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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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  • 2
    Electronic Resource
    Electronic Resource
    Effects of the bradycardic agent ZD 7288 on membrane voltage and pacemaker current in sheep cardiac Purkinje fibres (1994)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 350 (1994), S. 677-684 
    Details
    ISSN: 1432-1912
    Keywords: Sheep cardiac Purkinje fibre ; Pacemaker current ; Action potential ; Bradycardic agent ; ZD 7288
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The bradycardic mechanism of ZD 7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride) was investigated in sheep cardiac Purkinje fibres. The pacemaker if-current measured with the two-microelectrode voltage-clamp technique, as well as the diastolic depolarization rate and the frequency of spontaneously active fibres were evaluated. ZD 7288 did inhibit if-current. The if-amplitude recorded with a 0.8s-lasting test pulse from about −50 mV to −100 mV was reduced to 50% of control at 0.85 μmol/l and to 5% of control at 10 μmol/l. The threshold potential of if-activation was unaffected at a concentration of 1 μmol/l ZD 7288. The time constant of if-activation at different test potentials was not changed by 1 μmol/l ZD 7288. The drug was equally effective during if-activation with a 0.5 s-lasting test pulse applied at 0.05 Hz or 0.5 Hz. During long lasting (5 s) hyperpolarizing test pulses (−120 mV) the inhibition of if-current was removed. In constantly stimulated Purkinje fibres (0.5 Hz) the slope of the early diastolic depolarization was decreased by ZD 7288. The half-maximal effect occurred at 0.92 μmol/l. There was strong correlation over the concentration range of 0.01 to 10 μmol/l ZD 7288 between the decrease of the slope of early diastolic depolarization and inhibition of if-amplitude recorded with 0.8s-lasting test pulses to −100 mV. The correlation coefficient was r = 0.97. These results will explain the decrease in frequency of spontaneously active (about 0.6 Hz) Purkinje fibres. At 0.3 μmol/l ZD 7288 spontaneous activity had stopped in 8 of 11 preparations. Complete recovery of drug-induced effects on the frequency was gained after 3 h of wash-out with drug-free solution.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169374
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  • 3
    Electronic Resource
    Electronic Resource
    Modulation of pacemaker activity in sheep cardiac Purkinje fibers by stimulation of β-adrenoceptor subtypes (1997)
    Springer
    Basic research in cardiology 92 (1997), S. 25-34 
    Details
    ISSN: 1435-1803
    Keywords: Sheep cardiac Purkinje fibers ; action potentials ; automaticity ; β1-β2- ; adrenoceptors-(−) ; isoproterenol ; (−)-noradrenaline ; procaterol ; bisoprolol ; ICI 118,551
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The electrophysiological effects mediated by β1- and β2- in spontaneously active sheep cardiac Purkinje fibers were investigated using the non-selective agonist (−)-isoproterenol (IPN) and the selective agonists (−)-noradrenaline (β1) and procaterol (β2) in the absence and presence of the selective antagonists bisoprolol (β1) and ICI 118,551 (β2). IPN (0.01 μmol/l) increased the spontaneous rate by 54% and the slope of diastolic depolarization by 68% of the respective control values. Further, IPN increased the action potential duration at −20 mV (APD −20 mV) from 96 to 154 ms, reduced the APD −70 mV by 17% and the duration of the diastole by 39% and slightly hyperpolarized the maximum diastolic potential. These effects were partially inhibited by ICI 118,551 (0.03 μmol/l), diminished by bisoprolol (0.1 μmol/l) and almost completely blocked by the combination of both antagonists. Concentration response curves of IPN were influenced by the selective antagonists as follows: ICI 118,551 (0.03 μmol/l) shifted the curves to the right by 0.2–0.4 log units and increased the slope factor. Bisoprolol (0.1 μmol/l) induced a greater shift to the right by 1.1–1.5 log units. Combination of bisoprolol with ICI 118,551 shifted the curves to the right by 1.5–1.7 log units. Noradrenaline (0.3 μmol/l) elicited similar actions as IPN. Bisoprolol (0.1 μmol/l) shifted the concentration response curves of noradrenaline to the right by 1.1–1.9 log units. Actions of procaterol (0.1 μmol/l) were weak, attained only 15–35% of the maximal effects of IPN and could be blocked by ICI 118,551 (0.03 μmol/l). These results show that the increase of pacemaker activity induced by catecholamines in sheep cardiac Purkinje fibers is predominantly mediated by stimulation of β1. However, contribution of β2 mediated effects could be demonstrated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00803754
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    Paper (German National Licenses)
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