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  • 1
    Electronic Resource
    Electronic Resource
    Inhibition of pacemaker current by the bradycardic agent ZD 7288 is lost use-dependently in sheep cardiac Purkinje fibres (1995)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 353 (1995), S. 64-72 
    Details
    ISSN: 1432-1912
    Keywords: Sheep cardiac Purkinje fibre ; Voltage-clamp ; Pacemaker current ; Use dependence ; Specific bradycardic agent ; ZD 7288
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The inhibition of the pacemaker current (i f) in sheep cardiac Purkinje fibres by ZD 7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride] is lost use-dependently. This disinhibition of i f was investigated by using the two-microelectrode voltage-clamp technique. The pulse protocol consisted of a rest period (holding potential of about -50 mV, 1–10 μmol/l ZD 7288) followed by a train of test pulses (potential negative to -100 mV, stimulation frequency 0.05 Hz). At the beginning of the first test pulse there was an immediate reduction of i f but inhibition was lost during continued stimulation. Activation of i f is sigmoidal and the early delay in current activation was prolonged from 33 ms (no ZD 7288) to 424 ms (10 μmol/l ZD 7288). Therefore hardly any disinhibition occurred during short test pulses (0.5 s). During longer test pulses (5 s, -120 mV, 10 μmol/l) disinhibition developed with a time constant of about 2 s. The inhibition of i f by ZD 7288 was lost voltage-dependently. With 10 μmol/l ZD 7288 the half-maximal disinhibition occurred at -92 mV and the slope factor of the disinhibition/voltage curve (Boltzmann relation) was 4.8 mV. The voltage-dependent disinhibition could be abolished largely by extracellular application of protease (0.5 mg/ml, 7 min). After prior disinhibition, reinhibition at the holding potential (about -50 mV) followed a bi-exponential time course indicating that inhibition may be produced by a fast (τ=0.7 min) and a slow component (τ=20–30 min). Increasing ZD 7288 concentration from 1 to 10 μmol/l accelerated reinhibition, mainly by an increase of the amplitude (A) of the fast component. The ratio A fast/A sIow was 0.399 at 1 μmol/l and 2.65 at 10 μmol/1 ZD 7288. The reinhibition of i f was unchanged by shifting the holding potential from -50 mV to -20 mV Trials to wash out the effects of 10 μmol/l ZD 7288 gave two results. The inhibition of i f was slightly reversed after a wash-out of 1.5 h with drug-free solution. A second effect of the drug, the fast reinhibition, could be completely removed by washout. In summary i f is inhibited by ZD 7288 at membrane potentials at which the virtual i f gate is closed. Disinhibition occurs during long-lasting hyperpolarization but will hardly be operative in unclamped fibres under physiological conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168917
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Inhibition of pacemaker current by the bradycardic agent ZD 7288 is lost use-dependently in sheep cardiac Purkinje fibres (1995)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 353 (1995), S. 64-72 
    Details
    ISSN: 1432-1912
    Keywords: Key words Sheep cardiac Purkinje fibre ; Voltage-clamp ; Pacemaker current ; Use dependence ; Specific bradycardic agent ; ZD 7288
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The inhibition of the pacemaker current (i f) in sheep cardiac Purkinje fibres by ZD 7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride] is lost use-dependently. This disinhibition of i f was investigated by using the two-microelectrode voltage-clamp technique. The pulse protocol consisted of a rest period (holding potential of about –50 mV, 1–10 μmol/l ZD 7288) followed by a train of test pulses (potential negative to –100 mV, stimulation frequency 0.05 Hz). At the beginning of the first test pulse there was an immediate reduction of i f but inhibition was lost during continued stimulation. Activation of i f is sigmoidal and the early delay in current activation was prolonged from 33 ms (no ZD 7288) to 424 ms (10 μmol/l ZD 7288). Therefore hardly any disinhibition occurred during short test pulses (0.5 s). During longer test pulses (5 s, –120 mV, 10 μmol/l) disinhibition developed with a time constant of about 2 s. The inhibition of i f by ZD 7288 was lost voltage-dependently. With 10 μmol/l ZD 7288 the half-maximal disinhibition occurred at –92 mV and the slope factor of the disinhibition/voltage curve (Boltzmann relation) was 4.8 mV. The voltage-dependent disinhibition could be abolished largely by extracellular application of protease (0.5 mg/ml, 7 min). After prior disinhibition, reinhibition at the holding potential (about –50 mV) followed a bi-exponential time course indicating that inhibition may be produced by a fast (τ=0.7 min) and a slow component (τ=20–30 min). Increasing ZD 7288 concentration from 1 to 10 μmol/l accelerated reinhibition, mainly by an increase of the amplitude (A) of the fast component. The ratio A fast/A slow was 0.399 at 1 μmol/l and 2.65 at 10 μmol/l ZD 7288. The reinhibition of i f was unchanged by shifting the holding potential from –50 mV to –20 mV. Trials to wash out the effects of 10 μmol/l ZD 7288 gave two results. The inhibition of i f was slightly reversed after a wash-out of 1.5 h with drug-free solution. A second effect of the drug, the fast reinhibition, could be completely removed by wash-out. In summary i f is inhibited by ZD 7288 at membrane potentials at which the virtual i f gate is closed. Disinhibition occurs during long-lasting hyperpolarization but will hardly be operative in unclamped fibres under physiological conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168917
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    The positive inotropic, antiarrhythmic and Na+, K+-ATPase inhibitory effects of the isoquinoline derivative, BIIA (1980)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 312 (1980), S. 187-192 
    Details
    ISSN: 1432-1912
    Keywords: Isoquinoline derivative BIIA ; Na+, K+-ATPase ; Action potential ; Antiarrhythmic activity ; Positive inotropic action
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of the isoquinoline derivative 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-5,1-a-isoquinoline-hydrochloride (BIIA) were studied in the cat in situ and guinea-pig isolated heart preparations: 1. Administration of BIIA (2 mg/kg i.v.) to anaesthetized cats results in a rapid rise in cardiac (dP/dt)max, decrease in heart rate and increase in systolic and diastolic blood pressure. These effects reach their maximum within a minute and disappear within 20 min. With increasing dosage a depression in the S T-segment of the ECG is observed, being similar to that induced by cardiac glycosides. Toxic doses lead to ventricular flutter and fibrillation. 2. In the concentration range of 0.3–10 μmol/l, BIIA exerts a strong positive inotropic effect in isolated guinea-pig heart preparations which is not mediated via α- or β-adrenoceptors and a negative chronotropic effect in spontaneously beating right atria. 3. BIIA inhibits Na+, K+-ATPase preparations isolated from guinea-pig heart and kidney in the range of 5–100 μmol/l. Unlike that of cardiac glycosides, this inhibition is competitive with Na+. The concentration response curves for the positive inotropic and Na+, K+-ATPase inhibitory effects of BIIA are both one order of magnitude higher in concentration than the respective concentration response curves found for ouabain. 4. BIIA is more potent than quinidine in increasing the threshold for arrhythmia induced by alternating current in isolated guinea-pig atria and papillary muscles. However, at a concentration of 3 μmol/l, BIIA can itself be arrhythmogenic. 5. A delay of repolarisation of the cardiac action potential may account for the antiarrhythmic properties of this drug, whereas strong inhibition of Na+, K+-ATPase and a decrease in resting potential may account for its toxicity at high concentrations. As there is a decrease in the plateau phase of the action potential at positive inotropic concentrations of BIIA, the increase in the force of contraction cannot be explained by alterations in the transmembrane potential, but similar to cardiac glycosides may be attributed to an inhibition of the Na+, K+-ATPase of the cell membrane.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00569729
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    Paper (German National Licenses)
    Fulltext
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