seemed to be less sensitive to LSD. We therefore suggest that long‐term treatment with ZIM reduces the sensitivity of the postsynaptic serotonin receptor.
Nitroglycerin Tolerancein Vitro: Effect on cGMP Turnover in Vascular Smooth Muscle
Authors: Axelsson Krister L. , Karlsson Jan‐Olof G.
Published: July 2010

Abstract:Bovine mesenteric arteries (BMA) were made tolerant to nitroglycerin (GTN) by incubation with high concentrations of GTN at elevated pH. This treatment has previously been shown to reduce the relaxant and cGMP‐elevating action of a challenging dose of GTN. The stimulatory action of nitroprusside (NP) or GTN/cysteine on guanylate cyclase (GC) was reduced by 50–60% in GTN‐tolerant vessels as compared to control vessels. The stimulatory action of GTN and NP on GC has been suggested to occur through formation of S‐nitrosothiols, probably with a previous denitration step required for GTN. However, tolerance induction to GTN was not found to change the rate of nitrite formation from GTN, and exogenous addition of thiols in the GC assay, in order to increase S‐nitrosothiol formation, did not restore the GC activity in tolerant vessels back to control level. This is suggested to indicate a direct effect of GTN tolerance on GC. Since the cGMP‐phosphodiesterase activity was not affected in GTN‐tolerant vessels, the reduced GC activity may be of a crucial importance for the reduced cGMP response in GTN‐tolerant BMA as found earlier (Axelssonet al.1982).
Effect of Cadmium and Colcemide on the Mitoses of a Human Epithelial Cell Line with High Content of Cytoplasmic Metallothionein
Authors: Bakka Arnte , Digernes Vemund
Published: July 2010

Abstract: Cultures of cell strains with and without metallothionein were exposed to CdCl2 in doses ranging from 10 μmol to 200 μmol/1. Cell growth parameters were monitored by flow cytometric DNA‐measurements, cell counts and counting of mitoses during the first two days after exposure. CdCl2 inhibited cell growth in a dose dependent way. The cadmium resistant cells were inhibited with concentrations above 100 μmol/1, the concentration which the metallothionein‐containing cells had previously been adjusted to. Microscopy of the cell cultures showed a dose dependent accumulation of cells in the mitotic prophase, whereas the other phases of the cell cycle were unaffected as measured by flow cytometry. When exposed to colcemide, however, the two cell strains showed identical responsiveness.
Aspects on pharmacokinetics of some diuretics
Authors: Beermann Björn
Published: July 2010

Abstract:This review summarizes the present knowledge of some commonly used diuretics.

Bendroflumethiazide and bumetanide are completely absorbed from the gut while the uptake of hydrochlorothiazide, chlorthalidone and furosemide averages about 65%. The degree of uptake of amiloride and spironolactone is unknown but exceeds 50%.

Plasma t 1/2 of bumetanide and furosemide are approximately 1 h. The clinically important phase of the plasma concentration of bendroflumethiazide has a t 1/2 of 3 h, although a slower phase with a t 1/2 of 9 h has been described. Hydrochlorothiazide and amiloride, often used in combination, both have a t 1/2 of about 10 h. Canrenone, an active metabolite of spironolactone, has a t 1/2 of 15–20 h. Chlorthalidone is eliminated very slowly with a t 1/2 of about two days. This is partly caused by an extensive binding to carbonic anhydrase in the erythrocytes.

The protein binding of bendroflumethiazide, bumetanide, canrenone and furosemide is approximately 95%. The binding of chlorthalidone and hydrochlorothiazide is about 75 and 40% respectively.

All mentioned diuretics except spironolactone are in part eliminated renally, mainly via tubular secretion. This is the major elimination route for amiloride and hydrochlorothiazide, while it constitutes one third to two thirds for bendroflumethiazide, bumetanide and furosemide. Spironolactone is exclusively eliminated as metabolites.
Hypokalemia in cardiac decompensation
Authors: Johansson Bengt W.
Published: July 2010

Abstract: The problem of hypokalemia in cardiac decompensation is reviewed. Some methodological sources of error in connection with blood sampling is discussed, as is the definition of hypokalemia. “Hypokalemia” may be present with a serum potassium value within the reference range of 3.5–5.0 mmol/l. Although diuretics are the most common cause of hypokalemia in patients with cardiac decompensation, there are other factors at work. One is an increase of the plasma aldosterone concentration and another the increased sympathetic nervous activity–adrenaline administration reduces the plasma potassium concentration. The clinical importance of hypokalemia, especially for cardiac arrhythmias, is discussed.
The Biological Relevance of the Protein Binding of Diazoxide
Authors: Andreasen F. , Bøtker H. E. , Christensen J. H. , Østergaard J. R.
Published: July 2010

Abstract:The biological importance of the binding of diazoxide to serum protein was studiedin vitro.Contractions in the rings of the rabbit pulmonary artery evoked by electrical field stimulation or exogenous noradrenaline (NA) were studied in the absence and presence of serum albumin (45 g/1) in Krebs–Henseleit (K–H) solutions. Diazoxide concentrations up to 128 μg/ml in the K–H solution and to 256 μg/ml in albumin K–H solutions diminished the contractions and albumin reduced this diminishing effect. Because of an apparent binding of exogenous noradrenaline to albumin only the experiments with electrical field stimulation were used to assess the biological importance of the protein binding of diazoxide. At 2 μg/ml of diazoxide the free drug fraction determined by ultrafiltration was 5% but determined by our biological method the free (active) fraction was 65%. In accordance with a previous clinical study we conclude that the binding of diazoxide to serum protein is important for the transportation of the drug to the arteriolar wall which apparently has a much higher affinity for the drug than serum albumin
Effect of Glyceryltrinitrate and 8–Br–cGMP on Tension and PhosphorylaseaActivity in Vascular Smooth Muscle
Authors: Axelsson Krister L. , Karlsson Jan‐Olof G. , Pettersson Göran
Published: July 2010

Abstract:The aim of the present study was to examine the effect of glyceryltrinitrate (GTN) and 8–Br–cGMP on tension and cytosolic calcium concentration in pre–contracted bovine mesenteric arteries (BMA). The activity of glycogen phosphorylaseawas used as a measure of the cytosolic calcium concentration. The activity of this enzyme is regulated by the cytosolic calcium concentration and/or cAMP. Since the cAMP level was not found to be affected by GTN–treatment, the use of phosphorylaseaactivity to monitor changes in the cytosolic calcium concentration can be justified. The vessels were contracted with phenylephrine (10 μM) or 100 mM K+–depolarization, which caused an increase in phosphorylaseaactivity. Addition of 1 μM GTN to the phenylephrine–contracted vessels resulted in a 3–4–fold rise in intracellular cGMP level, which was accompanied by a large decrease in tension and phosphorylaseaactivity. The K+–depolarized vessels, on the other hand, were largely resistant to the relaxant action of GTN, and there was only a slight reduction of the phosphorylaseaactivity. In phenylephrine–contracted vessels, made tolerant to GTN by incubation at elevated pH in the presence of GTN (0.44 mM), no changes in tension and phosphorylaseaactivity were seen after stimulation with a test dose of GTN (1 μM). The cGMP response was also markedly blunted in the tolerant vessels. Relaxation of phenylephrine–contracted BMA induced by 8–Br–cGMP (0.5 mM) was also accompanied by a reduction in phosphorylaseaactivity. The close association between the relaxation of BMA and the reduction in phosphorylaseaactivity suggests that GTN and 8–Br–cGMP exert their effects mainly by reducing the cytosolic free calcium concentration although a contributing effect on the contractile apparatus can not be excluded
Ion Pair Formation and Gastrointestinal Absorption of Emepronium
Authors: Hallén Bengt , Sundwall Anders , Sandquist Sören
Published: July 2010

Abstract: Ion pair forming agents were evaluated in vitro for their ability to form lipophilic ion pairs with the quaternary ammonium compound emepronium and in vivo to enhance its gastrointestinal absorption. A 5–to 100–fold excess of trichloroacetate (TCA), diethylhexylphosphate (DEHPA), heptafluorobutyrate (HFBA), sodium lauryl sulphate (SLS), bromide or chloride all increased the extractability of the emepronium ion into methylene chloride. The additive with the most marked effect on the apparent partition coefficient of emepronium (Kapp) was SLS. At emepronium 10–4M, Kapp increased from a basal value of 0.1 to 368 with a 100–fold molar excess. However, the increased partitioning to methylene chloride was not reflected in an increased gastrointestinal absorption of the emepronium ion when this was given orally to mice. When intestinal juice, instead of distilled water or buffer, was used as the aqueous phase, the partition coefficient was markedly higher (Kapp∼2) but it was significantly less influenced by addition of sodium lauryl sulphate (Kapp∼6). The preexisting positive influence of the intestinal juice on the lipophilic character of emepronium and the rather limited additive effect of agents that form lipophilic complexes with emepronium, lead to the conclusion that the ion pair concept is not a suitable approach to enhance the gastrointestinal absorption of this drug
Localization of Oestradiol in the Rat Nasal Mucosa
Authors: Brittebo Eva B.
Published: July 2010

Abstract: The metabolism of 4–14C–oestradiol in the rodent respiratory tract has been investigated in vitro. Using thin–layer radiochromatography, at least 3 and 2 metabolites were found at incubation with slices from the rat olfactory mucosa and lung, respectively. Autoradiography of the nasal region of rats injected intravenously with 4–14C–oestradiol showed a high level of radioactivity in the mucosa covering the respiratory region, and in the subepithelial parts of the olfactory mucosa. Autoradiography of rat and mouse lung slices incubated with 4–14C–oestradiol showed that a selective localization of radioactivity occurred in the bronchial mucosa. The radioactivity in the mucosa of the respiratory tract was reversibly bound and could be extracted with organic solvents
Bioavailability of Indomethacin after Intramuscular Injection and Rectal Administration of Solution and Suppositories
Authors: Jensen K. Møiler , Grenabo L.
Published: July 2010

Abstract: The pharmacokinetics of indomethacin was studied after intravenous and intramuscular injection of 50 mg and administration of rectal solution and suppositories of 100 mg to 8 volunteers. Peak plasma concentrations of indomethacin occurred 20 min. after administration of the rectal solution (3.7 μg × ml–1), 40 min. after intramuscular injection (2.7 μg × ml–1), and 60 min. after suppositories (3.7 μ × ml–1). The bioavailability after the two rectal forms was found to be almost the same, about 80%. After intramuscular injection the bioavailability was calculated to be complete. These results suggest that indomethacin administered as a rectal solution or as intramuscular injection may be an alternative to intravenous administration when an early plasma peak of the drug is required
Respiratory Arrest as Main Determinant of Toxicity due to Overdose with Different β–Blockers in Rats
Authors: Langemeijer Johanna , de Wildt Dick , de Groot Gerard , Sangster Bart
Published: July 2010

Propranolol, timolol and sotalol were compared regarding their toxicological effects on the cardiovascular and respiratory system. Each drug was administered intravenously to anaesthetized spontaneously breathing and artificially ventilated rats. After the start of infusion in spontaneously breathing rats each drug induced an expected decrease in arterial blood pressure and heart rate. An increase in PQ, QRS and QT interval was observed. From 5/8 of the survival time onwards these changes were accentuated. PaO2, pH and respiratory rate decreased and PaCO2 increased. The rats died as a result of respiratory arrest. Artificial ventilation of rats infused with the same doses increased the survival time significantly. The total doses administered before the animals died as a result of cardiovascular failure were significantly higher for each drug. The initial decreases in arterial blood pressure and heart rate were similar to those in spontaneously breathing rats. Thereafter, significantly smaller decreases were observed. The increases in PQ, QRS and QT interval were significantly less than in spontaneously breathing rats. Blood gases remained unchanged except for a decrease in pH in case of timolol
Attempts to Antagonize the Effect of Histamine on the Cold–Stimulated Thyrotropin Secretion in Male Rats
Authors: Tuominen R. K.
Published: July 2010

Abstract:Histamine given directly into the 3rd ventricle inhibits the enhancement of thyrotropin secretion induced by cold–exposure (4°, 30 min.) in male rats. This effect was antagonized neither by mepyramine, a H1–receptor antagonist, nor by cimetidine, a H2–receptor antagonist. Histamine would not have an indirect mechanism of action through adrenergic α1– or α2–receptors in rat hypothalamus, since pretreatment with neither phenoxybenzamine nor yohimbine had any effect on histamine suppressed TSH cold–response. Further, it was also tested if histamine could decrease the TSH secretion through cholinergic–, GABA–, serotonergic– or dopaminergic receptors but no results supporting such a mechanism of action were obtained. The effect of histamine was not modified by pretreatment with naloxone or desipramine either. Imidazole acetic acid, IAA, a metabolite of histamine, had no effect on cold–induced TSH secretion. It is concluded that the effect of exogenous histamine on cold–stimulated TSH secretion is not mediated through H1– or H2–receptors. Histamine may decrease brain noradrenergic activity which is important in the generation of TSH cold–response. In addition, the effect of exogenous histamine might be due to decreased endogenous histaminergic activity in rat brain
Effects of Theophylline on Small Human Placental Arteries in Vitro
Authors: Nielsen‐Kudsk Jens Erik
Published: July 2010

Effects of theophylline on contractions induced by relevant physiological agents in tubular segments of small human placental arteries were measured in an isometric myograph. Theophylline 10−7‐ 3 × 10−3M caused marked relaxation of steady contractions produced by prostaglandin F2a (PGF2a), prostaglandin E2 (PGE2), vasopressin or potassium. EC50 for theophylline relaxation of the PGF2a ‐ contraction was 1.6 × 10−4 M. Emax was 91.5% relaxation. Theophylline was less potent in relaxing the potassium induced contraction. Pretreatment experiments with 10−4 and 10−3 M theophylline showed a pronounced decrease in contractile Emax‐values for PGF2a, PGE2 and vasopressin as a possible indication of non‐competitive antagonism. The results motivate further studies to elucidate possible effects of theophylline and other xanthines on the vascular resistance and blood flow in placenta.
Pitfalls in the Interpretation of Whole‐Body Autoradiograms: Long‐time Retention in Brain and Adrenal Cortex Caused by Metabolic Incorporation of 14C from Various Labelled Xenobiotics
Authors: Darnerud Per Ola , Brandt Ingvar
Published: July 2010

The long‐time retention of radioactivity in mice was studied by whole‐body autoradiography after administration of 1‐14C‐alkanes (C12 and C16), 1‐14C‐polychlorododecanes (56 and 68% Cl w/w), U‐14C‐polychlorohexadecane (23% Cl w/w), ethyl‐14C‐phenacetin and ring‐3H‐phenacetin. All the labelled xenobiotics, except the high‐chlorinated (68% Cl) polychloroalkane and the ring‐3H‐phenacetin, gave rise to longtime (12–60 days) retention of radioactivity in the central nervous system and in the adrenal cortex; the distribution of radioactivity within the brain corresponded to the stain intensity of myelin stained sections. Administration of 1‐14C‐fatty acids (C12 and C16) and 1‐14C‐acetylcoenzyme A gave a similar distribution pattern. The lipophilic radioactivity in brain and adrenal tissue was extracted and separated with thin‐layer chromatography. In the adrenal extracts, the label co‐chromatographed mainly with cholesteryl ester, and in the brain extracts with cholesterol and with more polar lipids (mainly phosphatidyl‐choline and ‐ethanola‐mine). The brain homogenate contained a non‐extracted, probably proteinaceous, residue, with comparably high radioactivity. The results show that several 14C‐labelled xenobiotics which give long time retention of radioactivity in the adrenal cortex and brain, are degraded to intermediates with the possibility to become incorporated into endogenous substances. The high‐chlorinated alkane (1) and ring‐3H‐phenacetin (2) did not give such long time retention due to its persistance towards degradation (1), and lack of labelling of the degradable part of the molecule (2). It is concluded that erroneous interpretations can be drawn from distribution studies if the routes of degradation and positions of label of the 14C‐labelled compounds are not considered.
Detection and Characterization of Four Binding Sites for Opioids in the Mouse Brain
Authors: Neil Anders
Published: July 2010

The binding sites labelled by3H‐dihydromorphine,3H‐ethylketocyclazocine and3H‐D‐Ala2‐L‐Leu5‐enkephalin in mouse brain membranes were characterized in cross‐competition studies. The data was evaluated by simultaneous non‐linear least‐squares regression analysis with the “Ligand” program (Munson & Rodbard 1980), that had to be upgraded to handle more than three binding sites. By statistical analysis four different binding sites were identified. Three of the sites probably correspond to the pharmacologically well characterized μ, ∂ and δ‐opioid receptors, respectively, and their binding capacities relate as 1:1.5:2.5. Classification of the fourth site is more problematic. Using3H‐ethylketocyclazocine it had higher capacity than the others and bound ethylketocyclazocine with a relatively high affinity (Kd= 10 nM), dihydromorphine with a very low affinity (Kd> 10−5M) and showed no binding of D‐Ala2‐L‐Leu5‐enkephalin. In displacement studies, N‐allylnorcyclazocine (SKF 10,047), though unselective, bound with highest affinity to the μ and the fourth site. Since naloxone did not bind to this fourth site, it can not be termed an opioid site in a strict sense, but it might have some relevance in view of non‐naloxone‐reversible effects reported for some opioids.
Hepatotoxicity of Hornet's Venom Sac Extract in Isolated Perfused Rat Liver
Authors: Neuman Manuela G. , Eshchar Jerachmiel , Cotariu Dita , Ben‐Sason Rivka , Ziv Ehud , Bar‐On Hanoch , Ishay Jacob S.
Published: July 2010

The changes in the activity of some enzymes in parenchymal liver cells were measured in the perfusate of rat isolated liver after a single envenomation with two different doses of Hornet's (Vespa orientalis) venom sac extract (VSE). The maximal observed enzymatic changes were significant: twenty four fold rise of alkaline phosphatase E.C.3.1.3.1(ALP), six fold rise of alanine aminotransferase E.C.2.6.1.2. (ALT) and nine fold rise of aspartate aminotransferase E.C.2.6.1.1. (AST) activity. There were moderate changes (four fold) in lactic dehydrogenase activity E.C.1.1.1.2.7. (LDH) and a non‐significant change in γ‐glutamyl‐transferase E.C.2.3.2.1. (GGT) activity. These changes varied with the venom's dose. Also a decrease in the rate of effluent draining outviathe hepatic vein was noted as an additional sign of liver damage. In light of the biochemical evidence presented here, as well as in previous work, it seems that no further biochemical proof is needed to establish the hepatotoxicity of VSE in rats, cats and probably humans too. It seems that VSE is a predictable hepatotoxin causing a pattern of enzyme changes of the cholangiocellular type.
Effects of Dinitrophenol on Phosphorylase a Activity, Adenine Nucleotide Levels and Tension in Rabbit Colon Smooth Muscle
Authors: Pettersson Göran
Published: July 2010

Glycogen Phosphorylase a activity, the contents of adenine nucleotides and isometric tension were measured in rabbit colon smooth muscle after exposure to 2,4‐dinitrophenol (DNP). DNP caused a dose‐dependent increase in phosphorylase a activity, with an ED50 value of 1 × 10−4M. Since adenine nucleotides, especially 5‐AMP by inhibiting the Phosphorylase a to b conversion, might increase the phosphorylase a activity, a time‐response study was undertaken in order to analyse the time course of changes in the adenine nucleotide content and phosphorylase a activity after addition of DNP. The latter activity was increased after only 1 min. of incubation. At this time no changes were found in the contents of ATP, ADP, 5‐AMP or CP. Not until the phosphorylase a activity had reached its maximum after 5–7.5 min. did the 5‐AMP content increase. The phosphorylase a activity then started to decline, but the 5‐AMP content continued to rise. The effect of DNP on isometric tension was also studied to test whether the cytoplasmic Ca2+ concentration was increased. An increase in tension was observed 5 min. after administration of the drug and was maximal at 15 min. The results seem to dispute against 5‐AMP as being a mediator for the DNP‐stimulated increased in phosphorylase a activity in smooth muscle. The finding that DNP elicited a contraction of rabbit colon supports the earlier suggestion that the cytoplasmic Ca2+ concentration was increased (Pettersson 1983).
Task‐Dependent Development of Cross‐Tolerance to Psychomotor Effects of Lorazepam in Man
Authors: Aranko Kari
Published: July 2010

Development of cross‐tolerance between lorazepam and four other benzodiazepines (BZ) was studied in two trials by measuring objective psychomotor performance and by subjective assessments. In trial I, nitrazepam 10 mg (NZ), temazepam 20 mg (TZ) or placebo were administered to 14 healthy students for 10 consecutive nights. After each pretreatment, psychomotor impairment by the challenge dose of lorazepam 3 mg (LZ) was measured. In trial II, responses to LZ after pretreatment with diazepam 5 mg (DZ) (8 subjects) or alprazolam 0.25 mg (AZ) (10 subjects), both t.i.d., were compared to LZ responses measured after one‐month wash‐out period. In trial I no cross‐tolerance between BZs was found in objective tests, and LZ induced exophoria was even increased. However, the subjects rated LZ to cause less drowsiness after pretreatment with NZ in a situation where the manifestation of cross‐tolerance was facilitated by ingestion of caffeine. In trial II a clear but task‐dependent development of tolerance to the challenge dose of LZ was documented. One‐week pretreatment with DZ reduced subjects responses to LZ. The total serum BZ activity bioassayed by radioreceptor method after intake of LZ was significantly (P<0.05) higher after pretreatment with DZ than in the end of wash‐out period. Thus a functional cross‐tolerance was documented on complex tasks after the subjects have been continuously working under DZ burden.
Contraction and Cyclic AMP‐related Relaxation of the Intimal and Medial Smooth Muscle Layers of Pig Thoracic Aorta
Authors: Andersson R. G. G. , Lundholm L. , Wingren G.
Published: July 2010

The contractile responses of an α‐adrenoceptor agonist, phenylephrine, and of histamine were compared in the intimal and medial smooth muscle layers of the pig aortic arch. Further, the relaxant effects evoked by some compounds influencing the cyclic AMP system were compared in the two muscle layers, as well as their effects on the cyclic AMP content and phosphodiesterase activity. Phenylephrine and histamine induced contraction of the smooth muscle layers. The increase in tension was faster in the intimal than in the medial layer. The α‐adrenoceptor agonist phenylephrine was a more potent contractile agent in the intimal than in the medial smooth muscle. With histamine, no significant difference in the dose‐response curves between the two muscle layers was found. Histamine‐contracted muscle preparations were relaxed in a dose‐dependent manner by the phosphodiesterase‐inhibiting compound 3‐isobutyl‐1‐methylxanthine (MIX) and by 8‐bromo‐cyclic AMP. The two substances were more potent relaxants in the medial than in the intimal smooth muscle layer. The content of cyclic AMP in the intimal and the medial smooth muscle was increased by MIX. Isoprenaline had no relaxing effect on the muscle preparations and did not change the content of cyclic AMP. There were no differences in the basal levels of cyclic AMP in the intima and media. Vmaxof phosphodiesterase activities differed, however, between the two preparations. This study demonstrates that the intimal layer is characterized by a larger contractile responsiveness to phenylephrine and a lower relaxant response to compounds influencing the cyclic AMP‐system than those of the medial layer.
Local Tissue Damage after Intramuscular Injections in Rabbits and Pigs: Quantitation by Determination of Creatine Kinase Activity at Injection Sites
Authors: Diness Viggo
Published: July 2010

The creatine kinase (CK) method, which is based on differences in CK activity at injection sites and in control tissue, was used for quantitation of local tissue damage after intramuscular injection of varying volumes and preparations in rabbits and pigs. Injections were given in the central part of the longissimus dorsi muscle. Three days after the injections the animals were killed and the arbitrary amounts of tissue without CK were calculated from the CK activity in muscle tissue at the injection sites and in control tissue. Determination of tissue damage by the CK method was in good agreement with macroscopic and microscopic changes, whether a well demarcated necrotic area or little or no necrosis was found at the injection site. Tissue damage was proportional to injection volumes between 0.25 and 1 ml in rabbits and 0.5 and 3 ml in pigs. In rabbits tissue damage per injected ml was found to be more than twice the damage seen in pigs. It is concluded that the CK method is a reliable method for quantitation of local tissue damage after intramuscular injections and that injection of even small volumes of 0.25–0.5 ml in the longissimus dorsi muscle of rabbits is a sensitive test of the local toxicity of drugs.
Effectiveness of Diltiazem for Chronic Stable Angina Pectoris
Authors: Crawford Michael H.
Published: July 2010

Abstract: Diltiazem can be effective monotherapy for most patients with chronic stable angina pectoris. The exact mechanism(s) of action of diltiazem for producing a salutary effect in patients with angina pectoris is unknown, but probably involves a reduction in myocardial oxygen demand and an increase in supply via coronary artery dilatation. Administration of ≤240 mg/day in divided doses uncommonly produces any side effects. Doses of 360 mg/day may be required in some patients. The major adverse effect of high dose therapy is mild pedal oedema. Caution concerning orthostatic hypotension is advised when high dose diltiazem is combined with nitrate therapy or used in patients with poor left ventricular function. Also, diltiazem may potentiate bradycardia or atrio‐ventricular block, especially when combined with digitalis preparations or β‐blockers. However, in patients with severe angina, diltiazem may be additive to nitrate and/or β‐blocker therapy.
Short‐term Oral Terbutaline Does not Induce Myocardial Hypertrophy in Man
Authors: Eskilsson J. , Conradson T.‐B.
Published: July 2010

Abstract: Seven healthy male subjects, with an average age of 32 years, received 15 mg oral terbutaline daily for 14 days. Echocardiography was used to evaluate myocardial wall thickness. The terbutaline dose given resulted in plasma concentrations of terbutaline which improve lung function in asthmatic patients. Echocardiographic measurements were, however, unchanged during the study compared to pretreatment values. Thus, contrary to what has been reported in animal models, short‐term terbutaline treatment in man does not seem to induce cardiac hypertrophy.
Structural and Pharmacological Differences between Codfish and Rat Brain α1‐Adrenergic Receptors Revealed by Photoaffinity Labeling with125I‐APDQ
Authors: Bergström Ann , Wikberg Jarl E. S.
Published: July 2010

Abstract:The photoaffinity probe125I‐APDQ has been used to characterize α1‐receptor peptides in the cod and rat brains. In the cod brain a major specific peptide of Mt= 68,000 could be covalently labeled by125I‐APDQ as revealed by SDS‐PAGE. In the rat brain a specific peptide with Mt= 77,000 was instead labeled. When a number of adrenergic agonists and antagonists were tested for their ability to protect the labeling by125I‐APDQ their potencies were those expected for α1‐receptors in both species. The ligand binding peptide in the cod brain also distinguished between stereoisomers of epinephrine as expected for a physiological receptor. However, there was a distinct difference between the cod and rat α1‐receptor in that the β‐agonist 1‐isoprenaline was equipotent to 1‐norepinephrine in the cod whereas it was less potent in the rat. The protecting ability of the tested agents were also matched by their ability to displace the α1‐adrenergic ligand3H‐prazosin from α1‐receptor binding sites in brain membranes from both species. Thus, the codfish α1‐receptor seems to be different from mammalian α1‐receptors both structurally and pharmacologically.
The Xanthine Derivative 1‐(5′‐Oxohexyl)‐3‐methyl‐7‐propyl Xanthine (HWA 285) Enhances the Actions of Adenosine
Authors: Fredholm Bertil B. , Lindström Karin
Published: July 2010

Abstract: The effect of two closely related xanthine derivatives, pentoxifylline and HWA 285, on cyclic AMP accumulation in rat hippocampal slices and on adenosine uptake in erythrocytes was examined. Pentoxifylline was a weak competitive antagonist of adenosine effects on cyclic AMP accumulation. HWA 285, by contrast, had a small stimulatory effect per se and also potentiated the effect of adenosine (10–30 μM). Neither pentoxifylline nor HWA 285 significantly affected the cyclic AMP accumulation induced by the stable adenosine analogue NECA or by α‐ or β‐adrenoceptor activation. HWA 285 was a much more potent inhibitor of adenosine uptake into human erythrocytes than pentoxifylline and other examined xanthines including thiocaffeine, 8‐p‐sulphophenyltheophylline, theophylline, caffeine and enprofylline. It is suggested that HWA 285 may potentiate, rather than antagonize, the effects of endogenous as well as exogenous adenosine, partly as a consequence of adenosine uptake inhibition.
A Central Serotonin Receptor Agonist, 8‐Hydroxy‐2‐(di‐n‐propylamino)tetralin, has Different Effects on Prolactin Secretion in Male and Female Rats
Authors: Carlsson Maria , Eriksson Elias
Published: July 2010

Abstract: Male and female rats were compared with respect to alterations in prolactin secretion induced by the serotonin receptor agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT). The dose‐response curves after 8‐OH‐DPAT were irregular and had different shapes in the two sexes. In males, 0.1 and 0.3 mg/kg enhanced serum prolactin concentrations to about 200% of control values, whereas higher doses (1 and 3 mg/kg) had no effect on prolactin release. In females, in contrast, 0.1 mg/kg of 8‐OH‐DPAT tended to decrease serum levels of prolactin, while 0.3, 1, and 3 mg/kg elevated them in a dose dependent manner to maximally 700% of control values. The serotonergic agonist 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeODMT) (5 mg/kg), too, caused increased prolactin release in both sexes, and, again, females responded more forcefully. In males, but not in females, pretreatment with 8‐OH‐DPAT (1 mg/kg) reduced the 5‐MeODMT‐induced elevation of serum prolactin levels. The mechanism underlying the sexually differentiated effects of 8‐OH‐DPAT on prolactin secretion is discussed.
Plasma Kinetics of DDAVP in Man
Authors: Vilhardt H. , Lundin S. , Falch J.
Published: July 2010

Abstract:After a bolus injection, DDAVP was infused in normal volunteers over a period of 3½ hours. Blood was sampled during and after the infusion and was analyzed for DDAVP using a specific RIA. The total clearance for DDAVP was 2.6 ml/min./kg b. wt., and half‐life in plasma 55 min.
Effects of Prenatal Alcohol Exposure on Neonatal Sleep‐wake Behaviour and Adult Alcohol Consumption in Rats
Authors: Hilakivi Leena
Published: July 2010

Abstract: Our previous experiments showed that suppression of early postnatal active (REM) sleep increases alcohol intake in adult rats. To study the effects of prenatal alcohol exposure on neonatal sleep‐wake behaviour and adult alcohol consumption pregnant rat dams were given 7% to 12% alcohol, 1% sucrose solution, or tap water as a sole liquid throughout gestation. Sleep‐wake behaviour of the pups was studied at 6, 8, 12 and 15 days of age by using a movement sensitive mattress. The offspring who were exposed to alcohol in utero had significantly less active sleep and more wakefulness from total recording time than the controls. Their quiet state was also interrupted more often by waking episodes. At the age of 2 months voluntary alcohol intake of the rats exposed prenatally to alcohol was elevated compared to the controls. These findings suggest that early postnatal active sleep and the neurotransmitter systems regulating it may be the means by which in utero alcohol exposure affects adult alcohol drinking.
Sensory Irritation and Pulmonary Irritation of Cumene and n‐Propanol: Mechanisms of Receptor Activation and Desensitization
Authors: Kristiansen U. , Hansen L. , Nielsen G. D. , Holst E.
Published: July 2010

Abstract: Cumene and n‐propanol, model substances for alcohols and alkylbenzenes, were investigated for sensory irritation in mice. The concentrations within the first 2 min. depressing the respiratory rate by 50% due to the effect in the upper respiratory tract were 2,058 p.p.m. and 22,080 p.p.m., respectively. Activation of the sensory irritant receptor followed the dynamics of reversible bimolecular reactions. The extrapolated maximum response and the apparent dissociation constant were 114.3% and 2,723 p.p.m. for cumene and 68.4% and 8,178 p.p.m. for propanol, respectively. Later on desensitization was observed. The effect was weak for cumene but conspicuous for propanol. For cumene desensitization had the origin in the rise of a threshold. No change in the dissociation constant or the maximum response was found. For propanol a decrease in the maximum response, which may be explained by an allosteric effect, was observed. The pulmonary irritation response was weak for cumene but was for propanol more important than sensory irritation at high concentrations. The following hypotheses are put forward: the effect of pulmonary irritation on the tidal volume is mediated via the stretch receptors while the effect on the respiratory frequency is mediated via the J‐receptors.
Pharmacokinetics of Zimeldine in Male Alcoholics
Authors: Gottfries Carl‐Gerhard , Grind Margareta , Lundström Jan , Alling Christer
Published: July 2010

Abstract: The pharmacokinetics of zimeldine, a 5‐HT reuptake blocker with antidepressive effects, was studied after a single oral dose and after multiple oral administration in 19 alcoholic males, 10 with and 9 without chronic liver damage. The average plasma concentration of zimeldine as assessed by the AUC values (area under the plasma concentration‐time curve) was significantly higher in the chronically liver damaged patients than in the patients without chronic liver damage. The plasma half‐life of zimeldine was also significantly longer in the chronically liver damaged patients. There were no differences in the obtained pharmacokinetic parameters between the patients having nonchronic liver damage and healthy control subjects. The pharmacokinetics of the active metabolite norzimeldine (resulting from N‐demethylation of zimeldine) showed no differences between the two groups of alcoholics and the healthy controls. The IgA values were significantly correlated to both the AUC and plasma half‐life of zimeldine. No other correlation between clinical chemistry parameters and pharmacokinetic parameters of zimeldine and norzimeldine were found.
Compared Effects of the Two Antiinflammatory Drugs Indoprofen and Lonazolac on Thromboxane Generation and on Platelet Aggregation, Related to Plasma Concentrations after Single Oral Doses
Authors: Vinge Ellen , Björkman Sven
Published: July 2010

Abstract:Single doses of indoprofen 100 mg and lonazolac‐Ca 200 mg were given orally to eight healthy volunteers. Blood samples were taken prior to and at various times until 24 hours after the dose. Drug concentrations in plasma were analyzed by HPLC and thromboxane B2(TXB2) in serum by radioimmunoassay. Platelet aggregation in plasma was induced by various concentrations of arachidonic acid and evaluated with respect to different phases in the aggregatory response. The drugs were rapidly absorbed and for both compounds the decline in plasma concentrations described two phases. Although concentrations of indoprofen were up to ten times higher than those of lonazolac, the two drugs were almost equally potent inhibitors of generation of TXB2, with IC50 for indoprofen of 1.4–1.5 × 10−7M and for lonazolac 2.1–3.0 × 10−7M. Their effects on the lag phase in platelet aggregation parallelled the inhibition of TXB2formation. However, the rate and extent of aggregation were more inhibited by indoprofen than by lonazolac, and the discrepancy was greater than would be expected from concomitant values for TXB2suppression. The rate of aggregation appeared to be the most sensitive variable, since the extent of aggregation followed an all‐or‐none pattern. The present results show that the concentrations reached after clinically used doses of antiinflammatory drugs may vary widely in relation to the concentrations needed for maximum inhibition of platelet cyclooxygenase. The results from aggregation tests may support the idea that non‐steroid antiinflammatory drugs can differ in their mechanisms of action.
Vasomotor Responses of Isolated Human Coronary Arteries to Magnesium, Nitroglycerin and Verapamil: A Comparison with Coronary Arteries from Cat and Rat
Authors: Sjögren Anders , Edvinsson Lars , Ottosson Anders
Published: July 2010

Abstract:The vasomotor responsesin vitroto magnesium, nitroglycerin and verapamil were investigated in human coronary arteries. In order to examine possible species differences in reactivity to these agents, experiments were performed also on cat and rat coronary arteries. Potassium (124 mM) regularly produced stable contractions suitable for experiments with dilator agents. The order of potency for eliciting relaxation was the same in all three species; verapamil > nitroglycerin > magnesium. Maximum relaxation induced by nitroglycerin or magnesium was significantly lower in arteries from cat as compared to that obtained in coronary artery segments from man and rat. Spontaneous rhytmic activity was often present in human coronary arteries but never in arterial segments from cat or rat. The rhytmic activity was frequently enhanced by the addition of prostaglandin F2α(3 μM) to the tissue bath, on the other hand the rhythmic activity was depressed, or even abolished, by potassium (124 mM), magnesium (1.2–13.2 mM), nitroglycerin (2.2 × 10−5M) or verapamil (10−8‐10−7M). The magnitude of the vasomotor response of feline coronary arteries to nitroglycerin or verapamil was dependent on the extracellular concentration of magnesium; in the presence of a high concentration of magnesium (4.4 mM) the dilator effect of nitroglycerin was enhanced while that of verapamil was slightly depressed. The dilator activity of the two agents was not changed by incubation of the vessel segments in a magnesium‐free medium as compared to that obtained in the standard (1.2 mM Mg) buffer solution.
Relation between Potassium Excretion and Proximal Tubular Fluid Output in Conscious Unoperated Rats Adapted to Different Dietary Potassium Contents
Authors: Thomsen Klaus , Olesen Ole Vendelin
Published: July 2010

Abstract: The effect of dietary potassium content on the proximal tubular fluid output (Vprox), and the relation between Vprox and potassium excretion was examined in conscious unoperated diabetes insipidus rats adapted to five dietary potassium contents in the range 25–400 mmol/kg. The lithium clearance (CLi) and the urine flow (V) were used as measures of Vprox, CLi being equal to and V being about one‐third of Vprox. Increase of the dietary potassium content from 25 to 400 mmol/kg led only to a slight, barely statistically significant increase of Vprox. However, repeated measurements in the same rats on different days showed considerable intraindividual variation of Vprox and the potassium excretion. At each dietary potassium level except the lowest one the potassium excretion was linearly correlated to CLi (r = 0.60–0.92) and to V (r = 0.56–0.85). Errors in bladder emptying could not explain these correlations. The slopes of the regression lines increased with increasing dietary potassium content, and the regression lines all intercepted the CLi axis at approximately the same CLi value, i.e., on the average about 70 μl/min./100 g body weight. The results indicate that an increase of the dietary potassium content leads to a slight increase of Vprox. Spontaneous intraindividual variation of Vprox is considerable and is associated with linearly related variation of the potassium excretion. The change of the potassium excretion for a given change of Vprox increases with the dietary potassium content.
Relationship between Sodium Clearance and Proximal Tubular Fluid Output in Conscious Unoperated Rats Adapted to Different Dietary Sodium Contents
Authors: Thomsen Klaus , Olesen Ole Vendelin
Published: July 2010

Abstract: The relationship between the proximal tubular fluid output (Vprox) and the sodium clearance (CNa) was examined in conscious unoperated diabetes insipidus rats adapted to different dietary sodium contents ranging from 5 to 300 mmol/kg. The lithium clearance (CLi) and the urine flow (V) were used as measures of Vprox, CLi being equal to and V being about one‐third of Vprox. Variations in the dietary sodium content had almost no influence on CLi and V. However, repeated 2‐hour clearance measurements on different days in the same rat showed considerable intraindividual variations of CLi and V, and at each dietary sodium level CNa was linearly correlated to CLi (r = 0.83–0.90) and to V (r = 0.57–0.89). Errors in bladder emptying could not explain these correlations. The slopes of the regression lines increased with increasing dietary sodium content, and the regression lines all intercepted the abscissa at approximately the same value of CLi, i.e. on the average about 40 μl/min./100 g body weight. The results suggest that Vprox is almost independent of the dietary sodium content. Spontaneous intraindividual variation of Vprox is considerable and is associated with linearly related variation of CNa. The change of CNa for a given change of Vprox increases with the dietary sodium content.
Further Studies of the Mechanism Behind Scopolamine‐induced Reversal of Antistereotypic and Cataleptogenic Effects of Neuroleptics in Rats
Authors: Arnt Jørn , Hyttel John , Bach‐Lauritsen Thomas
Published: July 2010

Abstract: Scopolamine is known to attenuate the amphetamine antagonistic and cataleptogenic effect of selective DA D‐2 antagonists. To study further the influence of other receptor systems three approaches were taken: 1) concomitant treatment with receptor blockers (scopolamine, prazosin and ketanserin) and a selective D‐2 antagonist YM 09151–2, 2) testing of a neuroleptic droperidol, with mixed D‐2, α1 and 5‐HT2 antagonistic properties and 3) testing a selective D‐1 antagonist SCH 23390. Scopolamine markedly attenuated both effects of YM 09151–2 and droperidol. In contrast neither prazosin nor ketanserin influenced the effects of YM 09151–2. Furthermore, prazosin did not influence the interaction between scopolamine and YM 09151–2 in the tests of stereotypy and catalepsy. Scopolamine did not change the amphetamine antagonistic potency of SCH 23390, but decreased moderately its cataleptogenic potency. It is concluded that 5‐HT2 and α1‐adrenergic receptor blockade are of minor importance in order to determine the sensitivity of a DA D‐2 antagonist to the reversal induced by scopolamine. Thus, our earlier hypothesis, that DA D‐1 receptor blockade is the main mechanism stabilizing these neuroleptic effects against scopolamine reversal, are further supported by the present experiments.