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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
    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
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    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    Different inhibition patterns of tedisamil for fast and slowly inactivating transient outward current in rat ventricular myocytes (1998)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 357 (1998), S. 291-298 
    Details
    ISSN: 1432-1912
    Keywords: Key words Rat ventricular myocyte ; Voltage-clamp ; Transient outward current ; Action potential ; Tedisamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tedisamil has been described as a selective inhibitor of a fast inactivating transient outward current (ito,f) in rat ventricular myocytes. Because recent reports demonstrated the existence of a second slowly inactivating transient component (ito,s) we investigated ito,s and differentiated the effects of tedisamil on both transient outward current components and their influence on action potential duration. Standard electrophysiological techniques were used for whole cell recordings at 24–26° C from enzymatically isolated myocytes. Inhibition of ito,f by tedisamil was the result of an acceleration of inactivation at positive test potentials with a concentration for halfmaximal inhibition (EC50) of 4–7 μmol/l, which is confirmatory to reports from other investigators. Our new results show that ito,s is more sensitive to tedisamil with an EC50 of 0.5 μmol/l. Furthermore the pattern of ito,s inhibition is different compared with ito,f, because inactivation of ito,s is not accelerated by tedisamil. Instead the amplitude of the steady state inactivation curve of ito,s is attenuated which indicates a reduction of maximally available current. Ito,s was evaluated by three different methods as time-dependently inactivating current (7.5 s test pulse duration), voltage-dependently inactivated current and tedisamil-sensitive current. All approaches yield similar inactivation curves. The potential for halfmaximal inactivation of ito,s lies about 35 mV more negative than that for ito,f and the slope factor (K = –23 mV) is different to that of ito,f (K = –3 mV). Effectiveness of tedisamil-induced modulation of ito,f and ito,s on action potential repolarization was tested. Action potentials stimulated at 0.5 Hz were not prolonged by 1 μmol/l tedisamil (dominant ito,s block) at a repolarization level of 0 mV but prolonged to about 120% of control at –70 mV. This indicates that ito,f was sufficient to guarantee a regular early repolarization whereas decrease of ito,s delayed the final repolarization. In conclusion, the observation that tedisamil inhibits ito,f and ito,s differently supports the hypothesis that the two ito-components are related to two different channel populations expressed in rat ventricular myocytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005170
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  • 4
    Electronic Resource
    Electronic Resource
    Effects of 17β-estradiol on action potentials and ionic currents in male rat ventricular myocytes (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 788-796 
    Details
    ISSN: 1432-1912
    Keywords: Key words 17β-Estradiol ; Action potential ; Transient ; outward currents ; Calcium current ; Rat ventricular ; myocyte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study describes electrophysiological effects of estrogens in isolated male rat ventricular myocytes. According to the literature these cells do not express the nuclear estrogen receptor. Action potentials or membrane currents were recorded in the whole-cell configuration with standard techniques. Action potential durations (APD) measured at a level of 0 mV (APD 0) and –70 mV (APD –70) were prolonged by 17β-estradiol (0.5 Hz stimulation frequency, 24–26° C). Threshold concentration was 1 μmol/l. At the highest concentration used (30 μmol/l) no saturation of the response was reached and APD 0 was 162% and APD –70 was 230% of the respective control. The resting potential remained unaffected in most cells. The prolongation induced by 17β-estradiol developed rapidly and reached a steady state 10 min after start of hormone superfusion. Effects of estrogen were completely reversible during 10–15 min wash-out with hormone-free solution. The extent of prolongation (10 μmol/l 17β-estradiol) was frequency dependent. Expressed as percentage of the respective control APD 0 (or APD –70) was 115% (188%) at 0.05 Hz, 118% (163%) at 0.5 Hz and 99% (129%) at 5 Hz stimulation frequency. The response was stereoselective, because 30 μmol/l 17α-estradiol did not prolong action potentials (APD 0: 101%, APD –70: 104% of the respective control, 0.5 Hz stimulation frequency). The endogenous estrogens estrone and estriol were less effective than 17β-estradiol. With 30 μmol/l estrone (0.5 Hz stimulation frequency) APD 0 was 103% and ADP-70 148% of control and with 30 μmol/l estriol APD 0 was 135% and APD –70 137% of control. The prolongation of action potentials can be explained by inhibition of transient outward current which, in rat ventricle, is composed of fast (i to,f) and slowly (i to,s) inactivating components. At 30 μmol/l 17β-estradiol i to,f was reduced to 50% and i to,s to 43% of their maximal amplitudes. The voltage sensor of i to,f or i to,s was hardly affected. Additionally, 17β-estradiol decreased the calcium current (i Ca,L) to 76% (10 μmol/l) and 38% at 30 μmol/l. The inwardly rectifying potassium current (i K1) was reduced partly with 30 μmol/l 17β-estradiol and its amplitude was 72% of control at –90 mV (inward current flow) and 65% at –40 mV (outward current flow). These results show that 17β-estradiol is active in cardiac cells which do not express the nuclear estrogen receptor. The hormone exerts class III activity and reduces calcium inward current. These effects, however, occur in vitro with concentrations above the physiological level and therefore may be without significance in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005119
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