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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 63 (1985), S. 1253-1264 
    ISSN: 1432-1440
    Keywords: Cardiac glycosides ; Tolerance ; Heart cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In cultured heart muscle cells from 10–13 day-old chicken embryos, the effects of acute (4 h) and chronic (3 days) exposure of the cells to varying concentrations of ouabain have been studied. In these cells, the cardiac glycoside ouabain binds to a specific cardiac glycoside receptor (KD=4 × 10−7 M; 750,000 receptors/cell). Binding to this receptor results in inhibition of active Na+/K+-transport [EC50 for active (86Rb+ + K+)-influx=4 × 10−6 M], and in an increase in beating velocity (“positive inotropic effect”;; EC50=4 × 10−7 M); toxic signs (arrhythmias) appear at concentrations ≥ 6 × 10−7 M. During exposure of the cells to 3 × 10−6 M ouabain for 3 days, tolerance develops with respect to both the positive inotropic and the toxic effect. The mechanism underlying this tolerance is identified as an increase in the number of active sodium pump molecules per cell, while the binding properties of the cardiac glycoside receptor remain unchanged. The development of cardiac glycoside tolerance is only observed in the presence of severe impairment of Na+/K+-homeostasis, due to cardiac glycoside-induced inhibition of active Na+/K+-transport. This, however, only occurs in the presence of toxic (receptor occupation ≥ 60%), but not in the presence of positive inotropic, non-toxic (receptor occupation 20–60%), ouabain concentrations. We conclude that the development of cardiac glycoside tolerance during long-term treatment in patients with heart failure should not occur with submaximal dose regimens, when toxic signs (arrhythmias) are absent.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 65 (1987), S. 308-316 
    ISSN: 1432-1440
    Keywords: Beta-blocker ; Withdrawal phenome-non ; Endogenous noradrenaline ; Heart cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An in vitro model to evaluate the role of endogenous noradrenaline in the beta-blocker withdrawal phenomenon is described: Beating chicken heart muscle cells (5000 beta1-adrenoceptors/cell) and heart nonmuscle cells (3000 beta2-adrenoceptors/cell) were cultured in serum-free, hormone-supplemented medium. Basal state, subtype selective down-regulation of beta-adrenoceptors by endogenous noradrenaline (decrease in receptor number, beta1 more than beta2) was simulated by addition of noradrenaline to the culture medium; chronic beta-blockade was simulated by exposure of the cells for 3 days to various betablockers (propranolol, no ISA; timolol, slight ISA; pindolol, strong ISA). Beta-blocker withdrawal phenomenon — increased response in isoproterenol-induced cAMP production and positive inotropy — is correlated with the increase in the number of beta-adrenoceptors after withdrawal of the drugs. Propranolol induces a withdrawal phenomenon at every degree of noradrenaline-induced basal state down-regulation of beta-adrenoceptors; in contrast, a withdrawal phenomenon by pindolol is only seen at a higher degree of beta-adrenoceptor down-regulation. In the presence of physiological noradrenaline concentrations pindolol affects beta-adrenoceptor subtypes in a qualitatively different manner: the number of beta1-adrenoceptors is increased, the number of beta2-adrenoceptors is decreased. This finding demonstrates that the intrinsic sympathomimetic activity of nonselective beta-blockers can manifest itself only if the receptors are not strongly down-regulated. As beta2-adrenoceptors are present in a much less down-regulated state than beta1, ISA mainly acts on beta2-adrenoceptor subtype, thus, presenting a beta2-“pseudo-selectivity” of ISA.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0738
    Keywords: Cholinesterase ; Soman ; Oxime ; HI 6 ; Dopamine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of atropine and the oxime HI 6 on running performance, brain and plasma cholinesterase activity and brain catecholamines were investigated in mice intoxicated with sublethal doses of soman (100 μg/kg s.c.). The running time on a rotating mash wire drum (total running time 60 min) after injection of soman was reduced to 17.2 min. Treatment with atropine (10 mg/kg i.p.) or HI 6 (55 mg/kg i.p.) improved the running peformance to 48.2 and 44.8 min, respectively. Cholinesterase activity was decreased in soman poisoned mice to 47.3% in plasma and 43.5% in brain. Therapy with the oxime HI 6 resulted in a reactivation of soman-inhibited peripheral cholinesterase to 76.6%, but failed to reactivate central cholinesterase. Dopamine levels in mice brain were elevated in soman poisoning by 23.2%, whereas noradrenaline levels remained unchanged. The increase in brain dopamine levels was antagonized by atropine as well as by HI 6. The results of this study lead to the speculation that central dopaminergic mechanisms may be involved in soman toxicity as well as in the antidotal action of atropine and the mainly peripherally acting oxime HI 6.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0738
    Keywords: Muscarinic acetylcholine receptor ; G-protein ; Oxime ; HGG-12 ; Cardiac tissue
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Direct interactions of the bispyridinium oxime HGG-12 with muscarinic acetylcholine receptors were investigated in porcine cardiac atrial membranes. Competition binding experiments using the radiolabeled muscarinic receptor antagonist (3H)QNB revealed specific binding of HGG-12 to muscarinic acetylcholine receptors of porcine atrial membranes with a dissociation constant of 3.8×10−7 mol/l. Muscarinic acetylcholine receptor-stimulated binding of the radiolabeled GTP analog (35S)GTP[S] to guanine nucleotide binding proteins (G-proteins) was used to study antagonistic and possible agonistic effects of HGG-12 at muscarinic acetylcholine receptors. HGG-12 completely inhibited carbachol- and oxotremorine-stimulated (35S)GTP[S] binding to pertussis toxin sensitive and insensitive G-proteins in a competitive manner. Inhibition constants (KI) of HGG-12 for blockade of carbachol- and oxotremorine-stimulated GTP[S]-binding (9.7×10−7 mol/l and 1.7×10−6 mol/l, respectively) were higher by about a factor of 100 than those of the muscarinic acetylcholine receptor antagonist atropine. In the absence of muscarinic acetylcholine receptor agonists, HGG-12 by itself had no stimulatory effect on (35S)GTP[S] binding in porcine atrial membranes. The results of this study show that the oxime HGG-12 is a competitive antagonist without intrinsic activity at porcine atrial muscarinic acetylcholine receptors. The stimulatory action of HGG-12 on muscarinic acetylcholine receptors which has been described by several authors is, therefore, suggested to be due to partial inhibition of acetylcholinesterase by the oxime rather than to direct agonism at muscarinic acetylcholine receptors.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Molecular and Cellular Endocrinology 82 (1991), S. C215-C221 
    ISSN: 0303-7207
    Keywords: Adenylyl cyclase ; Desensitization ; G-protein ; Up-regulation ; βγ-Dimers
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1435-1285
    Keywords: Schlüsselwörter Repetitive monomorphe ventrikuläre Tachykardie – Katheterablation – idiopathische ventrikuläre Tachykardie – programmierte elektrische Stimulation ; Key words Repetitive monomorphic ventricular tachycardia – catheter ablation – idiopathic ventricular tachycardia – programmed electrical stimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Repetitive monomorphic ventricular tachycardia (RMVT) is defined by the presence of numerous monomorphic isolated, premature ventricular complexes, couplets, and runs of unsustained ventricular tachycardia having the same morphology in patients without structural heart disease. Patients with RMVT mostly demonstrate the typical left bundle branch block morphology with normal or rightward axis during tachycardia. At our institution 20 patients with RMVT have been systemically studied: a syncope had occurred in 35% of our patients, in three cases a syncope was the first manifestation of the RMVT. Of our RMVT patients, 25% developed sustained episodes (〉3 min) of ventricular tachycardia as documented by Holter ECG. The salvos of ventricular tachycardia are generally short in RMVT. This behavior and the typical exercise dependence differentiates RMVT from paroxysmal sustained idiopathic ventricular tachycardia. Exercise testing is mandatory for correct diagnosis of RMVT. In our institution 85–90% of RMVT patients demonstrated runs of ventricular tachycardia or sustained ventricular tachycardia while on a treadmill (exercise test) or during isoproterenol infusion. RMVT was inducible by programmed electrical right ventricular stimulation in only 13% of our patients. Therefore, in patients with suspected RMVT programmed electrophysiological stimulation is only useful to differentiate a ventricular tachycardia from a supraventricular tachycardia with bundle brunch block or in patients with unexplained syncope. The prognosis is considered generally good; in our patients no life threatening ventricular tachyarrhythmias were observed during a follow-up of up to 4 years. Verapamil and β-adrenoceptor antagonists generally offer symptomatic improvement. In some cases treatment with a class III antiarrhythmic agent is necessary. While drug-refractory paroxysmal sustained idiopathic ventricular tachycardia can be abladed with both immediate and long-term success, catheter ablation of RMVT is only rarely indicated.
    Notes: Zusammenfassung Als repetitive monomorphe ventrikuläre Tachykardie (RMVT) wird eine rechtsventrikuläre Tachykardie bei Patienten ohne strukturelle Herzerkrankung mit überwiegend singulärer, bigeminiformer oder salvenartiger monomorpher ventrikulärer Extrasystolie bezeichnet. Zumeist liegt eine Linksschenkelblock-Konfiguration mit Indifferenz- oder Steiltyp während der ventrikulären Tachykardie vor. In unserem Kollektiv von 20 Patienten war es bei 35% anamnestisch zu Synkopen gekommen. In drei Fällen war eine Synkope Erstmanifestation der RMVT. Bei 25% unserer RMVT-Patienten waren auch anhaltende ventrikuläre Tachykardien mit einer Dauer 〉3 min im Langzeit-EKG dokumentiert. Wesentliche Differentialdiagnose einer RMVT ist die paroxysmale anhaltende Form der idiopathischen ventrikulären Tachykardie. Neben dem typischen salvenartigen Auftreten der ventrikulären Extrasystolie ist die Belastungsabhängigkeit wegweisend für die Diagnose einer RMVT. In 85–90% der Fälle gelang in unserem Patientenkollektiv die Auslösung von Salven einer RMVT oder einer anhaltenden RMVT mittels Ergometrie oder eines Isoproterenol-Testes. Die Auslösung einer RMVT mittels programmierter rechtsventrikulärer Stimulation gelang in unserem Patientenkollektiv nur in 13% der Fälle. Somit ist die Durchführung einer elektrophysiologischen Untersuchung nur zur Unterscheidung einer ventrikulären von einer supraventrikulären Tachykardie mit Schenkelblock oder zum Ausschluß einer anderen ventrikulären Tachyarrhythmie bei stattgehabter Synkope erforderlich. Die Prognose der RMVT ist gut; in unserem Kollektiv von RMVT-Patienten traten während einer Nachbeobachtungszeit von bis zu 4 Jahren keine lebensbedrohlichen ventrikulären Tachyarrhythmien auf. Die Mehrzahl der Patienten mit RMVT läßt sich mit Verapamil oder β-Blocker ausreichend gut einstellen. Gelegentlich ist eine Therapie mit einem Klasse-III-Antiarrhythmikum erforderlich. Während bei der paroxysmalen anhaltenden Form der idiopathischen ventrikulären Tachykardie bei medikamentöser Therapierefraktärität eine Katheterablation mit hervorragenden Erfolgsaussichten vorgenommen werden kann, ist die Durchführung einer Katheterablation bei RMVT nur in seltenen Fällen indiziert.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1435-1285
    Keywords: Key words Electroanatomic 3D-map – sinuatrial activation ; Schlüsselwörter Elektroanatomisches 3D-Map – sinuatriale Aktivierung
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die erfolgreiche Radiofrequenz-Katheterablation tachykarder Rhythmusstörungen setzt eine genaue Lokalisation des arrhythmogenen Substrats während der elekrophysiologischen Untersuchung voraus. Mit Hilfe der elektromagnetischen Technologie des neuen Mappingsystems CARTO™ ist die dreidimensionale farbcodierte elektroanatomische Darstellung der Aktivierungssequenz möglich. Mapping der sinutrialen Aktivierung des rechten Vorhofs bei 11 Patienten lieferte erste klinische Erfahrungen mit diesem neuen System. Die physiologische Aktivierungssequenz ließ sich bei allen Patienten komplikationslos dreidimensional darstellen und der Sinusknoten als physiologischer Aktivitätsfokus mit interindividueller Variabilität lediglich in der Sagittalebene lokalisieren. Das nichtfluoroskopische Mappingsystem erlaubt eine Visualisierung der elektrischen Aktivität und kann dadurch die Lokalisierung des arrhythmogenen Substrats während Tachykardie vor erfolgreicher Ablation erleichtern.
    Notes: Summary Prerequisite for successful radiofrequency catheter ablation of tachycardias is the exact mapping during the electrphysiologic study. The new mapping system CARTO™ allows a three-dimensional color-coded electroanatomic map of impulse propagation using electromagnetic technology. Mapping of sinuatrial activation in the right atrium of 11 patients represents the first clinical experience with this new system. The physiological activation sequence could be determined in all patients three-dimensionally, and the sinus node could be localized as a physiological activation focus with interindividual variability only in the sagital plane without complications. The nonfluoroscopic mapping system allows high resolution visualization of electrical activity and may therefore improve precision and simplify the determination of the arrhythmogenic substrate during tachycardias for successful catheter ablation.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1912
    Keywords: Key words Muscarinic cholinoceptor ; Adenylyl cyclase Gi-protein ; β-Adrenoceptor ; Heart cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Exposure of neonatal rat cardiomyocytes for 3 days to the muscarinic cholinoceptor agonist carbachol led to a concentration-dependent increase in adenylyl cyclase stimulation by the β-adrenoceptor agonist isoproterenol by up to 115% (at 1 mmol/l carbachol). In addition, direct adenylyl cyclase stimulation by forskolin was increased in carbachol (1 mmol/l)-treated cells by 32%. Pretreatment of the rat cardiomyocytes with pertussis toxin, which enhances adenylyl cyclase activity by a functional inactivation of the inhibitory G-protein (Gi), was performed to investigate the possible role of Gi-proteins in carbachol-induced sensitization of adenylyl cyclase stimulation. After pretreatment of the cells with pertussis toxin, the carbachol-mediated increase in forskolin-stimulated adenylyl cyclase activity was lost and the carbachol-mediated increase in β-adrenoceptor-stimulated adenylyl cyclase activity was attenuated. Labelling of the 40 kDa pertussis toxin substrates in cardiomyocyte membranes was decreased by carbachol in a concentration-dependent manner by up to 34% (at 1 mmol/l carbachol). The number and affinity of β 1-adrenoceptors was unaltered following the chronic carbachol treatment. The specific protein synthesis inhibitor Pseudomonas exotoxin A was used to study whether the carbachol-induced decrease in the level of pertussis toxin-sensitive G-proteins and increase in adenylyl cyclase activity depend on de-novo protein synthesis. Pseudomonas exotoxin A inhibits peptide chain elongation by ADP-ribosylating elongation factor 2. Treatment of the cells with 1 ng/ml Pseudomonas exotoxin A for 3 days led to a reduction in the subsequent ADP-ribosylation of elongation factor 2 in the cytosol of the heart muscle cells by 57%. Exposure of the cells to 1 mmol/l carbachol for 3 days increased ADP-ribosylation of elongation factor 2 by 40% concomitant with a slight (about 20%) increase in the total protein content of the cardiomyocytes. The partial protein synthesis inhibition by Pseudomonas exotoxin A had no influence on the carbachol-induced decrease in the level of pertussis toxin-sensitive G-proteins. Similarly, the carbachol-induced increase in adenylyl cyclase responsiveness also remained unaltered by Pseudomonas exotoxin A. The data presented indicate that chronic muscarinic cholinoceptor agonist treatment decreases the level of α-subunits of Gi-proteins. This decrease in Gia-subunits is apparently at least in part responsible for the observed increase in adenylyl cyclase responsiveness after chronic carbachol treatment.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1912
    Keywords: Key words α1-adrenoceptor ; β-adrenoceptor ; Inositol triphosphate ; n-3 fatty acid ; Cardiomyocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The beneficial effects of n-3 polyunsaturated fatty acids of fish oil in the prevention of fatal arrhythmias in myocardial ischemia were suggested to be at least in part mediated by a modulation of dihydropyridine-sensitive L-type calcium channels. As cardiac α1-adrenoceptor stimulation has been suggested to have no significant effect on L-type calcium channels, the aim of this study using cultured neonatal rat cardiomyocytes was to investigate whether chronic n-3 polyunsaturated fatty acid exposure may have an influence on α1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias. Pretreatment of the rat cardiomyocytes for 3 days in the presence of the n-3 polyunsaturated fish oil-derived fatty acid docosahexaenoic acid (60 μmol/l) markedly decreased α1-adrenoceptor-stimulated increase in contraction velocity and induction of arrhythmias. The increase in contraction velocity of the cardiomyocytes induced by the β-adrenoceptor agonist isoprenaline was also markedly reduced by the n-3 fatty acid pretreatment. Basal contractile amplitude and spontaneous beating frequency of the cardiomyocytes were not significantly altered by the docosahexaenoic acid exposure. The pretreatment of the rat cardiomyocytes for 3 days in the presence of docosahexaenoic acid (60 μmol/l) decreased α1-adrenoceptor-stimulated formation of the calcium-mobilizing second messenger IP3 and its metabolites IP2 and IP1 by 55%. The depression of IP3 formation by docosahexaenoic acid treatment was not mediated by a decreased uptake of myo-inositol into the cardiomyocytes nor by a decreased synthesis of phosphatidylinositol bisphosphate (PIP2), the substrate of phospholipase C. The level of glycerol-3-phosphate, an important substrate of the phosphoinositide cycle, was unaltered by the docosahexaenoic acid pretreatment. Receptor binding studies revealed that the dissociation constant and maximal binding capacity of the α1-adrenoceptor antagonist (3H)prazosin was unchanged by the n-3 polyunsaturated fatty acid exposure. β-Adrenoceptor- and forskolin-stimulated adenylyl cyclase activities were not diminished by the docosahexaenoic acid pretreatment. Chronic exposure of the cardiomyocytes to the n-6 polyunsaturated fatty acid arachidonic acid (60 μmol/l) did neither significantly alter α1-adrenoceptor-induced inositol phosphate formation nor α1-adrenoceptor-stimulated increase in contraction velocity. The results presented show that chronic n-3 polyunsaturated fatty acid pretreatment of rat cardiomyocytes leads to a marked impairment of α1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias concomitant with a n-3 fatty acid-induced decrease in IP3 formation. This derangement of the phosphoinositide pathway by chronic n-3 fatty acid exposure may, thus, contribute to the beneficial effects of fish oil-derived fatty acids in the prevention of fatal arrhythmias in myocardial ischemia.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1912
    Keywords: Muscarinic cholinoceptor ; Adenylyl cyclase Gi-protein ; \ Adrenoceptor ; Heart cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Exposure of neonatal rat cardiomyocytes for 3 days to the muscarinic cholinoceptor agonist carbachol led to a concentration-dependent increase in adenylyl cyclase stimulation by the \-adrenoceptor agonist isoproterenol by up to 115% (at 1 mmol/l carbachol). In addition, direct adenylyl cyclase stimulation by forskolin was increased in carbachol (1 mmol/l)-treated cells by 32010. Pretreatment of the rat cardiomyocytes with pertussis toxin, which enhances adenylyl cyclase activity by a functional inactivation of the inhibitory G-protein (Gi), was performed to investigate the possible role of Gi proteins in carbachol-induced sensitization of adenylyl cyclase stimulation. After pretreatment of the cells with pertussis toxin, the carbachol-mediated increase in forskolin-stimulated adenylyl cyclase activity was lost and the carbachol-mediated increase in \-adrenoceptor-stimulated adenylyl cyclase activity was attenuated. Labelling of the 40 kDa pertussis toxin substrates in cardiomyocyte membranes was decreased by carbachol in a concentration-dependent manner by up to 34010 (at 1 mmol/l carbachol). The number and affinity of \1-adrenoceptors was unaltered following the chronic carbachol treatment. The specific protein synthesis inhibitor Pseudomonas exotoxin A was used to study whether the carbachol-induced decrease in the level of pertussis toxin-sensitive G-proteins and increase in adenylyl cyclase activity depend on de-novo protein synthesis. Pseudomonas exotoxin A inhibits peptide chain elongation by ADP-ribosylating elongation factor 2. Treatment of the cells with 1 ng/ml Pseudomonas exotoxin A for 3 days led to a reduction in the subsequent ADP-ribosylation of elongation factor 2 in the cytosol of the heart muscle cells by 57%. Exposure of the cells to 1 mmol/l carbachol for 3 days increased ADP-ribosylation of elongation factor 2 by 40% concomitant with a slight (about 20%) increase in the total protein content of the cardiomyocytes. The partial protein synthesis inhibition by Pseudomonas exotoxin A had no influence on the carbachol-induced decrease in the level of pertussis toxin-sensitive G-proteins. Similarly, the carbachol-induced increase in adenylyl cyclase responsiveness also remained unaltered by Pseudomonas exotoxin A. The data presented indicate that chronic muscarinic cholinoceptor agonist treatment decreases the level of α-subunits of Gi- proteins. This decrease in Giα- subunits is apparently at least in part responsible for the observed increase in adenylyl cyclase responsiveness after chronic carbachol treatment.
    Type of Medium: Electronic Resource
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