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  • Voltage-clamp  (5)
  • Sheep Purkinje fibre  (3)
  • Use dependence  (2)
  • 1
    Digitale Medien
    Digitale Medien
    Activation of a potassium outward current by zymosan and opsonized zymosan in mouse peritoneal macrophages (1994)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 349 (1994), S. 594-601 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Macrophage ; Voltage-clamp ; Potassium current ; Zymosan ; Platelet activating factor ; Calcium ionophore A 23187
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The effects of zymosan and human serum opsonized zymosan on membrane currents of adherent mouse peritoneal macrophages which had been cultured for 5 to 20 days were investigated with the whole-cell voltage-clamp technique. Both stimuli activated an outward current. The outward current activation was transient and lasted about 5 min. In solutions with 10 or 50 mmol/l extracellular potassium concentration the activation of an outwardly directed current occurred at test potentials positive to the respective potassium equilibrium potential. This particle-induced current resembled a calciu-mactivated potassium current which could be activated with the calcium ionophore A 23187 and with platelet activating factor. The order of maximal responses (test potential +55 mV, amplitude given as percentage of the respective control) was: 0.1 μmol/l platelet activating factor (222±36%,n=8,P〈0.01) 〉 1 μmol/l A 23187 (190±24%,n=11,P〈0.01) 〉900 μg/ml opsonized zymosan (134±7%,n=22,P〈0.01) 〉900 μg/ml zymosan (116±5%,n = 21,P〈0.01) The lower efficiency of zymosan as compared to opsonized zymosan is explained in part by a lower percentage of responding cells which was 48% for zymosan and 73% for opsonized zymosan. Macrophages which were pretreated with particles showed a greater reactivity to calcium as compared to untreated cells. Elevation of extracellular calcium from 0.9 to 4.5 mmol/l activated the outward current to 145±12% (n = 11,P〈 0.01) after preincubation with opsonized zymosan and to 144±21% (n = 12,P〈 0.01) under the influence of zymosan while in untreated cells current increase by elevation of extracellular calcium was not significant (120±10%,n = 9, n.s.).
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01258465
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  • 2
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Sheep cardiac Purkinje fibre ; Voltage-clamp ; Pacemaker current ; Use dependence ; Specific bradycardic agent ; ZD 7288
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00168917
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  • 3
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Key words Sheep cardiac Purkinje fibre ; Voltage-clamp ; Pacemaker current ; Use dependence ; Specific bradycardic agent ; ZD 7288
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00168917
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  • 4
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Sheep Purkinje fibre ; Action potential ; Potassium outward currents ; Pacemaker current ; YS 035
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00174749
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  • 5
    Digitale Medien
    Digitale Medien
    Activation of membrane outward currents by human low density lipoprotein in mouse peritoneal macrophages (1993)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 348 (1993), S. 207-212 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Macrophage ; Voltage-clamp ; Ionic current ; Low density lipoprotein ; Acetylated low density lipoprotein
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The aim of the present study was to search for electrophysiological effects of human lipoproteins on membrane currents in mouse peritoneal macrophages which had been cultured for 5 to 20 days. Whole-cell currents were recorded by using a voltage-clamp technique. Low density lipoprotein (LDL, 100 μg/ml) increased a slowly activating nonspecific cation current (iso) in the positive potential range to 244 ± 23% of the reference (test potential + 55 mV, n = 13, P 〈 0.005). Augmentation of current resulted out of a negative shift of the activation curve along the voltage axis (−22 mV) and an increase of maximally available current. Furthermore, LDL increased a rapidly activating outward current (ifo) at test potentials positive to the potassium equilibrium potential. At +55 mV ifo-amplitude increasedto 165 ± 14% ofreference (n = 16, P 〈 0.005). LDL-induced effects on ifo-current could be mimicked by application of the calcium ionophore A 23187 (1 μmol/l) which led to an increase of ifo-current to 161 ± 25% of the reference (test potential + 55 mV, n = 11, P 〈 0.005). Acetylated-LDL (100 μg/ml, 5–15 min) produced no significant effect on the membrane currents under investigation.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00164800
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  • 6
    Digitale Medien
    Digitale Medien
    Effects of (+)- and (±)-sotalol on repolarizing outward currents and pacemaker current in sheep cardiac Purkinje fibres (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 696-704 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Sheep Purkinje fibre ; Outward currents ; Pacemaker current ; (+)-Sotalol ; (±)-Sotalol
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary This study was aimed to differentiate the action of (+)- and (±)-sotalol (10–1000 μmol/l) on membrane currents which are active during the repolarization of cardiac action potentials Effects where studied in shortened sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique Action potentials were activated at a frequency of 0.25 Hz and membrane currents at 0.03 Hz or 0.05 Hz in most experiments. Out of the currents investigated the transient outward current (ito) reacted most sensitively to (+)- and (±)-sotalol. Ito-amplitude was decreased on the average to 77% of reference at 10 μmol/l and to 53% at 1000 μmol/l (+)- or (±)-sotalol. The maximally available ito-current was decreased but the voltage-dependent control of inactivation was left nearly unchanged. The initial inwardly rectifying current (iKi), which propels the last repolarization phase of the action potential and controls resting potential to a large extent was reduced on the average to 93% of reference at 10 μmol/l and to 62% at 1000 μmol/l (+)- or (±)-sotalol. Time-dependent (delayed) outward current (iK) was on the average not affected by (+)- or (±)-sotalol up to 100 μmol/l and was decreased to 84% of reference current under the influence of 1000 μmol/l. An initial outward current, which is activated at positive membrane potentials (iinst) was not clearly affected by (+)- or (±)-sotalol at concentrations up to 1000 μmol/l Pacemaker current (if) was not influenced by the drugs up to 100 μmol/l. Only at 1000 μmol/l was the amount of available if-current decreased to 79% of reference. (The potential-dependent control of activation was not affected) Time constants of time-dependent currents ito, iK and if did not change in concentrations up to 1000 μmol/l of the drug. Action potential duration increased at (+)- or (±)-sotalol concentrations ≥ 10 μmol/l and maximal prolongation was achieved at concentrations of 100–300 μmol/l Resting potential remained nearly unchanged at these concentrations, but the membranes depolarized at 1000 μmol/l. According to our data action potential prolongation in sheep Purkinje fibres under the influence of (+)- and (±)-sotalol correlates to the drug-induced block to ito-current and inwardly rectifying iK1-current.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00717747
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  • 7
    Digitale Medien
    Digitale Medien
    Effects of the calcium entry blocker bepridil on repolarizing and pacemaker currents in sheep cardiac Purkinje fibres (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 339 (1989), S. 638-646 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Sheep Purkinje fibre ; Voltage clamp ; Ionic outward currents ; Calcium entry blocker ; Bepridil
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary (1) Effects of bepridil (0.3–100 μmol/l) on transmembrane currents which are active during the repolarization of the cardiac action potential were studied in sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique. Transmembrane currents were activated at a frequency of 0.03 Hz. (2) The initial inwardly rectifying current (i K1) was reduced by 1.8 μmol/l bepridil to 70% of the reference i K1-current in the absence of the drug. (3) An initial outward current, which is activated at positive membrane potentials (i inst) was depressed to 70% of reference by 14 μmol/l bepridil. (4) The time-dependent outward current (i K) was decreased by 1.8 μmol/l bepridil to 70% of its amplitude in the absence of bepridil. The biexponential time course of i K-current activation changed to be monoexponential with 100 μmol/l bepridil. The effect of bepridil on i K-current resulted in a shift of the activation curve of i K-current to more positive membrane potentials (10 μmol/l bepridil) and an additional decrease of driving force and/or conductance of the i K-channels with higher bepridil concentrations (100 μmol/l). (5) The transient outward current (i to) was completely blocked by 30 μmol/l bepridil. Inhibition to 70% of reference occurred with 1 μmol/l bepridil. The voltage-dependent inactivation of i to-current was affected by bepridil: the amplitude of the steady-state inactivation curve was reduced and i to-current was inactivated faster after application of bepridil. Bepridil caused no pronounced shift of the steady-state inactivation curve along the voltage axis. (6) The pacemaker current (i f) was slightly increased under the influence of low bepridil concentrations (0.3, 1 μmol/l) while it was reduced to 70% of reference by 100 μmol/l bepridil. (7) The blocking action of bepridil on outward currents in sheep cardiac Purkinje fibres will explain the action potential prolongation, which is observed in different mammalian cardiac tissues under the influence of bepridil.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00168656
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  • 8
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Key words Rat ventricular myocyte ; Voltage-clamp ; Transient outward current ; Action potential ; Tedisamil
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/PL00005170
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