bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Extracellular Calcium on Allyl Alcohol‐Induced Hepatotoxicity
Authors: Strubelt O. , Younes M. , Pentz R.
Published: July 2010

Abstract:The role of calcium in allyl alcohol‐induced hepatotoxicity was investigated in the isolated haemoglobin‐free perfused rat liver. At a Ca++concentration of 2.5 mmol/l in the perfusate, allyl alcohol (initial concentration 1.17 mmol/l) produced an enhanced release of GPT and SDH from the liver, an increase in the lactate/pyruvate ratio of the perfusate, a decrease in hepatic oxygen consumption and an increase of both hepatic calcium and malondialdehyde content. In the absence of Ca++in the perfusate, no hepatic calcium accumulation occurred with allyl alcohol, but all other signs of hepatic damage were as severe as with 2.5 mmol/l Ca++. On the other hand, high extracellular Ca++(5 mmol/l) alone led to a threefold increase of liver calcium but produced only marginal hepatotoxicity and only slightly enhanced the hepatotoxic effects of allyl alcohol. The concentrations of allyl alcohol in the perfusate were not altered at different Ca++concentrations. In conclusion, the primary allyl alcohol‐induced hepatotoxic injury does not appear to depend upon an influx of extracellular calcium.
Effects of Methylene Chloride on Body and Organ Weight and Plasma Butyrylcholinesterase Activity in Mice
Authors: Kjellstrand P. , Bjerkemo M. , Adler‐Maihofer M. , Holmquist B.
Published: July 2010

Abstract:Exposure to methylene chloride produced a time and concentration related increase in liver weight. The effect was more prominent in female mice than in male. The activity of plasma butyrylcholinesterase (BuChE) increased even more than the liver weight at corresponding exposures, but only in the males. Fatty infiltration was noticeable after exposure to 75 p.p.m. and was more prominent in the females than in the males. Thirty to 60 days of continuous exposure were required to reach stable maxima. Intermittent exposure was less effective than continuous exposure in producing the effects. Most effects were fully reversible after exposure for both 30 and 90 days if the animals were transferred to a solvent‐free environment. However, after exposure for 90 days, BuChE activity in the males did not return to normal within 30 days but after 90 and 120 days free from exposure only slight if any effects on BuChE activity remained.
Cholinergic and Dopaminergic Alterations in the Mouse Central Nervous System Following Acute Trimethyltin Exposure
Authors: Ali Syed F. , Slikker William , Newport Glenn D. , Goad Phillip T.
Published: July 2010

Abstract:Male mice were given a single oral dose of 0, 1 or 3 mg/kg TMT‐hydroxide and sacrificed 48 hrs, 1 and 2 weeks later. Brain areas were removed, dissected and frozen for later analysis of neurotransmitter receptor binding by filtration techniques and determination of concentrations of monoamines and their metabolites by HPLC/EC. Muscarinic cholinergic receptor binding was measured over a [3H]‐quinuclidinyl benzilate (QNB) concentration range of 0.02 to 2.0 nM. Two days after TMT treatment, affinity of [3H]‐QNB binding in frontal cortex increased. Gradual return to control binding affinity was seen over the next 2 weeks. The number of receptors decreased only at high dose after 1 week. In hippocampus, a similar increase was seen only at the 3 mg/kg dose after 1 and 2 weeks. Homovanillic acid (HVA) and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations were significantly decreased in the caudate nucleus 2 weeks after TMT treatment; concentrations of serotonin (5‐HT), dopamine (DA), and 3,4‐dihydroxyphenylacetic acid (DOPAC) were unaltered, nor was there a change in dopamine receptors as measured by [3H]‐spiroperidol binding in the caudate nucleus or frontal cortex. To determine if TMT altered monoamine turnover or metabolite efflux, mice were dosed with 0 or 3 mg/kg TMT; 2 weeks later, pargyline (75 mg/kg, intraperitoneally) was administered and the mice sacrificed 0, 30 and 60 min. later. Monoamines and their metabolites were measured in caudate nucleus. The HVA elimination rate was unchanged. The data suggests that the lower concentrations of dopamine metabolites observed 2 weeks after TMT treatment were due to a decrease in dopamine turnover. The decrease in muscarinic receptor affinity in frontal cortex and hippocampus and the decrease in the rate of dopamine turnover in the caudate nucleus indicate that these 2 systems are affected by TMT and may participate in the expression of its toxicity.
Biochemical Effects and Monitoring of Exposure of Rats to 4‐Methylcyclohexyl‐1,6‐dicarboxylic Acid Anhydride Vapour
Authors: Savolainen Heikki , Pfäffli Pirkko
Published: July 2010

Abstract: Male Wistar rats exposed to 5, 10 or 20 p.p.m. 4‐methylcyclohexyl‐1,6‐dicarboxylic acid anhydride vapour for 2–11 weeks showed dose‐dependent blood anhydride concentrations. The maximum concentrations were found after two weeks. At five exposure weeks, they were smaller but they did not decrease further thereafter. The change was coincident with increased epoxide hydrase activity in liver. The excretion of 4‐methylcyclohexyl‐1,6‐dicarboxylic acid was detected in the urine. The excretion was linearly related to the exposure in specimens collected during the 10th and 11th week. Brain acetylcholinesterase activity was transiently inhibited by the exposure at the two higher doses while decreased enzyme activity in the isolated spinal cord axons was only found after 11 weeks. This change was simultaneous with increased creatine kinase activity in the cerebellar homogenate. In the occupational setting, acetylcholinesterase activity might only be significantly inhibited in lungs because of the low exposure levels.
Effects of Dimethylsulfoxide (DMSO), Nocodazole, and Taxol on Mast Cell Histamine Secretion
Authors: Nielsen Ellen Holm , Johansen Torben
Published: July 2010

Abstract:Nocodazole depolymerized microtubules and increased the number of microfilaments, and dimethylsulfoxide increased the number of microfilaments. Both drugs inhibited compound 48/80‐induced histamine release from rat mast cells. Taxol, which increased the number of microtubules, had no effect on histamine release. These observations support the view that microtubules may not be directly involved in secretion, but apparently an increased number of microfilaments is associated with a decreased capacity of the mast cells for histamine release. We suggest that microfilaments have to be depolymerized or rearranged before secretion can take place.
Pharmacokinetics and Clinical Effects of Scopolamine in Caesarean Section Patients
Authors: Pihlajamäki K. K. , Kanto J. H. , Oksman‐Caldentey K.‐M.
Published: July 2010

Abstract: A new method (ELISA) was used to evaluate the pharmacokinetics of scopolamine following intravenous (0.005 mg/kg), intramuscular (0.01 mg/kg), and oropharyngeal (0.035 mg/kg) administration of the drug to pregnant patients anaesthetized for caesarean section. After intravenous (N = 4) the drug fast disappeared from the circulation with a half‐life of about 5 min., and the serum levels generally were measurable up to 3 hours, mean elimination half‐life was 1.85 hours. A fast absorption was found after intramuscular injection, tmax = 10 min. (N = 4), and the drug had a clinically significant oropharyngeal absorption as well, tmax was around 1 hour (N = 6). The intramuscular and oropharyngeal, but not the intravenous, administrations produced a marked postoperative sedative and amnesic effects. All three administration ways caused a significant antisecretory action.
Guanine Nucleotides Regulates Both Agonist and Antagonist Binding to Cod Brain α1‐Adrenoceptors
Authors: Bergström Ann , Wikberg Jarl E.S.
Published: July 2010

Abstract:The effect of guanine nucleotides on the binding of3H‐prazosin and its displacement by various agonists and antagonists were studied in membranes prepared from the cod brain. When cod brain membranes were maintained in a buffer containing 8 mM Mg2+, GTP (1 mM) was found to increase the specific binding of3H‐prazosin Computer modelling3H‐prazosin saturation curves, suggested that the number of binding sites for3H‐prazosin was increased by 18 ± 5% by GTP without affecting the affinity for3H‐prazosin (dissociation constant, Kd, 56±3 pM). Displacement of3H‐prazosin by adrenaline produced shallow displacement curves. Computer modelling these curves suggested that adrenaline bound to two sites ‐ one high and one low affinity site ‐ the Kd's being 0.14±0.03 (KH) and 7.6±0.5 μM (KL), respectively. When I mM GTP was present the displacement curves were shifted to the right and became steeper. Computer modelling these curves suggested that adrenaline now bound to only one low affinity site with a Kdof 7.6±0.5 μM. When unlabelled prazosin was used to displace3H‐prazosin the displacement curves were uniphasic and steep, irrespective of whether GTP was present or not. Computer modelling these curves suggested that prazosin bound to only one site with a Kdof 68±11 pM. In the absence of Mg2+and in the presence of EDTA (0.8 mM) the displacement curve of adrenaline became steeper and the effect of GTP was almost abolished. During these conditions the ability of GTP to enhance3H‐prazosin binding was also abolished. Substitution with 0.08–8 mM Mg2+concentration‐dependently restored the effects of GTP. The data is compatible with a ternary receptor model for the α1‐adrenoceptor in which the receptor may become associated with another membrane component, which presumably is a guanine nucleotide regulatory protein.
Presynaptic Dopamine Receptors in the Pithed Rat: Characterization with Apomorphine and Comparison with Central Dopamine Autoreceptors
Authors: Hietala J. , MacDonald E. , Scheinin M.
Published: July 2010

Abstract:Apomorphine, a dopamine agonist with high affinity for presynaptic dopamine receptors, caused dose‐dependent inhibition (10–300 μg/kg intravenously) of the stimulation‐induced increase in diastolic blood pressure in the pithed rat. This effect of apomorphine could be antagonized with (‐)‐sulpiride or haloperidol but not with yohimbine or atropine, indicating the involvement of inhibitory dopamine receptors. The α‐1‐adrenoceptor mediated pressor response to phenylephrine (5 μg/kg intravenously) was not significantly attenuated by apomorphine. The sensitivity of peripheral presynaptic dopamine receptors was then studied in the cardiovascular system of rats treated subchronically with haloperidol (2 mg/kg, twice daily intraperitoneally for 10 days). The inhibition of sympathetic vasoconstrictor responses exerted by apomorphine was found to be enhanced after subchronic haloperidol treatment suggesting the development of presynaptic dopamine receptor supersensitivity in the periphery. In addition, the previously reported supersensitivity of central dopamine autoreceptors to low doses of apomorphine could be confirmed in behavioural experiments.
Long Lasting Supersensitivity to 5‐HT Mediated Behaviour Following Monoamine Depletion in the Rat Brain
Authors: Rényi Lucy
Published: July 2010

Abstract:The effects of the depletion of 5‐hydroxytryptamine (5‐HT) in the rat brain upon the 5‐HT behavioural syndrome (ejaculatory response, abduction of hind‐limbs, forepaw treading, and Straub tail) induced by 5‐methoxy‐N,N‐dimethyltryptamine (1 mg/kg intraperitoneally) were investigated. The 5‐HT depletion was produced by p‐chlorophenylalanine (PCPA 2 × 200 mg/kg intraperitoneally) or by reserpine (5 mg/kg subcutaneously). It resulted in rapidly developing and long‐lasting supersensitivity of the behavioural responses which were enhanced between 2 and 14 days after the PCPA injections and between 1 and 42 days after a single dose of reserpine. The depletion of catecholamines by α‐methyltyrosine (250+125 mg/kg intraperitoneally) had no effect. These results underline the usefulness of the 5‐HT mediated behavioural models for studies of changes in 5‐HT receptor activity.
Saccadic Eye Movements in Determination of the Residual Effects of Flunitrazepam
Authors: Salonen M. , Aaltonen L. , Aantaa E. , Kanto J.
Published: July 2010

Abstract: Saccadic eye movements and the subjective assessments of the volunteers were used in the determination of the residual effects of a single evening dose of flunitrazepam 0.5 mg, 1 mg and 2 mg or placebo. Sleep inducing and maintaining effects were subjectively assessed, too. Flunitrazepam at all three dose levels possessed sleep inducing and increasing effects (n = 9), but in the number of nocturnal awakenings and sedation in the morning (10 hrs after drug intake), no significant differences between placebo and the active medications were reported. However, saccadic eye movement recording could differentiate the residual effects produced by placebo or the active medication. No correlation was detected between the serum levels (radioreceptor assay) and saccadic eye movement recordings.
Muscarinic Receptor Density in the Rat Urinary Bladder after Denervation, Hypertrophy and Urinary Diversion *
Authors: Nilvebrant Lisbeth , Ekström Jörgen , Malmberg Lars
Published: July 2010

Abstract:Parasympathetic denervation of the urinary bladder results in supersensitivity to muscarinic agonists and in bladder hypertrophy. In the present study, the effects of denervation on the muscarinic receptors in the rat bladder were investigated, using a receptor binding technique with (‐)3H‐QNB as radioligand. The density of muscarinic receptors was increased in denervated, hypertrophied bladders but it was decreased, below that in control bladders, when the development of hypertrophy was prevented by urinary diversion. A decreased receptor density was also found in innervated bladders after urinary diversion, whereas the receptor density was unaffected by hypertrophy alone. Competition experiments with methacholine revealed no changes in the agonist binding properties of the receptors. When the present data are combined with those in previous functional studies, it seems unlikely that the muscarinic receptors in the bladder are involved in the development of supersensitivity. It is suggested that the density of muscarinic receptors in the bladder may be related to the bladder function.
The Benzazepine, SCH 23390, Inhibits3H‐NPA Binding in Mouse BrainIn Vivo
Authors: Andersen Peter H. , Nielsen Erik B.
Published: July 2010

Abstract:The fact that SCH 23390, a selective dopamine (DA) DI antagonist, blocks the effects of D2 agonists suggests a functional coupling of D1 and D2 receptors. Therefore, the binding of SCH 23390 to D2 receptors was investigatedin vivousing3H‐N‐n‐propylnorapomorphine (NPA), a D2 agonist, and3H‐spiperone and3H‐raclopride, both D2 antagonists. SCH 23390 failed to inhibit3H‐spiperone or3H‐raclopride binding; however, SCH 23390 was relatively potent in inhibiting3H‐NPA binding. These results suggest that (some) antidopaminergic effects of SCH 23390 may result from antagonism of a D2 agonist conformation of the D2 receptor.
Actions of 1,1,1‐Trichloroethane on the cAMP Metabolism in Mouse Brain
Authors: Nilsson Karin B.
Published: July 2010

Abstract:Inhalation or intraperitoneal administration of 1,1,1‐trichloroethane (TCE) increased the cAMP content in the brain stem in a dose‐related and time‐dependent fashion. TCE had no effect on the cAMP level in the cerebellum and hippocampus, but slightly reduced that in the cerebral cortex. Following intraperitoneal administration of TCE the activity of norepinephrine‐ and F ‐activated adenylate cyclase (AC) in a brain stem homogenate was enhanced, while the serotonin‐stimulated AC activity was decreased. Neither the basal AC activity nor the guanine nucleotide‐ and forskolin‐activated enzyme was affected by TCE. TCE had no effect on the soluble cAMP‐dependent phosphodiesterase activity. It is suggested that the increased cAMP content in the brain stem induced by TCE may be mediated via adrenorcceptor interaction with the guanine nucleotide‐binding regulatory component, resulting in activation of the catalytic unit of the adenylate cyclase and thereby an increase in the cAMP level.
Tissue Distribution and Fate of Budesonide in the Mouse
Authors: Andersson Paul , Appelgren Lars‐Erik , Ryrfeldt Åke
Published: July 2010

Abstract:The tissue distribution and pharmacokinetics of3H‐budesonide were studied in the mouse after intravenous administration. The drug was rapidly (t1/2α= 0.062 hrs) and extensively distributed into tissues and organs (Vβ= 20.3 l/kg and VSS= 9.4 l/kg). The short elimination half‐life (t1/2β= 1.55 hrs) and high blood clearance (Cl = 9.04 l/hr/kg) demonstrated a rapid elimination of budesonide from the body. Whole‐body autoradiography showed very high amounts of radioactivity in the excretory organs liver and kidney. Also in the lung and lymphatic tissues high amounts of radioactivity were noted. The adrenal cortex but not the medulla was heavily labelled. Radioactivity passed the blood‐placenta barrier and to some extent the blood‐brain barrier. The identity of the radioactivity in some organs was analysed by liquid chromatography. At all times after dosing (up to 4 hours), the dominating part of the lung, spleen and brain radioactivity was attributable to unchanged budesonide. After 60 min., the dominating part of the kidney radioactivity was identified as polar metabolites of budesonide. The liver radioactivity was at all observation times found to consist mainly of polar metabolites, reflecting the efficient liver biotransformation of budesonide.
Calcium Entry Blockade and Excitation Contraction Coupling in the Cardiovascular System (with an attempt of pharmacological classification)
Authors: Godfraind Theophile
Published: July 2010

Abstract:Calcium may be considered as the final intracellular messenger of excitation‐contraction coupling. In this report the main mechanisms involved in the cellular regulation of calcium movements are reviewed. Most of the pharmacological agents actually available for therapy interfere with the processes responsible for increase in cytoplasmic activator calcium.

Study of the relation between contraction and calcium movements shows that blockade of calcium entry may cause inhibition of contraction. This has allowed to illustrate some of the characteristics of calcium channels in smooth muscle. Potential‐operated channels are activated by changes in membrane potential, that can be evoked by K‐rich solutions. They are completely blocked by calcium antagonistic dihydropyridines and diphenylpiperazines. This blockade shows (time‐)use‐dependence. They are opened by calcium agonistic dihydropyridines. Receptor‐operated channels are activated by the interaction of an agonist with its receptors; they are incompletely blocked by calcium antagonistic dihydropyridines and diphenylpiperazines.

Endothelium appears to modulate the response of the adjacent smooth muscle to vasoconstrictors. This may be accounted for by modulation of calcium metabolism, both at the level of membrane channels and of intracellular stores. As a consequence, endothelium modulates the action of calcium entry blockers.

Study of isolated human tissues illustrates difference in drug sensitivity between cardiac and smooth muscle. Human isolated coronary arteries are sensitive to nifedipine concentrations found in the blood of patients receiving therapeutic regimen. These concentrations do not alter the contractility of the isolated human myocardium.

Differences between drugs may be explained assuming that they may interact with one of the states (closed, open, inactivated) of the Ca channels. This also helps the understanding of tissue selectivity of some compounds.

A pharmacological classification of calcium entry blockers may be proposed. This classification is a rationale to differentiate between the various clinical indications of drugs affecting calcium movements.
Pharmacodynamic Profiles of Different Calcium Channel Blockers
Authors: Andersson Karl‐Erik
Published: July 2010

Abstract:The cardiovascular effects of different calcium channel blockers (CCB), exemplified by nifedipine, verapamil and diltiazem, are not identical. Some of these differences in effect may be due to the different CCBs interacting with different calcium channel subtypes in the tissues, and/or that the drug‐receptor sites are separate. The drugs also have different abilities to activate the sympathetic nervous system, nifedipine increasing and diltiazem decreasing the baroreflex sensitivity. Verapamil, but not nifedipine and diltiazem, has a postjunctional α‐adrenoceptor blocking effect, and can also increase the release of noradrenaline from adrenergic nerves by blocking pre‐junctional α‐adrenoceptors. In addition, verapamil may have a reserpine‐like action on sympathetic nerves. The vasodilator actions of CCBs are not uniform, but seem to vary between species, different vascular regions, and different agents. Mechanisms other than blockade of influx of calcium from the extracellular medium have been suggested to explain these differences, including inhibition of intracellular calcium release, blockade of postjunctional α – adrenoceptors, interaction with calmodulin, inhibition of cyclic AMP phosphodiesterase, stimulation of Na+–, K+‐activated ATPase, stimulation of a calcium pump, and a direct interaction with the contractile proteins. The heterogeneity in pharmacodynamic profile characterizing the CCBs is conspicuous, and may be of importance when selecting agents for the treatment of various cardiovascular and non‐cardiovascular disorders.
Pharmacokinetics of Calcium Channel Blocking Agents
Authors: Anderson Per
Published: July 2010

Abstract:Verapamil and nifedipine are the most frequently used calcium channel blocking agents in Sweden at present time. The pharmacokinetics of verapamil has been described both in healthy volunteers as well as in patients with supraventricular arrythmias, angina pectoris, liver cirrhosis, hypertrophic cardiomyopathy or hypertension. Intravenous pharmacokinetics of nifedipine has been investigated in healthy volunteers and oral pharmacokinetics in healthy volunteers as well as in patients with hypertension. The pharmacokinetics of verapamil and of one of its metabolites, norverapamil, is changed after multiple oral dosing as has been described in patients with supraventricular tachyarrythmias, angina pectoris or in patients with essential hypertension. Plasma concentration‐effect relationships have been established for verapamil in different clinical situations and in a few cases also for nifedipine. An update of the pharmacokinetics of these two important calcium channel blocking agents is presented.
The Relationship between Macro– and Microcirculation Clinical Aspects
Authors: Fagrell Bengt
Published: July 2010

Abstract: A large number of methods are today available for the clinical evaluation of the arterial blood supply to an extremity or part of an extremity. However, these methods are not sensitive enough for determining the nutritional status of a tissue in the extremity affected by vascular disorders. This is especially true for the skin where most of the blood is used for thermoregulation and only a small fraction goes through the nutritional capillaries. Blood may enter the subpapillary vascular network through AV‐shunts and bypass the nutritional skin capillaries. Therefore microcirculatory methods has to be used in order to be able to evaluate the nutritional status of a certain skin area.

One of the clinically most useful methods for this purpose is vital capillary microscopy. By classifying structural changes of the nutritional capillaries in an area susceptible to ischemia, the risk of necrosis can be evaluated. Marked discrepancies between the total circulation of the are and the nutritional status of the tissue can be seen especially in patients with peripheral vascular disorders and/or diabetes. The total circulation may be markedly reduced but necrosis does not occur until the nutritional circulation of the ischemic skin area is completely abolished for a certain period of time. On the other hand it is sometimes seen in clinical practise that ischemic skin necrosis may develop in a region with rather good macrocirculation. These findings are of utmost importance when the effect of a certain treatment should be evaluated. The effect has to be studied directly in the target organ, and that is the nutritional vascular bed of the ischemic area.
Calcium Channel Blockade and Renal Function
Authors: Odar–Cederlöf Ingegerd
Published: July 2010

Abstract: Since calcium channel blocking agents were introduced into the treatment of hypertension their influence on renal function has become an important issue.

In animal experiments calcium channel blocking agents have been shown to increase renal blood flow and glomerular filtration rate and to augment urine flow and electrolyte excretion.

In human acute studies the administration of calcium channel blocking agents have elicited similar renal hemodynamic and diuretic effects. Clinical studies on the renal effects of long‐term treatment are however still lacking.

Studies on the effect on renin release have given divergent results. In acute experiments renin release is increased by calcium channel blocking agents. En long‐term treatment, however, no change in peripheral plasma levels of renin has been demonstrated.

The influence of decreased renal function on the pharmacokinetics of calcium channel blocking agents has been studied in patients with renal disease. For verapamil the volume of distribution is smaller in uremic patients than in normals and both metabolic and renal clearances are decreased. For nifedipine, on the other hand, similar plasma levels, plasma half life and total plasma clearance are found in uremic patients and normal subjects.
ON THE MUSCARINIC RECEPTORS IN THE URINARY BLADDER AND THE PUTATIVE SUBCLASSIFICATION OF MUSCARINIC RECEPTORS
Authors: Nilvebrant Lisbeth
Published: July 2010

Abstract:The muscarinic cholinergic receptors in the urinary bladders of man, guinea pig, rat and rabbit were studied by means of a receptor binding technique, with L‐quinuclidinyl [phenyl4‐3H]benzilate, (‐)3H‐QNB, as radioligand. The potential role of the receptors in the supersensitivity of the rat bladder to muscarinic agonists, following parasympathetic denervation, hypertrophy and urinary diversion, was also investigated. In addition, the binding of various unlabelled antimuscarinic drugs in the guinea pig bladder was compared to that in other tissues in order to study the putative muscarinic receptor subtypes, commonly referred to as M1and M2. According to this classification the putative M1receptors prevail in discrete areas of the brain, whereas the M2‐receptors predominate in peripheral tissues, such as the exocrine glands and smooth muscles.

The receptor density (but not the qualitative properties of the receptors) in the bladder differed between the species. The affinities of various antimuscarinic drugs were virtually identical in the guinea pig and human bladders. In both species, the binding data were found to correlate with functionalin vitrodata. In the rat bladder, the receptor density was increased after denervation but decreased, below control values, when the denervation was combined with urinary diversion. A decrease was also found after urinary diversion of innervated bladders, whereas the receptor density was unaffected by hypertrophy. These results suggest that the receptors are not involved in the development of supersensitivity and that the receptor levels may be influenced by the functional state of the bladder.

Binding studies with classical muscarinic antagonists indicated that the receptors in the guinea pig bladder are indistinguishable from those in the ileum, heart, parotid gland and cerebral cortex. However, four drugs ‐ namely, oxybutynin, dicyclomine, benzhexol and pirenzepine had a much higher affinity for the receptors in the parotid gland and cortex than for those in the other tissues. Moreover, dicyclomine and benzhexol, like pirenzepine, seemed in the cortex to distinguish between two classes of sites exhibiting high and low affinity. The high affinity sites could be selectively labelled with3H‐benzhexol. The ability of oxybutynin, dicyclomine, benzhexol and pirenzepine to discriminate between the receptors in the parotid gland and those in smooth muscle provides further evidence that the M1/M2concept is inaccurate. The present data indicate that there may be three classes of muscarinic antagonist binding sites.
Biological effects of organic nitroesters and their mechanism of action
Authors: Ahlner Johan , Axelsson Krister L , Bornfeldt Karin
Published: July 2010

Abstract:Organic nitroesters e.g. glyceryltrinitrate (NTG) are of great clinical importance in the treatment of angina pectoris. The most important of their biological effects is vasodilatation of peripheral arteries, peripheral veins and coronary arteries. Other biological effects, of unknown clinical relevance, are effects on myocardial metabolism and on platelet aggregation. In recent years evidences have accumulated that the vasodilating effects of organic nitroesters are mediated via the cGMP‐system, although the exact mechnism of activation of the cGMP‐producing enzyme guanylate cyclase is still obscure. Further research about this may elucidate the mechanism behind the development of tolerance. Another theory concerning the mechanism behind the vasodilating properties of NTG is that arachidonic acid metabolites are involved. However no clearcut evidences have been presented to support this theory. We show in this paper results indicating that arachidonic acid metabolites are of no importance for the vasodilating effects of NTG, at least not in vitro. NTG has also been shown to decrease the intracellular Ca2+‐concentration, an effect probably mediated via cGMP but the exact underlying mechanism is not yet fully understood.
Tolerance development as a pharmacological and clinical problem
Authors: Andersson Karl‐Erik
Published: July 2010

Abstract:Two main forms of aquired pharmacological tolerance may be distinguished, dispositional (pharmacokinetic) and pharmacodynamic. Pharmacodynamic tolerance is common, and can in many cases be attributed to adaptive receptor changes. Such changes of beta‐adrenoceptors have been extensively studied and widely used as models for explaining the mechanisms of tolerance development. The mechanisms behind tolerance to adrenoceptor agonists are discussed, and also tolerance development to these and some other agents when used in the treatment of asthma, uterine hyperactivity and congestive heart failure.
Clinical pharmacological aspects on nitrate tolerance
Authors: Beennann Björn
Published: July 2010

Abstract:There is strong evidence that nitrate tolerance develops rapidly during repeated administration in the systemic resistance vascular bed and that there exists cross tolerance between different nitrates.

There are divergent opinions on how tolerance in the systemic capacitance and the pulmonary vascular bed develops. This may be explained by real differences in tolerance development in ischemic heart disease and congestive heart failure but also by the use of several different preparations of nitrates in the studies performed.

Available data on the pharmacokinetics of nitrates present a complex picture with highly variable bioavailability, clearance and apparent volume of distribution both inter‐ and intraindividually. It is suggested that nitrate tolerance should be studied in very homogenous groups of patients with well defined hemodynamics. The nitrate used should have a very short half‐life allowing for simulation of various modes of administration by intravenous infusion.
The use of invasive techniques to study circulatory effects of nitrates
Authors: Carlens Per
Published: July 2010

Abstract: The hemodynamic effects of NTG are easily studied whith the use of invasive techniques. This article presents and discusses the most commonly used parameters obtained from cardiac catheterization and angiography to describe the effects of nitrates on the central circulation and the left ventricular function.
Exercise testing in patients with heart disease
Authors: Åström Hans
Published: July 2010

Abstract: Exercise tests performed in the clinic give important qualitative and quantitative information. Psychological scaling of main symptoms is most valuable to define a patient's incapacitation and maximal performance. In pharmacological testing this is of utmost importance, particularly in patients with angina pectoris or heart failure. In chronic heart failure there is a poor correlation between the maximal working capacity and the performance of the heart.
Cardiovascular effects of nitroglycerin as evaluated by radioisotope methods
Authors: Svensson Sven‐Eric
Published: July 2010

Abstract: Radioactive methods have successfully been used to elucidate the cardiovascular effects of nitroglycerin for decades. Xenon‐clearance and the single probe technique were originally used to measure changes in myocardial flow caused by sublingual nitroglycerin. Later, similar studies were performed using the Anger camera permitting observations on regional myocardial flow. Microsphere techniques contributed to a better understanding of myocardial distribution of capillary flow. Modern methods in nuclear cardiology such as myocardial scintigraphy and gated blood pool scanning have shown their usefulness in demonstrating the cardiovascular effect of nitroglycerin on cardiac performance. The potential use of these non‐invasive methods to study nitroglycerin effects is discussed.
Microcirculatory methods for evaluating the effect of vasoactive drugs in clinical practice
Authors: Fagrell Bengt
Published: July 2010

Abstract:Microcirculatory methods have to be used in order to be able to evaluate the effect of vasoactive drugs in ischemic skin areas. During the past two decades several new such techniques for studying the microcirculation in man have been developed. These techniques have shown to be of great value for evaluating drug effects in patients with disturbed peripheral circulation. One such method is the non‐invasive Laser Doppler technique. It measures both the nutritional and the non‐nutritional thermoregulatory vascular bed of the skin. The data achieved are only semiquantative, but the method has been shown to be clinically very useful for studying the dynamics of total skin microcirculation in a specific area.

In order to be able to study directly what happens in the nutritional capillaries microscopical methods have to be used. Two such techniques are available in clinical practice. By an ordinary light microscope the capillaries can be directly visualized. A specific classification system can be used to evaluate the degree of ischemic damage to an area. The effect of different kinds of therapeutic procedures for improving the microcirculation in an ischemic area can be easily evaluated. By the combination of a light microscope and a sensitive TV‐camera the blood flow in single skin capillaries can be measured at a magnification of 250–1000 times. This method is well suited for testing the immediate effects of vasoactive substances on the nutritional skin circulation both in healthy subjects and in patients with different kinds of cardiovascular diseases.
Tolerance development during transdermal administration of nitroglycerin in angina pectoris
Authors: Rehnqvist Nina
Published: July 2010

Abstract: Nitroglycerin delivered by transdermal patch technology has been used in angina pectoris patients as well as in heart failure. In angina pectoris patients the plasma concentrations are low over the 24 hours. Effects can be found especially during the first 12 hours after application of the drug even during steady state conditions. The effect of the drug wanes after 24 hours and some studies suggest reduced effect when the patches have been applied for seven to 14 days. The attenuated effects have been claimed to be due to tolerance. Tolerance is, however, never absolute and in other studies this phenomenon is not shown. Furthermore, rebound phenomena may develop when nitroglycerin therapy is withdrawn. The optimal doses and schemes for nitroglycerin administration thus remain to be clarified.
Effects and development of tolerance using transdermal nitrates in the treatment of congestive heart failure
Authors: Sjögren Andreas
Published: July 2010

Abstract: Vasodilator therapy is an accepted mode of treating patients with severe congestive heart failure (CHF). Nitrates have a predominantly beneficial effect on preload, but also afterload may be beneficially modulated with higher doses. There is some evidence that long‐term treatment with isosorbide dinitrate is beneficial in patients with CHF. By contrast, recent reports of 24 hour hemodynamics following transdermal delivery seem disappointing and rapid development of tolerance has been observed.
Tolerance to organic nitroesters in experimental animals. An assessment of in vitro and in vivo investigations
Authors: Axelsson Krister L , Ahlner Johan , Ljusegren Marie Ekstam
Published: July 2010

Abstract:This paper will present a short survey of the literature dealing with nitrate tolerance in experimental animals.

Tolerance towards organic nitroesters has been experimentally established in animal models bothin vivoandin vitro.However the dose of drug used to provoke tolerance has invariably been very high, which makes it difficult to apply experiences from animal experiments to the clinical setting.

Several different hypothesis has been put forward in order to explain the mechanism of tolerance. Today, most evidence seem to point towards an altered metabolism of cGMP as a possible cause of tolerance. Cyclic GMP is the second messenger suggested to mediate the vasodilatory effect of organic nitroesters. The proposed role of critical tissue sulfhydryl groups in mediating the smooth muscle relaxant effect of nitroglycerin (NTG) have made experiments concerning reversal and prevention of tolerance to center on the use of various sulfhydryl reactive compounds. The results of these experiments are as yet ambigous.

Several studies show the existence of cross tolerance between NTG and various other vasodilatory organic nitroesters. In contrast no cross tolerance between NTG and chemically unrelated vasodilator drugs has been observed.

The endogenous vasodilators acetylcholine and atrial natriuretic factor are known to induce cGMP increases. In view of this, their effect on NTG‐tolerant bovine mesenteric arteries was investigated. However no cross‐tolerance appears to exist underin vitroconditions.
Nitrate tolerance. State of the art — Chairman's summary
Authors: Erhardt Leif
Published: July 2010

Abstract:The development of tolerance to the effects of nitrates is well documented in the literature. It can be induced and rapidly reversed with all types of nitrates and it is more pronounced in the arterial as compared to the venous circulation. Crosstolerance between different nitrates exists. Furthermore, tolerance seems more related to high and continuous plasma concentrations and may possibly be avoided by intermittent dosing. The importance of such factors as patient selection, type of nitrate preparation, duration of therapy, the significance of target organs, methods of evaluating the development of nitrate tolerance as well as a summary of the discussions during the workshop is presented.
STUDIES OF TRACE ELEMENTS IN CHILDHOOD CIRRHOSIS
Authors: Sharda B. , Bhandari B.
Published: July 2010

Abstract Cu, Zn, Mn, Cd, Se were studied i n blood, liver, urine, hair and nails in Indian childhood cirrhosis patients and control children by atomic absorption spectrophotometer with flame, carbon rod atomization and hydride generation. The mean copper level in cirrhosis patients and controls was : liver tissue 289.0 ± 79.2 and 62.6 ± 22.3 ug/g wet wt; plasma 1.21 ± 0.17 and 0.97 ± 0.11 ug/ml; urine 419.9 ± 187.1 and 28.2 ± 6.7 ug/24h; hair 42.2 ± 18.1 and 27.2 ± 11.3 ug/g; nails 31.3 ± 8.6 and 22.2 ± 10.1 ug/g, respectively . The mean zinc level in cirrhosis patients and controls was : liver 51.39 ± 7.99 and 84.13 ± 5.36 ug/g wet wt; 26.57 and 155.33 ± 5.04 ug/dl, respectively . The mean Mn, Cd and Se levels in liver, plasma, urine, hair and nails in cirrhosis patients and control children were statistically insignificant.
Aerobic training at moderate intensity reduced protein oxidation in adolescents with Down syndrome
Authors: Ordonez F. J. , Rosety I. , Rosety M. A. , Camacho‐Molina A. , Fornieles G. , Rosety M. , Rosety‐Rodriguez M.
Published: July 2010

Individuals with Down syndrome have been generally described as having high levels of oxidative stress, which have been associated to an increased morbidity. Fortunately, recent studies have reported that aerobic training may upregulate antioxidant defence system both in general population and individuals with trisomy 21. Accordingly, the present study was conducted to ascertain the effectiveness of aerobic training in reducing protein oxidation. To achieve this goal, 31 adolescents with Down syndrome performed a 12‐week training program on a treadmill with 3 days/week, consisting of warm‐up (15 min), main part (20–35 min) at a work intensity of 60–75% of peak heart rate (HRmax=194.5–[0.56 age]) and cool‐down (10 min). A control group included seven age‐, sex‐ and BMI‐matched adolescents with trisomy 21 that did not perform any training program. Plasma carbonyl content was determined by means of a slightly modified Levine method. Pre‐ and post‐training carbonyl contents were 1.98±0.2 [95% confidence intervals (95% CI): 1.94–2.02] nmol/mg protein and 1.16±0.1 (95% CI: 1.14–1.18) nmol/mg protein, respectively. When compared with baseline values, it was decreased significantly (1.98±0.2 vs 1.16±0.1; P<0.001). It was concluded that 12‐week exercise program significantly reduced protein oxidation in adolescents with Down syndrome. Further long‐term follow‐up studies are required to determine whether correction of this oxidant imbalance improves clinical outcomes of individuals with trisomy 21.
Biomechanical responses of different rat tendons to nandrolone decanoate and load exercise
Authors: Marqueti R. C. , Prestes J. , Wang C. C. , Ramos O. H. P. , Perez S. E. A. , Nakagaki W. R. , Carvalho H. F. , Selistre‐de‐Araujo H. S.
Published: July 2010

Androgenic‐anabolic steroids (AAS) have been associated with an increased incidence of tendon rupture. The aim of this study was to compare the biomechanical properties of the rat calcaneal tendon (CT), superficial flexor tendon (SFT), and deep flexor tendon (DFT), and to determine the effect of jump training in association with AAS. Animals were separated into four groups: sedentary, trained, AAS‐treated sedentary rats (AAS), and AAS‐treated and trained animals. Mechanical testing showed that the CT differed from the DFT and SFT, which showed similar mechanical properties. Jump caused the CT to exhibit an extended toe region, an increased resistance to tensional load, and a decreased elastic modulus, characteristics of an elastic tendon capable of storing energy. AAS caused the tendons to be less compliant, and the effects were reinforced by simultaneous training. The DFT was the most affected by training, AAS, and the interaction of both, likely because of its involvement in the toe‐off step of jumping, which we suggest is related to the rapid transmission of force as opposed to energy storage. In conclusion, tendons are differently adapted to exercise, but responded equally to AAS, showing reduced flexibility, which is suggested to increase the risk of tendon rupture in AAS consumers.
Excessive iodine intake during pregnancy in Somali refugees
Authors: Kassim Ismail A.R. , Ruth Laird J. , Creeke Paul I. , Gnat Danielle , Abdalla Fathia , Seal Andrew J.
Published: July 2010

Iodine deficiency and excess are both associated with adverse health consequences, with fetuses, children and pregnant women being most vulnerable to the devastating effects of severe deficiency. It is often assumed that the iodine status of a population if displaced or in a remote or emergency situation is low. However, there is little evidence available to support this assumption, especially among long‐term food‐aid‐dependent pregnant women. An effectiveness trial of a prenatal multiple‐micronutrient supplement that contained 150 µg day−1iodine was conducted in two refugee camps in the North Eastern Province of Kenya in 2002. Urinary iodine concentration (UIC) was measured in a subsample of pregnant women attending antenatal care in Dagahaley (control camp) (n = 74) and Ifo (intervention camp) (n = 63). There was no significant difference in median UIC between the two camps (P = 0.118). The combined median UIC was 730 µg L−1(interquartile range, 780) (5.77 µmol L−1) and exceeded the upper safe limit of 500 µg L−1(3.95 µmol L−1) for pregnant women (P < 0.001), indicating excessive iodine intake. About 20% of the study subjects had ‘more than adequate’ urinary iodine, while over 71% had excessive UIC. Salt iodine content varied between 5.1 and 80.1 ppm in the five market salt samples analysed. In conclusion, excessive iodine intake was evident in the Dadaab refugee camps. Further research needs to be conducted to investigate the source of excess iodine, to determine the measures needed to address excessive iodine intake and to reconsider the World Health Organization/World Food Programme/United Nations Children's Fund guidance on supplementation of vulnerable groups in emergencies.
Comparison of nurse practitioner job core competency expectations of nurse managers, nurse practitioners, and physicians in Taiwan
Authors: Fang Li‐Fen , Tung Heng‐Hsin
Published: July 2010

Purpose: The purpose of this study was to compare expectations of nurse practitioner (NP) job competencies among physicians, nurse managers, and NPs.

Data Sources: A quantitative survey was designed using the Analytic Hierarchy Process to determine the essential NP job competencies based on a checklist of 38 daily activities of NPs, which were recorded for a 10‐day period. Using purposive sampling, a demographic data tool and a Nurse Practitioner Job Competency Questionnaire were completed by 56 participants from 13 hospitals in Taiwan, for which they prioritized and assigned percentage weights for NP competencies. A qualitative open‐ended interview was undertaken to establish the meaning of the hierarchy outcomes that had been obtained.

Conclusions: NPs face the pressure of whether medical staff and nurses agree with NPs' perceptions of their role, which can result in conflicts between nurses and doctors. Taiwanese NPs are still seen as assistants to doctors and, as such, the benefits of the creation of this new field of nursing are not being fully utilized.

Implications for Practice: NPs should be aware of discrepancies among health professionals as to their role, make efforts to communicate what their competencies include to avoid conflicts, and use their abilities effectively.
Saliva crystallisation as a means of determining optimal mating time in bitches
Authors: Pardo‐Carmona B. , Moyano M. R. , Fernández‐Palacios R. , Pérez‐Marín C.C.
Published: July 2010

Objectives: To chart saliva crystallisation patterns throughout pro‐oestrus and oestrus in bitches, and to assess their reliability as a tool for optimising the timing of breeding.

Methods: Six beagle bitches with normal reproductive activity were used. Saliva ferning patterns were established during pro‐oestrus and oestrus. Vaginal cytology, progesterone (P4) levels and behavioural signs were used to determine the optimum mating time. Receiver operating characteristic (ROC) analysis was performed.

Results: Different ferning patterns were scored from 0 to 2. Although variations in saliva crystallisation were noted during the follicular phase of the oestrous cycle in bitches, the test did not prove accurate; test sensitivity was 40·6%, i.e. too low to reliably discriminate the fertile period, while specificity was 86·1%.

ClinicalSignificance: This test could be used to complement other methods of determining the fertile period in bitches, but its potential capacity remains to be demonstrated.