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  • 1
    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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  • 2
    Electronic Resource
    Electronic Resource
    Inhibition of potassium outward currents and pacemaker current in sheep cardiac Purkinje fibres by the verapamil derivative YS 035 (1991)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 344 (1991), S. 653-661 
    Details
    ISSN: 1432-1912
    Keywords: Sheep Purkinje fibre ; Action potential ; Potassium outward currents ; Pacemaker current ; YS 035
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The electrophysiologic mode of action and potency of the verapamil derivative YS 035 (N,N-bis-(3,4-dimethoxyphenethyl)-N-methyl amine) were investigated in sheep cardiac Purkinje fibres. Action potential duration measured at a repolarization level of −60 mV (APD-60) and membrane currents recorded with the two-microelectrode voltage-clamp technique were evaluated. At 10 μmol/l YS 035 APD-60 was increased to about 115% of reference. Prolongation measured as percentage of the respective control exhibited on the average no dependence on stimulation frequency (0.17–2 Hz). At 100 μmol/l membrane became depolarized to about −50 mV and action potentials could no longer be elicited. Further study was focussed on effects on outward currents, mostly activated at a frequency of 0.05 Hz. Transient outward current (ito) was completely blocked at 100 μmol/l and half-maximal inhibition occurred at about 14 μmol/l. Inwardly rectifying potassium current (iK1) was reduced to 47% of reference at 100 μmol/l. An initially activating outward current at positive membrane potentials (iinst) was reduced to 73% at 100 μmol/l. Time-dependent (delayed) outward current (iK) was on the average not affected up to 100 μol/l. Besides inhibition of repolarizing outward currents YS 035 completely blocked pacemaker current (if) at 100 μmol/l and half-maximal reduction was achieved at 5 μmol/l. YS 035 (1–100 μmol/l) did not clearly affect time constants of activation at selected test potentials (IK: +35 mV; if: −90 mV) or inactivation (ito: 0 mV). Voltage-dependent control mechanisms of currents (itto, if) were not influenced by YS 035 but the amount of available current was reduced. In conclusion, the verapamil derivative YS 035 inhibited pacemaker current and potassium outward currents which correlated to a prolongation of cardiac action po tentials. Electrophysiological actions of the compound favour it to be tested in vivo as an antiarrhythmic drug candidate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00174749
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  • 3
    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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  • 4
    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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