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  • Adenylyl cyclase Gi-protein  (2)
  • Cardiac glycosides  (1)
  • Key words Repetitive monomorphic ventricular tachycardia – catheter ablation – idiopathic ventricular tachycardia – programmed electrical stimulation  (1)
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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    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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